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Vol. 32 No.

1 January-March 2009

Drugs and Pharmaceuticals

Current R & D Highlights


Introduction R& D Technology

Diabetes 2 Risk Factors and Complications of
Diabetes 89
Diabetes: Cure by Nature 4 New Leads 100
Development of the Thiazolidinediones as
PPAR Agonists for the Treatment Natural Products
of Type 2 Diabetes 22 Withania coagulans: Role in Diabetes 106
Exploring Role of 5-Hydroxytryptamine in Marine Biota and Diabetics 113
Diabetes Mellitus and Cardiovascular
Complications 31 Biotechnology
System Biology Enables Novel Strategies for Latent Autoimmune Diabetes in Adults
the Management of Type 2 Diabetes 40 (LADA) 119
Overview of Diabetes Mellitus Management 51 Patents 123

News & Views 64 CDRI Publications 129

R&D Highlights
Cell-based Treatments for Diabetes 72

Current R&D Highlights, Jan.-Mar. 2009


Diabetes is not a disease but a disorder, affecting 10% of the human population where the body does
not produce insulin or does not properly use insulin due to which the glucose concentration remains high in
the blood stream.
Glucose, Insulin and Diabetes
Like any engine, our body needs fuel to keep it going and this fuel is glucose. Glucose is derived from
all sorts of foods that we consume. After every meal a large part of our food is converted into glucose,
thereby increasing the blood glucose levels. Pancreas, a small gland below the stomach secretes a hormone
called insulin. The insulin released carries the blood glucose present in the blood stream to cells that need
extra energy. The cells do not and can not use glucose without the help of insulin. Once inside the cells, the
glucose produces heat and energy. But if the insulin is not helping, then the glucose is not of use to body
and in fact it is bad for body to have too much of unused glucose. In a normal individual, body manages to
maintain a ideal level of glucose concentration. But in diabetes insulin is either not produced or not utilized
properly, and hence the glucose remains in the blood causing the condition Diabetes.
The problem in people with diabetes is that either they dont produce enough insulin, or the insulin
they do produce does not work properly, or their cells dont respond properly to insulin (insulin resistance).
The net result is that glucose is not cleared from their blood stream and they have high blood glucose
levels which the body tries to clear by various compensatory methods, such as increased urination.
Types of Diabetes
Diabetes due to absence of insulin
This is frequently seen in childhood and hence called, Juvenile Onset or Childhood Diabetes. In this
diabetes which is called Type 1, the patient has failed to produce insulin and the only remedy to overcome
this is to go in for Insulin injections. The problem can happen in any age of the individual, though majority
are from childhood. The injected insulin, the frequency and dose is decided by the medical expert. The
synthesized insulin is injected and it mimics the natural insulin and the individual can lead a normal life.
Diabetes due to ineffective insulin
This is commonly seen in adults and called as Type 2. Though the body produces insulin it has trouble
using it, that is body is resistant to its own insulin. High blood sugar is found in the blood without being
transported to the cells. Routine checkups with dietary restrictions and healthy life style along with regular
affordable physical and mental activities are the only solution. There are medicines available which make
insulin more effective in such individuals and a combination of medicines and calorie control can help the
patients a lot in keeping the disorder under control.
Diabetes Management
Both types of diabetes have different treatment options and in general population the Type 2 diabetes

2 Current R&D Highlights, Jan.-Mar. 2009

is more prevalent than Type 1. More than 80% of the patients have Type 2 which means it is a problem of
ineffective insulin.
In case of Type 1, the objective of treatment is to give adequate insulin, in right intervals so that the
patient will not have Hypo or Hyper sugar levels. This requires frequent monitoring for sugar levels
and require higher frequency of medical supervision and intervention.
In case of Type 2, the objective of treatment is to make insulin more effective and reduce the
consumption of unwanted food materials. This is achieved by reduction in quantity of food or
modifications in type of food, increase in physical exercises or avoid sedentary life styles and also take
such medicines which improve the action of insulin. This requires less often blood sugar monitoring,
compared to Type 1, but requires constant and periodic medical monitoring and supervision.
Diabetes is a manageable disease if one knows how to control the sugar levels. But uncontrolled
diabetes can give rise to so many health complications such as Heart Disease, Kidney Disease, Blindness,
Brain Failure and Amputations of legs or Limbs.
How to Control?
Some manage it well but a lot of people with diabetes struggle continuously. It requires a lot of will
power to change the lifestyle and also to follow disciplined day to day activities. Specialists advise diabetic
patients to adopt following guidelines to live healthy with the disease:
Do not skip medicines if they are advised.
Avoid temptations of eating such foods which are to be avoided.
Keep increasing the physical activity of the body.
Reduce weight and then maintain a constant weight.
Avoid Sugar, Rice, Potato and fruits in excess.
Avoid smoking.
Avoid or minimize alcohol.
Keep monitoring the sugar level at certain intervals.
Monitor periodically lipid profiles.
Monitor cardiac parameters at least once in a year

Views expressed in the journal are those of the authors and the
Editorial Board/Publisher takes no responsibility for the same. We are
a secondary abstracting service and the veracity of information is of
the source quoted and not our primary responsibility.

Current R&D Highlights, Jan.-Mar. 2009 3


Diabetes: Cure by Nature

Akanksha and Rakesh Maurya*
Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow
Introduction insulin. In absence of insulin, body cells dont
During evolutionary process of life on the get the required glucose for producing ATP,
earth, microorganisms, plants and animals get body starts breaking down the muscle tissue
originated. All the living organisms are and fat for producing energy hence, causing
interdependent in so many ways, as for food, fast weight loss. Dehydration is also usually
shelter etc. Some are parasitic saprophytic or observed due to electrolyte disturbance. In
mutualists too. Plants possess innumerable advanced stages, coma and death is also
number of compounds, having innumerable reported. In both types of diabetes, signs and
pharmacological profiles. By its wide range of symptoms are more likely to be similar as the
pharmacologically active compounds, plants blood sugar is high, either due to less or no
protect themselves from various diseases. At production of insulin, or insulin resistance.
the same time, animals are dependent on plants Common symptoms of diabetes are increased
for their food either directly or indirectly. fatigue, polydipsia, polyuria, polyphagia,
Animals taking food directly from plant get blurred vision, poor wound healing, quick
cured from various diseases. Humans take exhaustion, drowsiness. Synthetic drugs for
medication to cure or prevent diseases. From diabetes treatment are costly and they have
very ancient time, wide range of plants is many side effects too. Natural products have
reported to treat various diseases and safer side over synthetic drugs having less or
complications in various ancient medicinal no side effects. Effective treatment includes
systems. In Ayurveda a number of plants are controlling hyperglycaemia as well as
reported to be used in curing diabetes. secondary complications. About 800 plants
Diabetes mellitus, arising as a global problem, have been reported possessing anti-diabetic
potential.1 Since antiquity, diabetes has been
can be defined as a metabolic disorder, which
is most prevalent. Number of diabetic patients treated with medicines derived from plants.
is rising steadily day by day. Diabetes mellitus Biological activities of various plants have
is caused by the abnormality of carbohydrate been proved by phytochemical studies. Below
metabolism either by low blood insulin level are the briefs of some plants having
hypoglycaemic and/or antihyperglycemic
or insensitivity of target organs to insulin 42.
Diabetes can be defined as a group of potential.
syndromes characterized by hyperglycemia, Acacia arabica (Lam.) Muhl. ex Willd.
altered metabolism of lipids, carbohydrates (Family: Mimosaceae)
and proteins. In type 1 diabetes, the pancreas Common name is Babul in Hindi and
stops producing insulin due to autoimmune Indian Gum Arabic tree in English. Acacia has
destruction of pancreatic beta cells. In case of been used to treat high cholesterol, diabetes,
type 2 diabetes, body cells do not respond to cancer, gingivitis, stomatitis (mouth sores) and
4 Current R&D Highlights, Jan.-Mar. 2009
pharyngitis. The powdered seeds of A. arabica sugar in alloxanized rats by 42% at 375 mg/kg
were administered in doses of 2, 3 and 4 gm/kg and 48% at 500 mg/kg body weight. The
body-weight to normal and alloxan-diabetic extract also reduced blood sugar level of
rabbits. 2, 4, 6 and 8 hours after the alloxanized rats significantly upon chronic
administration the blood glucose levels were administration for 2 weeks48.
estimated. It exerted a significant (p<0.05) Allium cepa L. (Family: Liliaceae)
hypoglycemic effect in normal rabbits. It acts
through release of insulin from pancreatic beta Commonly known as Pyaj in Hindi and
cells8. Onion in English. It has been used to treat
diabetes and is reputed to lower blood sugar
Aegle marmelos (L.) Correa ex Roxb. levels. Oral administration of the
(Family: Rutaceae) hypoglycaemic fraction to alloxan-diabetic
Commonly known as Bael in Hindi. rabbits improved their glucose tolerance. After
Administration of an oral dose of 250 mg/ kg 7 days treatment, the more active
of alcoholic leaf extract of A. marmelos hypoglycaemic fraction was about half as
showed significant improvements in ability to active as Phenformin in lowering the fasting
utilize the external glucose load in glucose blood sugar of alloxan-diabetic rabbits43. S-
induced hyperglycemic rats. Efficacy of A. methyl cysteine sulfoxide (SMCS) isolated
marmelos was 71% of glybenclamide. This from Allium cepa was investigated for its lipid
increase in glucose utilization can be attributed lowering action in SD rats, in comparison to
either by direct stimulation of glucose uptake the hypolipidemic drug gugulipid. SMCS at a
or by enhanced insulin secretion64. Aqueous dose of 200 mg/kg body weight for 45 days
extract of fruits of A. marmelos is known to enhanced the hyperlipidemic condition.
exhibit hypoglycaemic effect in streptozotocin- Concentrations of cholesterol, triglyceride and
induced diabetes in rats. At the dose of 125 phospholipids were significantly reduced with
and 250 mg/ kg twice a day for 4 weeks respect to control38.
resulted in significant reductions in blood
glucose, plasma thiobarbituric acid reactive S
substances, hydroperoxides, ceruloplasmin and H 2N S O
-tocopherol and a significant elevation in OH
plasma reduced glutathione and Vitamin C.
S-methyl cysteine sulfoxide (SMCS)
The effect of the extract at a dose of 250 mg
kg1 was more effective than glibenclamide35.
The effect of methanolic extract of A.e
marmelos has been studied on a battery of The effects of two dietary doses of freeze-
targets glucose transporter (Glut-4), dried onion powder, i.e., onion low (ONL;
peroxisome proliferator activator receptor 0.5%) and onion high (ONH; 2.0%) on
gamma (PPAR) and phosphatidylinositol 3 streptozotocin (STZ)-induced diabetes rat
kinase (PI3 kinase) involved in glucose model was studied. After 4 weeks on the
transport. It was found active at 100 ng/ml experimental diets, fasting blood glucose
dose comparable with insulin and levels for both onion-fed groups were found
rosiglitazone5. elevated. Serum insulin concentrations and
insulin resistance were dose-dependently
Aerva lanata (L.) Juss. ex Schult. (Family: increased in the onion-fed groups. The ONH
Amaranthaceae) group had significantly higher lipid
It is commonly known as Sunny khur. Its concentrations, ONL group showed a similar
alcoholic extract reduced the increase in blood hyperlipidemic trend to a lesser extent31.

Current R&D Highlights, Jan.-Mar. 2009 5

Allium sativum L. (Family: Alliaceae) garlic is hydrated, therefore affecting gastro-
Commonly known as Lahasun in Hindi intestinal transit and slowing glucose
and Garlic in English. Ethanolic extract of absorption47. S-allyl cysteine sulphoxide, a
garlic at the doses of 0.1, 0.25 and 0.5 g/kg sulphur containing amino acid which is the
body weight was orally given to normal and precursor of allicin and garlic oil, has been
streptozotocin-induced diabetic rats for 14 found to show significant antidiabetic effects
days. The level of serum glucose, total in alloxan diabetic rats at a dose of 200 mg/kg
body weight. It increased significantly liver
cholesterol, triglycerides, urea, uric acid,
creatinine, aspartate amino transferase (AST) and intestinal HMG CoA reductase activity
and alanine amino transferase (ALT) were and liver hexokinase activity (Sheela &
found decreased. The antidiabetic effect of the Augusti, 1992). Allicin (thio-2-propene-1-
extract was found more active than that of sulfinic acid S-allyl ester), isolated from garlic,
produced significant blood glucose lowering
glibenclamide18. The antidiabetic effect of
garlic is thought to be due to the formation of a activity in experimental diabetic animals48.
colloidal type suspension in the stomach and
intestines when the mucilaginous fiber of

O Allicin
S-allyl cysteine sulphoxide

Aloe vera (L.) Burm.f. (Family: Aloaceae) and King of bitters in English.
Commonly known as Ghee Kunwar or Andrographolide, a principle present in
Kumar panthu in Hindi. Aloes have long been
used all over the world for their various
medicinal properties. Separate experiments on HO O
three groups of rats, namely, non-diabetic
(ND), type I (IDDM) and type II (NIDDM)
diabetic rats were carried out. A. vera leaf pulp
and gel extracts were ineffective on lowering
the blood sugar level of ND rats. Leaf pulp HO
extract showed hypoglycaemic activity on Andrographolide
IDDM and NIDDM rats. Whereas, leaf gel
extract showed hyperglycaemic activity on Andrographis paniculata is suggested to
NIDDM rats. This study directed that the pulps increase glucose utilization in peripheral tissue
of A. vera leaves devoid of the gel could be via an insulin-dependent mechanism80.
useful in the treatment of non-insulin Annona squamosa L. (Family: Annonaceae)
dependent diabetes mellitus54.
Commonly known as Sharifa or Sitafal in
Andrographis paniculata Nees (Family:
Hindi and Sugar apple or Custard apple in
Acanthaceae) English. Aqueous leaf extract has shown
Commonly known as Kalmegh in Hindi hypoglycemic activity in streptozotocin-

6 Current R&D Highlights, Jan.-Mar. 2009

nicotinamide induced diabetic rats. At the dose decreased on insulin, NSK and NSH
of 350 mg/kg ethanolic leaf extract has been treatments. The decrease in activities of
found to possess hypoglycemic as well as superoxide dismutase (SOD) and catalase
antihyperglycemic potential in normal, (CAT) and increase in lipid peroxidation
streptozotocin- diabetic rats and alloxanized (LPO) of erythrocytes as observed in diabetes
rabbits48 was regained after insulin, NSH and NSK
Areca catechu L. (Family: Arecaceae) treatments. Results suggest that NSH and NSK
prevent oxidative stress caused by STZ in
Commonly known as Supari in Hindi and heart and erythrocytes25. Pretreatment with A.
Betelnut in English. Subcutaneous indica leaf extract, blocked the depressive
effect of epinephrine in diabetic rabbits as well
as in normal ones. In in vitro trials, A. indica
OCH 3 leaf extract, failed to alter the hepatic
glycogen, but it partially blocked epinephrine
action on hepatic glycogen both in normal and
CH 3 diabetic rabbits12. A. indica leaf extract blocks
Arecoline significantly the inhibitory effect of serotonin
on insulin secretion mediated by glucose14.
administration of alkaloid fraction at the dose
0.05-0.5 mg/kg in alloxanized rabbits showed Barleria lupulina Lindl. (Family:
significant hypoglycemic effect15. Arecoline, Acanthaceae)
isolated from A. catechu is reported to have Commonly known as Snake bush in
hypoglycemic activity48. English. The methanol extract of aerial parts
Artemisia pallens Wall. ex DC. (Family: of Barleria lupulina Lindl. showed a
Compositae) pronounced blood-glucose-lowering potential
Commonly known as Davana in Hindi. in streptozotocin hyperglycemic rats. The
Oral administration of the methanol extract of extract at dose of 200 mg/kg body weight
the aerial parts of Artemisia pallens, led to exhibited a maximum activity (p<0.001) at 12
significant blood glucose lowering effect in h after administration. The most significant
glucose-fed hyperglycaemic and alloxan- activity (15.35% blood glucose reduction) was
induced diabetic rats. This effect of the extract observed for the group administered 300
was dose dependent and significant at 100 mg/kg body weight at 12 h after
mg/kg level in glucose-fed rats. In fasted administration, while the standard drug
normal rats, the extract caused a moderate glibenclamide (10 mg/kg body weight) showed
hypoglycaemic effect at 1000 mg/kg74. an 18.80% reduction of blood glucose at the
same time interval73.
Azadirachta indica A. Juss. (Family:
Meliaceae) Beta vulgaris L. (Family: Chenopodiaceae)
It is known as Chukander in Hindi and
Commonly known as Neem. Studies
showed that petroleum ether extract of neem Garden beet in English. Beta vulgarosides II-
seed kernel (NSK) and husk (NSH) showed IV, isolated have been shown to ameliorate
significant protection against the oxidative glucose tolerance in OGTT conducted in rats.
damage induced by STZ in heart and Uncontrolled induced diabetes caused
significant increases in nonenzymatic
erythrocytes of rats. NSK and NSH may act as
cardioprotective and free radical scavenger glycosylation of skin proteins, lipid
agent. Serum creatine phosphokinase (CPK) peroxidation and blood glucose.
increased in diabetic rats was significantly Administration of B. vulgaris extract inhibited

Current R&D Highlights, Jan.-Mar. 2009 7

these effects except the increase in lipid STZ administration, urine volume per day and
peroxidation. These findings indicated that the UAE levels were significantly higher
use of B. vulgaris may decrease the (P<0.0005) in diabetic controls as compared to
development of some diabetic complications23. normal controls24.
Biophytum sensitivum (L.) DC. (Family: Caesalpinia bonducella (L.) Roxb. (Family:
Oxalidaceae) Cesalpinaceae)
It is commonly called as Lajjalu in Hindi Commonly known as Kantkarej or
and Life plant in English. Leaf extract has Kantikaranja in Hindi and Fever nut or Bonduc
been proved to show antihyperglycemic effect nut in English. In normal rats, aqueous and
in alloxan diabetic male rabbits. It was found 50% ethanolic extracts of C. bonducella seeds
ineffective in severe diabetes23. exhibited hypoglycaemic activity at a dose of
100 mg/kg after 4 hour of administration. The
Boerhavia diffusa L. (Family:
Nyctaginaceae) hypoglycaemia produced by the aqueous
extract was of prolonged duration as compared
Commonly known as Punarnava in Hindi. to ethanolic extract. In diabetic rats, both the
Oral administration of B. diffusa leaf extract at extracts produced significant (p<0.01)
200 mg/kg of body weight for 4 weeks resulted antihyperglycaemic effect from day 5
in significant reduction in serum and tissue onwards66.
cholesterol, free fatty acids, phospholipids, and
triglycerides. It was found to be more effective Cajanus cajan (L.) Millsp. (Family:
than glibenclamide in the treatment of diabetic Fabaceae)
rats57. Common name is Tuvar in Hindi and Red
Bombax ceiba L. (Family: Bombacaceae) gram in English. Oral administration of graded
doses of aqueous extract of C. cajan leaves in
Common name is Semul in Hindi and Red streptozotocin induced type 2 diabetic rats
silk cotton tree in English. Shamimin, a showed significant increase in 14.3 % in
flavonol glucoside known as Shamimin, fasting blood glucose levels of normal rats.
isolated from the leaves of the plant has been The dose of 1000 mg/kg showed the maximum
reported to possess significant hypoglycemic rise of 17.1, 71.2 and 50.7 % in blood glucose
activity at dose of 500 mg/kg in rats65. levels of normal, sub and mild diabetic rats
HO OH respectively in glucose tolerance test32.
OH Camellia sinensis Kuntze (Family:
O OH Theaceae)
OH Commonly known as Tea in English. The hot
OH O water extract of C. sinensis significantly
Shamimin reduced the blood glucose level and was found
to possess both preventive and curative effects
Brassica juncea (L.) Czern. (Family: on experimentally produced diabetes in rats.
Brassicaceae) The green tea as well as black tea both possess
Common name is Rai in Hindi and Indian antidiabetic activity20.
mustard in English. Study was made on the Capparis decidua (Forsk.) Edgew. (Family:
effects of daily oral feeding of 10% powder of Capparidaceae)
seeds of Brassica juncea for 60 days on serum
glucose concentrations and kidney functions in Commonly known as Keekar, Karir, Kirir,
streptozotocin diabetic rats. After 60 days of Karril, etc. in Hindi and Caper plant in

8 Current R&D Highlights, Jan.-Mar. 2009

English. Oral feeding of diet containing (30%) Common name is Indryan in Hindi and
C. decidua fruit powder for 3 weeks to Bitter apple in English. Oral administration of
alloxanized diabetic rats showed significant 300 mg/kg of aqueous extract produced
hypoglycemia23. significant reduction in plasma glucose after 1
Casearia esculenta Roxb. (Family: hour and highly significant after 2,3 and 6 hour
Flacourtiaceae) in normal rabbits. The glycosidic extract at a
oral dose of 50 mg/kg significantly lowered
Commonly known as Saptarangi in Hindi. the fasting glucose levels after 2 and 3 hour
The plant root extract exhibited significant and highly significant after 6 hour. The
hypolipidaemic and antiperoxidative activity in saponin extract at the same oral dose
red blood cells of streptozotocin diabetic rats48. significantly lowered the fasting glucose levels
Cassia auriculata L. (Family: after 1 and 2 hour and highly significant
Cesalpinaceae) (p<0.001) after 3 and 6 hour1.

Common name is Tanners Cassia. Extract Coccinia indica Wight & Arn. (Family:
of flowers of C. auriculata suppressed the Cucurbitaceae)
elevated blood glucose and lipid levels in Common name is kundru. It have been
diabetic rats at doses of 0.15, 0.30 and 0.45 used in the traditional treatment of diabetes
g/kg body weight for 30 days. At the dose of mellitus. Toluene, chloroform, ethyl acetate
0.45 g/kg was found to be comparable to and n-butanol fractions of the dried alcoholic
glibenclamide. Extract significantly reduced extract of the aerial part were fed to alloxan
the levels of serum and tissue lipids56. treated diabetic rats orally, twice daily at a
Catharanthus roseus (L.) G. Don. / Vinca dose of 150 mg/kg. The toluene fraction
rosea (Family: Apocynaceae) prevented the elevation of lipid profile
significantly (p<0.001) in comparison to
Commonly called as Sadabahar in Hindi control diabetic rats16. Ethanol extract of C.
and Madagascar periwinkle in English. grandis showed significant triglyceride (TG)
Administration of aqueous extracts of V. rosea and cholesterol-lowering effects in
flower and leaf have been found to regulate the dyslipidemic hamster model. Activity was
blood sugar level in alloxan diabetic male proved to be concentrated in chloroform-
albino rats19. Ethanol extract of V. rosea soluble fraction. Chloroform soluble fraction
promotes significant wound healing and on repeated column chromatography,
closure in diabetic rats compared with furnished a polyprenol characterized as C60-
mupirocin At the dose of 100 mg/kg body polyprenol. It significantly decreased serum
weight, it significantly reduced (p<0.001) TG by 42%, total cholesterol (TC) 25% and
wound size in streptozotocin induced diabetic glycerol (Gly) 12%, accompanied HDL-C/TC
rats53. Alkaloids isolated catharanthine, ratio 26% in highfat diet (HFD)-fed
vindoline and vindolinine lower blood sugar dyslipidemic hamsters at the dose of 50 mg/kg
level48. body weight. Results are comparable to
standard drug fenofibrate at the dose of 108

H mg/kg70.

Catharanthine Vindoline Vindolinine

Citrullus colocynthis (L.) Schrad. (Family:


Current R&D Highlights, Jan.-Mar. 2009 9

Curcuma longa (Family: Zingiberaceae) Gentiaceae)
Commonly known as Haldi in Hindi and Commonly known as Chhota chirata in
Turmeric in English. Ethanol extract of Hindi and Whitehead in English. At the dose
rhizome significantly suppressed an increase in of 1.5 g/100g body weight/day of aqueous
blood glucose level in type 2 diabetic mice. extract of E. littorale increased HDL levels
The extract stimulated human adipocyte and decreased serum cholesterol, triglyceride,
differentiation in a dose-dependent manner and LDL, VLDL, LDL/HDL ratio in rats fed with
showed human peroxisome proliferator- hypercholesterolaemic diet. It showed a
activated receptor (PPAR)- ligand-binding decrease in activities of erythrocyte catalase,
activity in a GAL4-PPAR- chimera assay superoxide dismutase and lipid peroxidation
(Kuroda et al., 2005). Ferulic acid (4-hydroxy- levels, with an increase in reduced glutathione
3-methoxycinnamic acid) is found in many levels. It also showed decrease in liver and
plants, isolated from Curcuma too. It has kidney cholesterol levels and triglyceride
shown hypoglycemic activity in both type of levels76.
diabetes48. Eucalyptus globulus Labill. (Family:
HO Myrtaceae)

Commonly known as Safeda in Hindi. In
O diabetic rats, the repeated oral administration
O of E. globulus aqueous leaf extract
Ferulic acid significantly increased the basal plasma insulin
Cynodon dactylon (Family: Poaceae) concentrations (p<0.05)27. An aqueous extract
of E. globulus at the dose of 0.5 g/L
Commonly known as Doob in Hindi. At a enhanced 2-deoxy-glucose transport by 50%,
dose of 500 mg/kg, aqueous extract lowered glucose oxidation by 60% and incorporation of
blood glucose level around 31% after 4 hour of glucose into glycogen by 90% in mouse
administration in normal rats. During glucose abdominal muscle. In acute, 20 min
tolerance test (GTT) of mild diabetic rats, the incubations, administration of 0.25-0.5 g
same dose produced a fall of 23% in blood showed stepwise 70-160% enhancement of
glucose level within 1 hour. This dose has insulin secretion from the clonal pancreatic -
almost similar effect as that of standard drug cell line21.
tolbutamide at the dose of 250 mg/kg body
weight. A significant reduction of 59% was Eugenia uniflora L. (Family: Myrtaceae)
observed in fasting blood glucose level of Commonmly known as Surinam Cherry or
severely diabetic rats at same dose given for 14 Brazilian Cherry in English. Ethanolic extract
days. It reduced urine sugar level. In severely of the leaves of E. uniflora inhibited the
diabetic rats total cholesterol (TC), low density increase in plasma glucose level and plasma
lipoprotein (LDL) and triglyceride (TG) levels triglyceride level48.
were decreased by 35, 77 and 29%,
respectively, whereas, cardioprotective, high Ficus bengalensis (Family: Moraceae)
density lipoprotein (HDL) was increased by It is known as bargad in Hindi and Banyan
18%. These results suggested antidiabetic in English. 50 mg/kg of hot water extract of F.
potential of aqueous extract along with bengalensis was given orally to normal rabbits
significant hypoglycemic and hypolipidemic and rabbits with alloxan induced alloxan-
effects70,71. recovered, mildly diabetic and severely
Enicostemma littorale Blume (Family: diabetic states daily for three days. After a gap
of five days, the water extract was

10 Current R&D Highlights, Jan.-Mar. 2009

readministered for three days at the same dose chlorobenzoic acid derivative and nicotinic
level. There was no significant change in acid derivative showed potent
fasting blood glucose (FBG), or glucose antihyperglycemic activity at 100 mg/kg body
tolerance test (GTT) in normal rabbits. There weight52.
was no fall in FBG but improvement in Glycyrrhiza glabra L. (Family: Fabaceae)
glucose tolerance in alloxanrecovered rabbits.
In mildly diabetic rabbits there was 55.8% fall Commonly known as Licorice.
in FBG values and an improvement in glucose Glycyrrhizin, isolated from licorice root, is
tolerance. The extract produced 68% fall in composed of one molecule of glycyrrhetinic
FBG values in severely diabetic rabbits69. The acid and two molecules of glucuronic acid.
bark and aerial roots ethanolic extracts at a After oral administration, glycyrrhizin has
dose of 100 mg/kg been shown to be hydrolyzed by the
glucuronidase of intestinal bacteria to its



significantly (p<0.001), (p<0.01) lowered the
18-glycyrrhetinic acid
blood sugar level of hyperglycemic rats
respectively. Barks exhibited better activity
than aerial roots17. Leucodelphinidin, isolated
from the bark of F. bengalensis has been principal aglycone, 18-glycyrrhetinic acid.
reported for its hypoglycemic activity. 18-glycyrrhetinic acid when administered
orally at 100mg/kg of bodyweight, showed
Ficus racemosa (Family: Moraceae) potential antihyperglycemic effect that is
It is commonly known as Gular in India. comparable with glibenclamide34.
-amyrin acetate, isolated from the fruits of F. Gymnema montanum Hook.f. (Family:
racemosa at the dose of 100 mg/kg body Asclepiadaceae)
G. montanum leaf extract possess
antihyperglycemic and antiperoxidative effect.
Oral administration of 200 mg/kg body weight
of the alcoholic extract of the leaf for 3 weeks
resulted in a significant reduction in blood
O glucose and an increase in plasma insulin. The
decrease in lipid peroxides and increase in
reduced glutathione (GSH), ascorbic acid
-amyrin acetate (Vitamin C) and -tocopherol (Vitamin E)
showed its antioxidant properties6.
weight, lowered the blood glucose levels by
18.4 and 17.0% at 5 and 24 hour, respectively, Gymnema sylvestre R. Br. (Family:
in sucrose challenged streptozotocin induced Asclepiadaceae)
diabetic rat (STZ-S) model. Its p- G. sylvestre leaf extract lowers the blood

Current R&D Highlights, Jan.-Mar. 2009 11

glucose level in normal fasting, glucose-fed thiobarbituric acid reactive substances
hyperglycemic and diabetic rats compared (TBARS) and hydroperoxide in both liver and
with placebo-treated animals. The maximum kidney78.
glucose suppression occurred after 2 hour of Indigofera mysorensis (Family: Fabaceae)
treatment by the effective dose of 200 mg/kg,
PO, of the extract 12,13. In insulin resistant db/db mice extract of
the whole shrub of Indigofera at 300 mg/kg for
Helicteres isora L. (Family: Sterculiaceae) 10 days, produced a 63% reduction in plasma
Administration of the bark extract of H. glucose, 41% reduction in plasma triglyceride
isora at the doses of 100 and 200 mg/kg body and 77% reduction in plasma insulin levels,
weight for 21 days resulted in significant which is better than insulin sensitizer,
reduction in serum and tissue cholesterol, troglitazone (400 mg/kg). Study showed that
phospholipids, free fatty acids and the antidiabetic effect of the ethanolic extract
triglycerides in STZ diabetic rats. Significant of Indigofera is due to its insulin sensitizing
(p< 0.05) decrease in high-density lipoprotein property and is clearly different from that of
(HDL) whereas significant increase (p<0.05) sulfonylurea or acarbose10.
low-density lipoprotein (LDL) and very low- Ipomoea batatas (Family: Convolvulaceae)
density lipoprotein (VLDL) were observed in
STZ diabetic rats. The bark extract possesses Commonly known as sweet potato. White-
definite hypotriglyceridemic and skinned sweet potato is useful in the
antiatherogenic properties in STZ diabetic rats prevention and improvement of diabetic
after 3 weeks of treatment39. symptoms by stimulating human immunity. It
increased phagocytic activity and phagosome-
Hibiscus rosa-sinensis (Family: Malvaceae)
lysosome fusion in neutrophils and monocytes
Commonly known as Gudhal in Hindi and in a dose-dependent manner46.
shoe flower in English. In streptozotocin Lantana camara (Family: Verbenaceae)
induced diabetic rats, oral administration of an
ethanol flower extract of Hibiscus rosa In Hindi, it is known as Caturang.
sinensis lowered the total cholesterol and Administration at the dose of 1500 mg/kg/day
serum triglycerides by 22 and 30%, for 14 days showed significant hypoglycemic
respectively. Maximal diminution in blood effect in rats23.
glucose (4146%) and insulin level (14%) was Lactuca indica (Family: Asteraceae)
noticed after 21 days. The hypoglycemic
activity of this extract is comparable to that of Commonly known as Indian Lettuce.
glibenclamide63 . Lactucain C and lactucaside have shown
significant hypoglycemic activity48.
Hygrophila auriculata (Family:
Acanthaceae) O
It is a wild herb widely used in O
Ayurveda as Rasayana drug for treatment H

of various disorders. aerial parts of H. O

auriculata extract possesses significant O

antidiabetic activity along with potent Lactucain C Lactucaside

antioxidant potential in diabetic conditions. Mangifera indica L. (Family:

Treatment of diabetic rats at the doses of 100 Anacardiaceae)
and 250 mg/kg body weight for 3 weeks
showed significant reduction in blood glucose, It is known as Aam in Hindi and Mango in

12 Current R&D Highlights, Jan.-Mar. 2009

English. Aqueous leaf extract at the dose of 1 stimulates glycogen storage by the liver and
g/kg p.o. showed hypoglycemic effect when improves peripheral glucose uptake62.
given 60 mins prior to glucose administration Charantin, a steroidal saponin isolated have
in streptozotocin-induced diabetic rats2. The hypoglycemic potential.
chronic intraperitoneal administration of
mangiferin, a xanthone glucoside isolated from
the leaves of Mangifera indica at the doses of
10 and OH
OH Charantin
Momordica cymbalaria Fenzl ex Naudin
(Family: Cucurbitaceae)
Commonly known as Kadavanchi in
Hindi. It exhibited both hypoglycemic as well
20 mg/kg once daily for 28 days exhibited as hypolipidemic properties. Its powdered fruit
antidiabetic activity by significantly lowering exhibited significant reduction in fasting blood
fasting plasma glucose level at different time glucose levels in alloxanized rats23.
intervals in STZ-diabetic rats. At the same Morus alba L. (Family: Moraceae)
doses, mangiferin showed significant
antihyperlipidemic and antiatherogenic Commonly known as Shetut in Hindi and
activities as evidenced by significant decrease White Mulberry in English. Hot water extract
in plasma total cholesterol, triglycerides, low- of leaves of M. alba showed hypoglycemic
density lipoprotein cholesterol (LDL-C) levels activity in fasted and non-fasted STZ diabetic
coupled together with elevation of high- mice at the dose of 200 mg/kg23.
density lipoprotein cholesterol (HDL-C) level Mucuna pruriens (L.) DC. (Family:
and diminution of atherogenic index in Leguminosae)
diabetic rats50.
It is called as Kavach in Hindi and
Memecylon umbellatum Burm. f. (Family: Cowitch in English. In normal rats, at the the
Melastomataceae) oral administration of 100 and 200 mg/kg body
Commonly known as Anjani in Hindi. Oral weight, the aqueous extract of the seeds of M.
administration of alcoholic extract of the pruriens significantly reduced the blood
leaves of M. umbellatum (250 mg/kg) caused a glucose levels after an oral glucose load from
significant reduction in the serum glucose 127.53.2 to 75.64.8 mg %. It also
levels in normal and alloxanized rats at 30, 60 significantly lowered the blood glucose in STZ
and 90 min after administration23. diabetic rats from 240.57.2 to 90.65.6 mg %
after 21 days of daily oral administration of the
Momordica charantia L. (Family: extract (Pb0.001)9.
Murraya koeingii (L.) Spreng. (Family:
Common name is karela in Hindi and Rutaceae)
bittergourd in English. The anti-diabetic
potential of Momordica charantia is well One month oral administration of M.
established in streptozocin or alloxan induced koenigii aqueous leaves extract in STZ induced
diabetic animals. Momordica charantia severe diabetic rats, at the dose of 300 mg/kg
displays insulin-like properties, remarkably body weight fasting blood glucose (FBG)
levels reduced by 48.2% after 30 days

Current R&D Highlights, Jan.-Mar. 2009 13

treatment with the aqueous leaves extract. A glucose levels in normal, glucose-fed
fall of 19.2 and 30.8% in total cholesterol (TC) hyperglycemic, insulin-treated and diabetic
and 22.97 and 37.1% in triglyceride (TG) rats. The extract improved glucose tolerance
levels were also observed in the case of treated and potentiated the action of exogenously
normal as well as diabetic rats, respectively. injected insulin, The hypoglycemic potential of
Feeding the extract increased the HDL- the extract was comparable with that of
cholesterol level by 16 and 29.4% in normal tolbutamide in normal and diabetic rats. It was
and diabetic rats, respectively, as compared observed that in normal and diabetic rats, the
with their initial values. In the normal rats after activity of the extract was 73 and 67%
1 month of oral administration of the extract compared with that of tolbutamide,
serum glutamate oxaloacetate and pyruvate respectively49.
transaminases (SGOT and SGPT) levels were Nigella sativa (Family: Ranunculaceae)
decreased by 21.7 and 25.0%. Serum alkaline
phosphatase values of the treated normal Nigella sativa seeds, commonly known as
animals were also reduced by 33% while Black cumin have been used traditionally for
negligible change was observed in the normal treating diabetes. The aqueous extract of N.
control animals. In the case of diabetic rats, sativa at 0.1 pg/ml to 100 ng/ml, exerted dose-
SGOT and SGPT levels were reduced by 36.7 dependent inhibition of sodium-dependent
and 32.2%, respectively, whereas phosphatase glucose transport across isolated rat jejunum.
(ALKP) levels decreased by 39.7%. The serum Chronic N. sativa treatment improved glucose
creatinine levels decrease in normal as well as tolerance as efficiently as metformin. It also
in the diabetic animals by 17.75 and 18.2%, reduced body weight without any toxic
respectively, as compared to initial values. In effect45.
the diabetic control animals the urinary sugar Ocimum sanctum (Family: Lamiaceae)
remains at +4 level but there was a decrease of
75% in urine sugar in the case of treated Common name is tulsi in Hindi and Basil
diabetic rats 37. in English. The hypoglycemic effect of the
alcoholic extract of leaves of Ocimum sanctum
Musa sapientum L. (Family: Musaceae) was investigated in both normal and alloxan-
Commonly known as Kela in Hindi and induced diabetic rats. Alcoholic extract of
Banana in English. Oral administration of leaves of O. sanctum reduced blood sugar
0.15, 0.20 and 0.25 g/kg of chloroform extract levels 204.48 11.0 to 131.43 7.86 in
of the M. sapientum flowers for 30 days normal rats and 73.54 3.7 to 61.44 2.3 in
resulted in a significant reduction in blood diabetic rats significantly (p<0.001). In
glucose, glycosylated haemoglobin and an addition, the extract also showed a favorable
increase in total haemoglobin, but in the case effect on glucose disposition in glucose fed
of 0.25 g/kg the effect was highly significant. hyperglycemic rats77.
It also prevents decrease in body weight. There Phyllanthus amarus Schumach. &
was a significant improvement in glucose Thonn./Phyllanthus niruri (Family:
tolerance in treated animals and the effect was Euphorbiaceae)
compared with glibenclamide57.
Commonly known as Jangli Amla in
Nelumbo nucifera Gaertn. (Family: Hindi. Oral administration of 5 g/day of a
Nymphaeaceae) preparation of the whole plant for 10 days
This is aquatic plant known as Kamal in reduces blood glucose in diabetic as well as
Hindi and Lotus in English. Ethanolic extract nondiabetic subjects23.
of the rhizome of N. nucifera suppressed blood Picrorrhiza kurroa Royle ex Benth. (Family:

14 Current R&D Highlights, Jan.-Mar. 2009

Scrophulariaceae) be the possible target for their activity75.
Alcoholic extract of P. kurroa at the dose Pterocarpus marsupium Roxb. (Family:
of 75 mg/kg reduced serum glucose by 43 % Fabaceae)
and at 150 mg/kg reduced by 60%33. Common name is Vijaysar in Hindi and
Pongamia pinnata (Family: Fabaceae) Indian Malabar in English. Pterostilbene
Commonly known as Karanja in Hindi. (trans-3,5-dimethoxy-4-hydroxystilbene), a
constituent derived from wood of Pterocarpus
The oral administration of ethanolic extract of
Pongamia pinnata flowers at a dose of 300 marsupium caused hypoglycemia in dogs (at
mg/kg body weight showed significant the dose of 10 mg/kg IV). Higher dose (20, 30
antihyperglycemic, and antilipidperoxidative and 50 mg/kg) caused initial hyperglycemia
effects and enhancement in antioxidants followed by hypoglycemia lasting for nearly
5h26. (-) Epicatechin, Marsupsin, Pterosupin,
defense system in alloxan induced diabetic
rats. It considerably reduced the blood glucose Pterostilbene, isolated from the bark and
concentration in a similar extent to that of the heartwood of the plant possess blood sugar
reference drug glibenclamide (600 g/kg body lowering activity (Mukherjee et al., 2006).
weight) in alloxan induced diabetic rats60.
Antidiabetic potential of the compounds OH
pongamol and karanjin isolated from HO O
Pongamia have been proved. In OH OCH 3 O
streptozotocin-induced diabetic rats, single OH OH
dose treatment of pongamol and karanjin (-) Epicatechin M arsupsin

lowered the blood glucose level by 12.8% OH

(p<0.05) and 11.7% (p<0.05) at 50mg /kg dose HO


and 22.0% (p<0.01) and 20.7% (p<0.01) at Glc

100 mg/kg dose, respectively after 6 h post- OH O OH OCH 3

oral administration. The compounds also Pterosupin Pterostilbene

significantly lowered blood glucose level in

Punica granatum L. (Family: Punicaceae)
db/db mice with percent activity of 35.7
(p<0.01) and 30.6 (p<0.01), respectively at 100 Commonly known as Pomegranate. 50%
mg/kg dose after consecutive treatment for 10 ethanolic extract of flower showed blood
days. The compounds were observed to exert a glucose lowering activity in glucose fed and
significant inhibitory effect on enzyme protein alloxanized hyperglycemic rats. At the doses
tyrosine phosphatase-1B. The results showed of 150, 300, 600 mg/kg showed hypoglycemic
that pongamol and karangin isolated from the activity 12 hour after administration in STZ-
diabetic rats48.

O O Ricinus communis (Family: Euphorbiaceae)

Commonly known as Eranda or
OCH3 Gandharva hasta in Hindi and Castor in
O OH O English. 50% ethanolic extract of roots of R.
pongamol Karanjin communis at the dose of five-hundred
milligram per kilogram body weight caused
fruits of P. pinnata possesses significant maximum lowering of the fasting blood
antihyperglycemic activity in Streptozotocin- glucose, both in normal as well as type 1
induced diabetic rats and type 2 diabetic db/db diabetic animals. It was considered as effective
mice and protein tyrosine phosphatase-1B may dose. Administration of the effective dose to

Current R&D Highlights, Jan.-Mar. 2009 15

the diabetic rats for 20 days showed favorable Salacia reticulata Wight. (Family:
effects not only on fasting blood glucose, but Celastaceae)
also on total lipid profile and liver and kidney Commonly known as Kothala himbutu.
functions on 10th and 20th day68. Aqueous extracts of Kothala himbutu stems
Rosmarinus officinalis (Family: Labiatae) decreases fasting blood glucose levels. Results
Commonly known as Rosemary. demonstrate that it exerts its effect by
Hypoglycaemic effects of oral administration gluconeogenic gene regulation in traditional
of various doses (50, 100 and 200 mg/kg) of diabetic medicine30.
the extract were examined in normoglycaemic Scoparia dulcis L. (Family:
and glucose-hyperglycaemic rabbits. Optimal Scrophulariaceae)
effect was observed in both of the animal Commonly known as Sweet Broomweed.
groups with a dose of 200 mg/kg of the extract
The administration of an aqueous extract of . S.
and this activity was independent from the dulcis at a dose of 200 mg/kg body weight
effects of insulin. Acute effect of various doses significantly decreased the blood glucose with
of the R. officinalis extract on blood glucose significant increase in plasma insulin level in
and serum insulin levels was studied in streptozotocin diabetic rats at the end of 15
alloxan-induced diabetic rabbits. Of the three days treatment. S. dulcis plant extract protected
doses of extract, the highest dose (200 mg/kg) against streptozotocin- mediated cytotoxicity
significantly lowered blood glucose level and (88%) and NO production in rat insulinoma
increased serum insulin concentration in cell line (RINm5F). Results suggest its glucose
alloxan-diabetic rabbits. At the doses of 100 lowering effect to be associated with
and 200 mg/kg, antihyperglycaemic effect of potentiation of insulin release from pancreatic
extract was accompanied by a significant islets41.
increase in serum insulin levels in diabetic
rabbits. Furthermore, during 1 week of Sida cordifolia L. (Family: Malvaceae)
treatment of diabetic rabbits with a dose of 200 Commonly known as Bala. It is used in
mg/kg of the extract showed that the extract Ayurvedic medicine. S. cordifolia extracts of
possessed a capability to inhibit the lipid the aerial and root parts showed good
peroxidation and activate the antioxidant analgesic, antiinflammatory and
enzymes7. hypoglycaemic activities. The methanol
Salacia oblonga Wall. (Family: Celastaceae) extract of root was found to possess significant
hypoglycaemic activity36.
S. oblonga root is an Ayurvedic medicine
with anti-diabetic and anti-obese properties. Swertia chirayita (Roxb. ex Fleming) H.
Chronic oral administration of the water Karst. (Family: Gentianaceae)
extract from the root of S. oblonga to Zucker Hexane fraction of S. chirayita at the dose
diabetic fatty rats, a genetic model of type 2 of 250 mg/kg body weight induced significant
diabetes and obesity, lowered plasma fall in blood sugar in albino rats. Daily
triglyceride and total cholesterol levels, administration for 28 days resulted in
increased plasma high-density lipoprotein significant lowering of blood sugar and
levels and reduced the liver contents of increase in plasma IRI along with a significant
triglyceride, non-esterified fatty acids and the rise in liver glycogen. Intestinal absorption of
ratio of fatty droplets to total tissue. By glucose was not inhibited by hexane fraction.
contrast, the extract had no effect on plasma It is suggested that hexane fraction of S.
triglyceride and total cholesterol levels in chirayita possibly acts through its insulin
fasted Zucker diabetic fatty rats29. releasing effect11. A xanthone was isolated

16 Current R&D Highlights, Jan.-Mar. 2009

from the hexane fraction of the plant, Terminalia catappa L. (Family:
identified as 1,8-dihydroxy-3,5-dimethoxy- Combretaceae)
xanthone (swerchirin). It has a very significant Commonly known as Badam in Hindi and
blood sugar lowering effect in fasted, fed, Indian Almond Tree in English. Terminalia
glucose loaded, and tolbutamide pretreated catappa fruit extracts have good antidiabetic
albino rat models. The ED50 for 40% blood activity. Petroleum ether, methanol and
sugar lowering in CF male albino rats (body aqueous extracts of T. catappa produced a
weight 140-165 g) is 23.1 mg/kg/oral8.
significant antidiabetic activity at dose levels
1/5 of their lethal doses. Methanol and aqueous
extracts of Terminalia catappa exhibited
significant anti-hyperglycemic activities in
alloxaninduced hyperglycemic rats without
significant change in body weight51.
Swerchirin Terminalia pallida Brandis (Family:
Syzigium cumini/ Eugenia jambolana Lam.
(Family: Myrtaceae) Different doses of ethanolic fraction of
fruits of Terminalia pallida were evaluated for
Administration of the extract for 6 weeks hypoglycemic and antihyperglycemic activity
resulted in significant reductions in plasma in normal and alloxan diabetic rats. The oral
lipid peroxide, ceruloplasmin and -tocopherol administration of ethanolic extract at a dosage
and a significant elevation in plasma reduced of 0.5 g/kg body weight exhibited a significant
glutathione and vitamin C in alloxan diabetic antihyperglycemic activity in alloxan diabetic
rats. Insulin restored all the parameters to their rats, whereas in normal rats no hypoglycemic
normal values. The seed extract was also more activity was observed61.
effective than glibenclamide in restoring the
values of these parameters58,59. Oral Trigonella foenum graecum L. (Family:
administration of 2.5 and 5.0 g/kg body weight Fabaceae)
of the aqueous extract of the seed for 6 weeks Commonly known as fenugreek.
resulted in a significant reduction in blood Galactomannan, extracted from T. foenum
glucose and an increase in total haemoglobin, reported to reduce postprandial blood glucose
but in the case of 7.5 g/kg body weight the response. Using this fiber, extracted from The
effect was not significant. It also prevents segments of jejunum and ileum from
decrease in body weight. The aqueous extract genetically determined lean and obese rats
also resulted in decreased free radical were incubated with labeled glucose (2 or 32
formation in tissues studied. Thus the study mmol/L) in the presence of different
shows that Jamun seed extract (JSEt) has concentrations of galactomannan ranging from
hypoglycaemic action. The decrease in 0.1% to 0.5% (wt/wt). The uptake of low or
thiobarbituric acid reactive substances high concentration of glucose was significantly
(TBARS) and increase in reduced glutathione and progressively reduced by increasing
(GSH), superoxide dismutase (SOD) and concentrations of galactomannan in both lean
catalase (CAT) clearly show the antioxidant and obese rats. No significant difference was
property of the JSEt. The effect of JSEt was observed in the uptake of glucose between the
most prominently seen in the case of animals 2 groups. The viscosity of various
given 5.0 g/kg body weight. JSEt was more concentrations of galactomannan solutions was
effective than glibenclamide. 58,59 determined after stirring for 60 minutes at a
temperature-controlled (37C) fixed sheer rate
Current R&D Highlights, Jan.-Mar. 2009 17
of 1.29 (1/s). The inhibitory effect of Withania coagulans (Family: Solanaceae)
galactomannan on glucose uptake was found to Commonly known as Paneer ke phool
be in parallel with the degree of viscosity of in Hindi and Vegetable Rennet in English. At
the fiber solutions. Because of its viscous the dose of 1 g/kg of aqueous extract of fruits
property, galactomannan has the potential to of W. coagulans significantly lowered the
reduce intestinal absorption of low or high blood sugar, serum cholesterol, serum LPO
concentrations of glucose and hence for the and hepatic LPO levels in streptozotocin
benefit of blood glucose management72 .
induced diabetic rats after 7 days of treatment
Tinospora cordifolia (Family: (p<0.001). It also significantly (p<0.01)
Menispermaceae) decreased blood glucose level in normal rats
Commonly known as Giloe in Hindi. (at the dose 1 g/kg; po)28. Coagulin C, 17-
Treatment with plant extract showed hydroxywithanolide K, withanolide F,
significant anti-hyperglycemic activity in mild coagulanolide and coagulin L, isolated from
to moderate degree of hyperglycemia. In mild the fruits, showed significant inhibition on
diabetes, the maximum percent reduction in postprandial rise in hyperglycemia post
glucose levels was 70.37%, seen in groups sucrose load in normoglycemic rats and in
receiving 400 mg/kg/day of aqueous extract of streptozotocin-induced diabetic rats. Coagulin
T. cordifolia. In moderate diabetes, 4 months L showed significant fall in peripheral blood
of T. cordifolia treatment resulted in a glucose profile and also improved the glucose
moderate reduction in plasma glucose level of tolerance of db/db mice. It also showed
48.81%. In severe diabetes, it did not show any antidyslipidemic activity in db/db mice that is
reduction in plasma glucose level. Since the comparable to median effective dose of
fenofibrate i.e., 50 mg/kg body weight. The
percentage fall in plasma glucose levels was
different in models with varying intensity of median effective dose of the coagulin L was
hyperglycemia, it implies that the anti- determined to be around 25 mg/kg in
hyperglycemic effect of these plants is streptozotocin-induced diabetic rats, which is
dependent upon the dose of diabetogenic agent better than the standard drug metformin.
Beside this, coagulin L also showed
and therefore on the degree of -cell
destruction23. antidyslipidemic activity in db/db mice44.



Coagulin C 17-Hydroxywithanolide K Withanolide F

Coagulanolide Coagulin L

Zingiber officinale Roscoe (Family: Zingiberaceae)

18 Current R&D Highlights, Jan.-Mar. 2009

Commonly known as Adrak in Hindi and
Ginger in English. Treatment with Z. officinale
produced a significant increase in insulin
levels and a decrease in fasting glucose levels
in diabetic rats. In an oral glucose tolerance Conclusion
test, treatment with Z. officinale was found to
decrease significantly the area under the curve Treatment of diabetes with synthetic drugs
of glucose and to increase the area under the is associated with several complications. The
curve of insulin in STZ-diabetic rats. most severe complication associated is
Treatment with Z. officinale also caused a condition of hypoglycemia. Plants and natural
decrease in serum cholesterol, serum products are in use to prevent and cure
triglyceride and blood pressure in diabetic diabetes since past. They show comparatively
rats3. 6-shogaol (6S) and 6-gingerol (6G), less or no side effects. As far as cost is
present in Z. officinale significantly inhibited concerned, herbal treatment is cheaper than
the tumor necrosis factor- (TNF-) mediated synthetic drugs. A wide and diverse range of
downregulation of the adiponectin expression plants is reported to prevent and treat diabetes.
in 3T3-L1 adipocytes. 6S functions as a A lot of work has been done on the
PPAR agonist with its inhibitory mechanism antidiabetic potential of various plants by
due to the PPAR transactivation, and 6G is an numerous workers. We have worked on
effective inhibitor of TNF- induced c-Jun- Pongamia pinnata, Pterocarpus marsupium,
NH2-terminal kinase signaling activation and Withania coagulans, Zingiber officinale and
thus, its inhibitory mechanism is due to this Ficus racemosa and have isolated antidiabetic
inhibitory effect99. principals from them. There is endless scope in
natural product chemistry for the identification
of active leads. Immense work is needed to
make new drugs for diabetes of natural origin.
Active leads can be derivatized to ameliorate
their antidiabetic potential

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Current R&D Highlights, Jan.-Mar. 2009 21


Development of the Thiazolidinediones as PPAR

Agonists for the Treatment of Type 2 Diabetes
Saman Raza and Seturam B. Katti*
Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow

Introduction lowering insulin resistance and increasing

Diabetes mellitus (DM) is a major and function of beta cells. Current therapeutic
growing public health problem throughout the approaches for type 2 DM include: 1) insulin;
world. Diabetes has reached epidemic 2) enhancers of insulin release eg.
proportions and affects more than 170 million Sulfonylureas, Dipeptidyl Peptidase IV (DPP-
individuals worldwide. It is a disease 4) Inhibitors and Meglitinides; 3) inhibitors of
hepatic glucose production eg. biguanides; 4)
characterized by high levels of blood glucose
resulting from defects in: insulin production, inhibitors of glucose uptake eg. -glucosidase
insulin action or both. The basic types of inhibitors; and 5) insulin sensitizers eg.
diabetes mellitus are type 1 and type 2. Type 1 peroxisome proliferator-activated receptor
(insulin dependant) DM can occur at any age (PPAR ) agonists [1]. As the number and types
of the therapeutic options are so vast and
and is characterized by the marked and
progressive inability of the pancreas to secrete varied, it is not possible to elaborate on all of
insulin because of autoimmune destruction of them and hence we have chosen to focus on
the beta cells. Therefore, these patients are the one which is of particular interest to
dependent on exogenous insulin. researchers today, that is: PPAR PPAR
agonists, dual and pan agonists as well as
Type 2 (non-insulin-dependent) DM, PPAR modulators have become exciting
which affects 90% of diabetic individuals, is therapeutic targets for type 2 diabetes as they
more of a lifestyle related disorder, with also address the complications related with
obesity being a major risk factor for its diabetes.
development. It is characterized by insulin
resistance: the inability of insulin-sensitive
Peroxisome Proliferator-activated
tissues to respond to normal circulating Receptor Gamma (PPAR ) Role in
concentrations of insulin. To offset resistance Type 2 Diabetes
to insulin, the beta cells of the pancreas The peroxisome proliferator-activated
increase insulin secretion. However over time, receptors belong to the superfamily of nuclear
beta-cell function deteriorates, less insulin is receptors and are ligand-activated transcription
secreted and hyperglycemia develops. factors. There are three PPAR isoforms, which
Treatment of type 2 diabetes is aimed at are the products of distinct genes and are

22 Current R&D Highlights, Jan.-Mar. 2009

commonly designated as PPAR , PPAR and general structure of PPAR as well as /
PPAR / . The three subtypes of PPAR bind agonists can be divided into three regions:
to fatty acids and fatty acid metabolites and A is the acidic head group,
regulate the expression of genes involved in
the transport, metabolism and buffering of B is the central spacer group, and
these ligands within the cells. PPARs are C is the linear lipophilic tail group (figure 1).
known to be activated by a wide array of
structurally diverse ligands, ranging from
prostaglandins and thiazolidinediones(TZDs)
to fibrates, eicosanoids, nonsteroidal NSAIDs,
glucocorticoids, PUFAs, and aromatic fatty
acids[2]. A
While PPAR regulates fatty acid C
oxidation and PPAR is involved in
cholesterol homeostasis, PPAR agonists
regulate adipogenesis and are effective insulin
sensitizers. Thus, the PPARs possess the Figure 1: General structure of PPAR and /
ability to address many features of the diabetic agonists
phenotype. PPAR agonists and PPAR /
dual agonists are interesting compounds for the The spacer connecting the lipophilic
development of anti-diabetic agents. PPAR heterocyclic tail and the central ring of the
agonists reduce plasma glucose, lipids and molecule has been examined. The compounds
insulin levels in type 2 diabetic patients while with three carbon spacer seem to be favorable
PPAR / dual agonists improve both lipid for agonism of PPAR over those with two
metabolism and glucose tolerance- two key carbon atoms [4]. Variation of the length of the
factors in the treatment of type 2 diabetes. spacer could alter its in vitro functional
activity profile without regularity.
Synthetic Agonists of PPAR -G
Structure For the lipophilic tail a variety of aryl and
heteroaryl groups such as, pyridyl, oxazoyl,
As the role of PPAR in adipogenesis, benzoxazoyl have been found to be tolerated.
energy storage and insulin sensitization came Also, when one tries to rationalize the shape of
into light, it quickly evolved over the last the heterocyclic moiety, the planar heterocycle
decade from a new orphan receptor to one of is preferred.
the best characterized nuclear receptors.
Structures of the ligand binding domain (LBD) The desired linker fragment between the
of the PPARs in the absence and presence of head group (2,4-thiazolidinedione) and the
ligands have been solved by x-ray central spacer group has been suggested to be
crystallography. The solved structures for the methylene moiety. Any deviation in the
ligand-bound PPARs reveal that its agonists, linker fragment length has been reported to
such as TZDs, fibrates and fatty acids, share a reduce the PPAR activity.
common binding mode in which their acidic Based on the chemical structure, some of
head groups participate in a hydrogen bonding the PPAR agonists have been broadly
network within a Y-shaped ligand binding classified as follows:
pocket in the ligand binding domain of the
receptor [3]. 1.The first generation thiazolidinediones

Guided by the mutual pharmacophore, the 2.The second generation glitazones:

Current R&D Highlights, Jan.-Mar. 2009 23

compounds with tail group modifications 3.Compounds with head group modifications.

Ciglitazone Troglitazone Rosiglitazone Pioglitazone

Figure 2: Structures of the first generation glitazones

1. The Thiazolidinediones or Glitazones In general, pioglitazone and rosiglitazone

The TZDs (figure 2) were developed over have similar clinical efficacy with both
a period of 15 years through empirical demonstrating improvements in insulin
compound screening in rodent models of sensitivity and the ability to lower fasting
insulin resistance. Ever since a plasma glucose levels [8]. However one
thiazolidinedione-based compound, potential area of distinction between these two
ciglitazone, was developed from a class of TZDs is the greater impact of pioglitazone on
fibrate lipid-lowering agents and was reported diabetic dyslipidemia. Although pioglitazone
as a novel anti-diabetic agent that enhanced was initially found to be a PPAR agonist,
insulin sensitivity in patients with type-2 additional preclinical data show that this
diabetes, many studies on new analogues have compound has some, although minimal,
been carried out. activity on PPAR as well in standard
cotransfection (CTF) assays [9]. Consistent
The molecular mechanism of action of the with these data are clinical findings showing
TZDs remained unknown until several reports that pioglitazone has beneficial effects on
in the mid-1990s suggested a possible lipids not seen with rosiglitazone, which is a
connection between these agents and the pure PPAR agonist.
PPARs. In 1995,
In addition to the improvement in
Lehmann et al [5] made the important glycemic control, the glitazones have a
discovery that the TZDs were potent and beneficial effect on many of the traditional as
selective activators of PPAR . well as the new risk factors and can help
Troglitazone was derived from ciglitazone inpreventing or lessening the impact of the
by replacing the lipophilic tail (which is a cardiovascular consequences of type 2
methylcyclohexylmethyl ether moiety), with a diabetes. They have been shown to lower the
vitamin E residue [6]. Troglitazone (Rezulin), levels of atherogenic dyslipidemia, lower
was the first TZD to reach the market as an blood pressure [10] as well as visceral obesity,
anti-diabetic agent, but was withdrawn from lessen the levels of the pro-inflammatory and
clinical use in 2000 due to reports of severe, pro-thrombotic cytokines and adipokines as
idiosyncratic hepatotoxicity [7]. well as increase the levels of the anti-
atherogenic adinopectin. Unfortunately, these
Two TZDs approved for clinical use today compounds are also associated with the side
are rosiglitazone (Avandia) and pioglitazone effects of obesity, hemodilution and edema [8].
(Actos); both have a pyridyl tail group. Thus, there is significant interest in the design

24 Current R&D Highlights, Jan.-Mar. 2009

of novel PPAR modulating drugs that retain minimizing potential adverse side effects.
efficacious insulin sensitizing properties while

DRF-2189 BRL-48482 PAT5A


O F3 C O
Englitazone KRP-297

Netoglitazone (X=C, R=F) CLX-0921
NC-2100 (X=N, R=H)

Figure 3: Structure of the Second Generation Glitazones

2. The Second Generation Glitazones: rosiglitazone despite their weak agonist

Compounds With Tail Group Modifications profiles. In mice, NC-2100 produced less
In an effort to reduce the side effects weight gain compared to other glitazones when
associated with the glitazones, the second similar mice maintained comparable levels of
generation glitazones were developed. Some of glycemic control.
these compounds have been profiled here. CS-011(rivoglitazone) which has a
They include netoglitazone (MCC-555), benzimidazolyl tail group, was reported to be
rivoglitazone (CS-011), CLX-0921, DRF- approximately three times more active than
2189, ciglitazone, englitazone, NIP-221 and rosiglitazone in a cell based PPAR
NIP-223 among others (figure 3). transfection assay. In vivo, it was found to be
The glitazones MCC-555 and NC-2100, more potent than rosiglitazone, which can be
which contain a naphthalene moiety as the explained not only by the enhanced in vitro
central linker group, represent a second class activity but also by its longer half life [12]. CS-
of PPAR modulators[11].These structurally 011 is in Phase I trials in US.
related glitazones (MCC-555: X=C, R=F; NC- The TZD analog KRP- 297(MK767) is a
2100: X=N, R=H; figure 3) profile as weak- PPAR agonist with similar affinity for PPAR
binding full agonists in cell-based reporter . In vivo, KRP-297 has been reported to
assays. Both MCC-555 and NC-2100 promote improve abnormal lipid metabolism in liver
adipocyte differentiation in cell culture. MCC- and elicit hypoglycemic, hypoinsulinemic and
555 and NC-2100 each possess in vivo activity hypolipidemic conditions in obese rats [13].
in obese insulin-resistant mice comparable to However, further development of KRP297 was

Current R&D Highlights, Jan.-Mar. 2009 25

recently terminated, owing to findings of a rare 3. Compounds with Head Group
malignant tumor in mice. Modifications
CLX-0921, that is derived from a natural Since the structure of the thiazolidine-2, 4-
product and has a polyphenol based structure dione ring was considered to be optimum and
is another second generation glitazone which the acidic functionality of the ring was
has shown encouraging findings in early considered to be essential for its insulin-
clinical testing. This TZD has a spectrum of sensitizing activity, replacement of this ring
activity that differs from commercially has been tried using closely related acidic
available TZDs. It is a weak activator of PPAR heterocyclic rings as well as acyclic acidic
compared to rosiglitazone. Despite this moieties.
difference, the drug maintains potent glucose 3.1. Compounds with Isoxazolidinedione
uptake activity in vitro and glucose-lowering Based Head Group
activity in vivo that is equipotent to that of
Rosiglitazone [14]. Replacement of the thiazolidine-2, 4-dione
ring with an oxazolidine-2, 4-dione ring or a 1-
DRF-2189 has an indole based tail group oxa-2,4-diazolidine-3,5-dione ring led to
and was reported to be equipotent to decreased activity. JTT-501(Figure 4), an
rosiglitazone yet distinct from it in its ability to isoxazolidine-3, 5-dione, was designed as a
lower cholesterol [15]. more acidic heterocyclic compound than
Benzoxazole derivatives such as BRL thiazolidine-2,4-dione. Although JTT-501 was
48482 have been reported to have potent less potent than its parent (a TZD with a
agonism to PPAR , comparable to phenyl oxazolidine tail group), the side-effect
rosiglitazone. profile was improved. It was found that JTT-
Balaglitazone (DRF2593) is a PPAR 501 is a PPAR agonist that possesses some
partial agonist that recently completed Phase II PPAR activity [18].
clinical trials and results from these studies Its activity is believed to be mediated
show that treatment with balaglitazone led to through a malonic amide metabolite derived
significant improvement in glycemic control from hydrolysis of the heterocyclic head
and HDL-C level, with minimum side effects group.
Another interesting compound in this O
category is PAT5A which has a pyridinyl O
pyrolidide tail group and a chemically distinct O
unsaturated linker fragment. PAT5A is a
PPAR partial agonist with a minimal amount
of PPAR activity. In contrast to
rosiglitazone, PAT5A inhibits cholesterol and Figure 4: JTT-501
fatty acid biosynthesis suggesting that PAT5A
possesses a unique receptor independent non- 3.2. Compounds with Acyclic Head Groups
PPAR related property. As expected, Replacement of the thiazolidine-2,4-dione
administration of PAT5A to a rodent model of ring with acyclic structures, such as
type 2 diabetes (db/db mice) resulted in a dose- carbonylated hydroxyureas, -heteroatom-
dependent reduction in plasma glucose that substituted carboxylic acids, -carbon
was similar to that seen with rosiglitazone but substituted carboxylic acids and 1,3-dicarbonyl
with less drug-induced weight gain[17]. compounds, was unexpectedly successful.

26 Current R&D Highlights, Jan.-Mar. 2009

a) A Carboxylated Hydroxyurea: The
first acyclic non-carboxylic acid compound, CO 2H

was able to normalize blood glucose level in N

an in vivo study [19]. N CF3


Figure 5: Carboxylated Hydroxyurea Derivative

b) -Carbon Substituted -
Phenylpropanoic Acid Based PPAR
Agonists: The thiazolidine-2,4-dione ring can
be replaced by -acyl-, -alkyl- and -
(aralkyl)-carboxylic acids. Inclusion of an Figure 6: -Oxy-acid Based PPAR Agonists
additional lipophilic moiety affords
compounds which are equipotent to BRL The PPAR / dual agonists
48482. These results were surprising since it muraglitazar, tesaglitazar, naveglitazar and
had previously been shown that in the ragaglitazar belong to this class of compounds
heterocyclic series, the thiazolidine-2, 4-dione (figure 7).
ring was preferred over the oxazolidine-2, 4- Muraglitazar (N-[(4-methoxyphenoxy)
dione. It was assumed that the role of the carbonyl]-N-{4-[2-(5-methyl-2-phenyl-1,3
acidic thiazolidine-2,4-dione was played by oxazol-4-yl)ethoxy]benzyl}glycine),
carboxylic acid in these compounds and that demonstrated significant glucose lowering,
an appropriate substituent at the -position reduction in triglycerides and increase in HDL-
could alter the chemical environment around C in patients with type 2 diabetes, in early
the carboxylic acid in such a way that the clinical studies[21].
whole group came to mimic the thiazolidine-
2,4-dione ring. Higher binding affinities and Tesaglitazar (2S)-2-Ethoxy-3-[4-[2-(4-
functional activity for PPAR were observed methylsulfonyl oxyphenyl) ethoxy] phenyl]
for the (S)-enantiomers of this series. propanoic acid), is an orally active, potent
PPAR / dual agonist under development
Several -oxy-acids showed activities an for the potential improvement of dyslipidemia
order of magnitude more potent than BRL- and glycemic control in individuals with type 2
48482. In particular the -ethoxyacid SB diabetes [22]. However in 2006, its further
213068 is one of the most potent anti- development was discontinued, after several
hyperglycemic agents yet reported[20](figure phase III clinical trials.
Naveglitazar( -methoxy-4-[3-(phenoxy-
phenoxy)propoxy]phenylpropanoic acid) is
another interesting PPAR / dual agonist in
clinical development. Data from a recent Phase
II clinical

Current R&D Highlights, Jan.-Mar. 2009 27


H 3C

Ragaglitazar Tesaglitazar

Muraglitazar Aleglitazar

Figure 7: Structures of a Few PPAR / Dual Agonists

trial in patients with type 2 diabetes showed advantages in preclinical models, ragaglitazar
that naveglitazar administration resulted in (DRF2725, NN622), which has a phenoxazinyl
significant reductions in mean fasting serum tail group, was suspended from clinical
glucose levels from baseline compared with development, owing to the development of
placebo at all doses and triglyceride levels urine bladder tumors in rodents.
were also significantly reduced[23]. c) Tyrosine Based PPAR Agonists: A
Aleglitazar ((2S)-2-methoxy-3-[4-[2-(5- series of tyrosine-based PPAR agonists have
methyl-2-phenyl-4-oxazolyl) ethoxy]- 7- also been developed [24] and represent some of
benzothiophenyl]propanoic acid ) is another the most potent agonists reported to date
PPAR / dual agonist. It is currently in (figure 8). The (S)-enantiomers have been
phase II clinical trials. shown to possess greater binding affinity and
The PPAR / dual agonist TAK559 was functional activity at PPAR than the
corresponding (R)-enantiomers [25].
placed on clinical hold owing to findings of
abnormalities in liver enzymes in a small In cell based transactivation assays, these
number of patients during the course of the analogs exhibit up to 1000-fold selectivity for
Phase III studies. Further development of this PPAR over the PPAR and PPAR
compound was discontinued in 2005. subtypes
Despite demonstrating glucose and lipid

Farglitazar GW-1929 GW-7845

Figure 8: Tyrosine Based PPAR Agonists

28 Current R&D Highlights, Jan.-Mar. 2009

GW1929 possesses potent and efficacious anti-hyperglycemic activity in ZDF rats.
Farglitazar has shown potent reduction of undesirable action of these agents, research is
glucose activity, reduction of triglycerides and now being done to develop partial PPAR /
elevation of HDL cholesterol in diabetic agonists, which combine the beneficial
patients in Phase II studies. The positive lipid metabolic effects of PPAR and PPAR
effects of farglitazar may be due to residual activation with fewer side effects. Along with
PPAR activity in the compound [26]. the dual agonists, PPAR pan agonists are also
However, owing to side effects, its further being explored which would combine the
development has been discontinued agonist activities of PPAR , PPAR and
Conclusion PPAR in a single ligand and may prove to be
the ultimate combination of PPAR activities
The demonstration that PPAR was the for the treatment of type 2 diabetes and its
receptor through which the glitazone drugs further complications. Also, recent findings
mediate their biological activity has led to from genetic and pharmacologic studies
resurgence in nuclear receptor research to suggest that activating PPAR in moderation
develop drugs for diabetes and cardiovascular can lead to better therapeutic outcomes
disease. Knowledge of the molecular targets compared with modifying the receptor with a
for the glitazones has enabled medicinal high affinity, full agonist. These results have
chemists to synthesize a new generation of been translated into the identification and
drugs that have been optimized for activity exploration of PPAR partial agonists and
against the human PPARs. Several of these selective PPAR modulators (SPPARMs) which
drugs are currently in clinical development. would retain efficacious insulin sensitizing
Compounds with dual PPAR and PPAR properties while minimizing the adverse side
activity, which may combine the benefits of effects. With recent advances in our
insulin sensitization and lipid lowering into a understanding of the molecular mechanism of
single drug, are also being investigated. The PPAR action, the future holds great promise
safety liabilities of the dual agonists may be towards developing anti-diabetic
the result of the imbalanced activities on PPARcompounds with greater efficacy as well
PPAR and PPAR . To overcome the as reduced side effect profile.
8. Diamant, M. and Heine, R.J., Drugs, 2003,
63, 13731405.
9. Sakamoto, J. et al., Biochem. Biophys.Res.
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49, 14171424. Diab Vasc Dis Res, 2007, 4 (3), 194203.
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30 Current R&D Highlights, Jan.-Mar. 2009


Exploring Role of 5-Hydroxytryptamine in Diabetes

Mellitus and Cardiovascular Complications
Dr. Ramesh K. Goyal* & Hitesh B. Vaidya+
*The M. S. University of Baroda,Vadodara; +L.M.College of Pharmacy, Ahmedabad
The prevalence of type 2 diabetes has controversy for last couple of decades. 5-HT is
surged in recent decades. A growing body of shown to have differential effects on blood
work suggests not only that central neural glucose levels, that is, hyperglycemia and
pathways may play an important role in hypoglycemia. Earlier studies reported that 5-
dysregulation of glucose homeostasis but also HT does produce hypoglycemia. In mice, it
that these pathways are potentially amenable to has been reported that 5-HT precursor 5-
therapeutic manipulation. Diabetes mellitus is hydroxytryptophan (5-HTP) produces
associated with regionally specific changes in hypoglycemia, and the effects of 5-HT are due
brain monoamines1 and the turnover rate of to formation of 5-HT4. It was shown that 5-
monoamines is reportedly decreased in HTP causes accumulation of 5-HT in liver and
diabetic rats2. Pharmacological compounds 5-HT then causes increase in serum insulin
augmenting the tone of the neurotransmitter levels resulting into hypoglycemia. 5-HT when
serotonin (5-hydroxytryptamine, 5-HT) were injected in rats or dogs is reported to produce
investigated for the treatment of obesity, a hypoglycemia36. The studies involving
major risk factor for type 2 diabetes. However, incubation of isolated pancreatic islets with 5-
the possibility of a direct role for serotonin in HT revealed that 5-HT stimulates increase in
the pathophysiology and treatment of type 2 insulin release from pancreatic islets37. This
diabetes received little attention. Mental illness action of 5-HT was later shown to be mediated
can be a manifestation of a diabetic brain state through 5-HT1 and 5-HT2 receptors using
or a sort of cerebral diabetes3. Mania and specific antagonists like methysergide and
positive schizophrenia have been reported to ketanserin5.
be associated with hyperglycemia, Although the earlier 5-HT was reported to
hyperdopaminergia, hyperserotonergia, cause hyperglycemia and many other
whereas, depression and negative activities, both centrally and peripherally
schizophrenia have been associated with acting 5-HT receptor agonists cause
hypoglycemia, hypodopaminergia and hyperglycemia. Centrally, 5-HT1A receptor
hyposerotonergia. This indicates link between agonist 8-hydroxy-2-di-n-(propylamine)
diabetes mellitus and neurotransmitters like 5- tetralin (8-OH-DPAT) and 5-HT1A receptor
HT and dopamine. In the present article we partial agonists including buspirone and
have made an attempt to explore the role of 5- ipsapirone are reported to induce
HT in diabetes mellitus and cardiovascular hyperglycemia in rats6. Similarly, 5-HT2
complication base on some of our own data. receptor agonists like 1-(2, 5-dimethoxy-4-
5-HT Receptor Subtype and Diabetic iodophenyl)-2-aminopropane (DOI) and 1-(3-
Mellitus chloro-phenyl) piperazine (mCPPP) are
The association between 5-HT and its role reported elicit hyperglycemia7. Peripheral 5-
in glucose control has been a subject of HT receptors have shown to be involved in
glycemic control. Peripheral administration of

Current R&D Highlights, Jan.-Mar. 2009 31

5-HT or a peripheral 5-HT receptor agonist mechanistically novel strategy in the treatment
can elevate plasma glucose levels in rats37,7. for type 2 diabetes may be developed.
Peripherally acting 5-HT1A/1D receptor agonist Several studies have indicated that 5-HT2
N, N-di-propyl-5-carboxamidotryptamine (DP- receptors play an important role in
5-CT) also elicits hyperglycemia in rats38,8. cardiovascular functions (Table-1)10.
Peripheral 5-HT3 receptor agonist 2-methyl-5- Sarpogrelate has shown to produce
HT does not produce any effect on blood cardioprotective11 and anti-platelet activity in
glucose, insulin or glucagons levels which rule
both, experimental12 and clinical settings13.
out the involvement of 5-HT3 receptor in blood Treatment with sarpogrelate was reported to
glucose, insulin or glucagons levels. These significantly lower fasting glucose levels with
conclude involvement of 5-HT1 and 5-HT2 in corresponding increase in insulin levels
glucose Homeostasis. However, involvement (Table-2). It also significantly prevented STZ-
of subtype 5-HT1 and 5-HT2 receptor namely,
induced polydypsia, hyperphagia,
5-HT1A, 5-HT2A and 5-HT2C receptors in 5-HT hypertension, and bradycardia but not the loss
induced hyperglycemia were studied38,7 and of body weight. 5-HT produced dose-
reported that 5-HT2A antagonist sarpogrelate dependent positive inotropic effect that was
and 5-HT2A/2C antagonist mianserin inhibited found to be decreased significantly in STZ-
5-HT induced hyperglycemia. However, a
diabetic rats. Hearts obtained from
fairly detailed characterization of 5-HT sarpogrelate treated diabetic rats did not show
receptor subtypes from our laboratory revealed any decrease in responsiveness to 5-HT.
that 5-HT2A and 5HT3 receptors are involved Relative platelet aggregation per se was found
in 5-HT induced hyperglycemia9. to be higher in STZ-diabetic rats as compared
Can Sarpogrelate be used in the to control and this was significantly prevented
treatment of Type 2 diabetes? by sarpogrelate treatment14. 5-HT produced a
Since sarpogrelate that produced a dose dependent increase in platelet aggregation
decrease in glucose levels is reported to be a in non-diabetic and sarpogrelate treated
specific 5-HT2A receptor antagonist, it could be diabetic rats. However, 5-HT failed to produce
any increase in platelet aggregation in
hypothesized that 5-HT2A receptors are
involved in glycemic control. Murine knockout untreated diabetic rats. From our laboratory, it
studies also revealed that only deletion of the was reported that STZ-induced diabetes may
gene encoding the 5-HT2C receptor (5-HT2C produce down regulation of cardiac 5-HT2A
receptor, formerly denoted 5-HT1C receptor) receptors and increased platelet aggregation.
Further suggested that treatment with
produces insulin resistance and type-2
diabetes, with antecedent hyperphagia and sarpogrelate prevented STZ-induced decrease
obesity. These genetic studies demonstrate that in responsiveness to 5-HT suggests that there
5-HT2C receptors are critical for energy may be a down-regulation of 5-HT2A receptors
homeostasis but do not indicate whether and that sarpogrelate produces beneficial
serotonin generally or 5-HT2CRs specifically effects in diabetic heart possibly by preventing
have a primary effect on glucose homeostasis diabetes induced down-regulation of 5-HT
that is dissociable from effects on body weight. receptors. Treatment with sarpogrelate seems
By targeting 5-HT2C receptors agonist which to prevent STZ-induced down-regulation of 5-
enhance glucose tolerance independently of HT receptors and increase in platelet activity
alterations in body weight an effective and in diabetic rats.14

32 Current R&D Highlights, Jan.-Mar. 2009

Table-1 summary of beneficial effect of sarpogrelate and its mechanism
Sarpogrelate (Beneficial effects on CVS) Mechanism
Anti platelets Inhibits collagen induced platelets aggregation
or ADP-epinephrine induced aggregation.
Antithrombotic It blocked induction of tissue factor and
plasminogen activator inhibitor-1 and reduced
thrombus formation.
Antiatherosclerotic It inhibits Matrix Metalloprotease I and II, it
also enhance production of Nitric Oxide.
Antianginal It inhibits vasoconstriction of non
atherosclerotic human coronary. It has
protective effect with the patients with stable
VSMCs Proliferation/Neointimal hyperplasia It inhibit 5-HT stimulated DNA synthesis, also
inhibit 5-HT mediated [Ca2+]i in VSMCs. It
also inhibits 5-HT mediated mitogen activated
protein kinase (MAPK) phosphorylation.
Heart failure and MI It also inhibit thrombotic and vasoconstrictor
effect of 5-HT. It causes marked reduction in
infract size and left ventricular diastolic
pressure helps to improve MI.
Sarpogrelate inhibits angiotensin-II and
endotheline-1 induced cardiac hypertrophy and
it also inhibits 5-HT mediated increase in
[Ca2+]i concentration in extra cellular and
intracellular myocytes which helps to improve
in heart failure.
Pulmonary Hypertension Reduced thickness of medial wall of small
pulmonary artery and right ventricle/left
ventricle and septum ratio. It also prevents
platelets aggregation in lungs.
Restenosis after coronary stenting Mechanism of action is not known exactly but
probably it inhibits intimal hyperplasia.

Current R&D Highlights, Jan.-Mar. 2009 33

Table-2 Effect of 6 week treatment with sarpogrelate on various parameters in STZ diabetic rats
Parameter Non-diabetic Non-diabetic Diabetic Diabetic treated
control treated with control with sarpogrelate
Body weight (g) 290.26 18.12 291.25 8.26 160.0 6.5* 181.66 9.29*

Food intake 41.29 5.63 44.5 2.20 115 2.88* 82.5 4.33**
Water intake 53.75 5.05 40.0 1.15 118.75 0.72* 87.5 7.21**
Blood pressure 105.62 10.12 98.23 8.23 146.23 3.75* 82.5 3.22**

Heart rate 405.23 22.68 385.56 23.73 321.25 378.75 10.48**

(beats/min) 12.31*

Serum glucose 4.34 0.7 4.58 0.41 14.89 0.6* 6.69 0.9**

Serum insulin 514.02 25.08 474.72 81.36 342 29.58* 595.98 62.88**

Data is shown as mean S.E.M. (n = 6). *Significantly different than non-diabetic control (p < 0.05), **significantly different than
diabetic control (p <0.05)

As mention earlier, 5-HT levels are high independent of insulin. Hajduch et al (1999)35
in diabetes and 5-HT is one of the stimuli for have reported that rat and human skeletal
the translocation of glucose transporters. Both muscles both express 5-HT2A receptors and
GLUT 1 and GLUT 4 levels were reported to that specific 5-HT2A receptor agonists can
be decreased in cardiomyocytes from STZ- stimulate glucose uptake in skeletal muscles by
diabetic rats15,9.. Insulin was found to prevent a mechanism which does not depend upon
only GLUT 4 in STZ-diabetic rats. However, components that participate in the insulin
sarpogrelate, a specific 5-HT2A receptor signaling pathway. Figure-1 illustrates
antagonist was found to increase both GLUT 1 proposed mechanism of sarpogrelate. tudies
and GLUT 4 levels in diabetic rats. These with extracts and fractions of Z. officinale
results indicate that not only 5-HT2A receptors (ginger) and active isolated compound 6-
are involved in glucose transport mechanisms Gingerol had shown insulin release activity in
but also that increase in glucose transporters in STZ-induced diabetic rats. To correlate in-vivo
cardiomyocytes by sarpogrelate may be and in-vitro actions of these drugs on insulin

34 Current R&D Highlights, Jan.-Mar. 2009

release activity and to show the evidence of Role of 5-HT in Cardiovascular
involvement of 5-HT receptors in insulin complications
release activity of extracts and fractions of Historically involvement of 5-HT in
drug, insulin release studies using cultured cardiovascular system was observed first time
pancreatic islet cells were carried out. In our between in 1869 an 1896. It was reported that
laboratory these experiments involved a substance active on blood vessels and the
incubation of 5-HT alone with diabetic heart appears in serum when blood is allowed
pancreatic islets and co-incubation of 5-HT
to clot. For instance, Weiss et al., (1896)39
with sarpogrelate (Sanjay, 2004). Thus reported that if serum was continuously but
involvement of 5-HT in insulin releasing effect slowly injected into a rabbit, cat or dog until it
of these agents, was evident from our data. caused death, the heart rate was increased and
at first the beat was stronger but gradually
Pancreas Sarpogrelate failed, although it persisted until the
5-HT2A Receptors
respiration had ceased; in addition, an increase
5-HT in blood in the peristalsis of the small intestines and
(Higher in Diabetes) death due to paralysis of the respiratory and
Insulin Receptor Glucose vasomotor centres was noticed. At the same
(-) time, cardiovascular 5-HT research was
(-) advanced by the development of two drugs,
ketanserin (a 5-HT2-receptor antagonist) and
8-hydroxy-2-(di-n-propylamino) tetralin (8-
OH-DPAT; a 5-HT1A-receptor agonist); both
Sarpogrelate drugs lower blood pressure. During the same
period, triptans, selective 5-HT1B/1D -receptor
Target Cell
(Cardiomyocyte, Skeletal muscle, Adipocyte) agonists (selective cranial vasoconstrictors),
Fig.1 Proposed mechanism for glucose lowering were also being developed for the treatment of
effect of Sarpogrelate in diabetic rats migraine16. The observation that ketanserin
lowers blood pressure generated a huge
with sarpogrelate and insulin. Diabetic control interest in the potential role of 5-HT in
islets produced significantly lower levels of cardiovascular regulation, but this action of
insulin secretion in response to glucose as ketanserin was shown to be primarily due to
compared to normal control. Diabetic islets blockade of 1-adrenoceptors17. Even now, 25
when treated with glibenclamide produced a years later, the involvement of 5-HT in
significant increase in insulin release in hypertension is poorly understood and the
response to glucose as compared to diabetic peripheral physiological role, that is the
control. Diabetic pancreatic islets when treated importance of 5-HT in control of vascular tone
with 5-HT alone did not show any significant and, thus, blood pressure, is poorly understood
change in insulin release in response to (even though 5-HT is found in large amounts
glucose as compared to diabetic control islets in platelets). Current views on the peripheral
but it produced significant increase in insulin mechanisms by which 5-HT affects the
secretion in response to glucose when co- cardiovascular system are summarized in
incubated 5-HT in diabetic pancreatic islets Table-3 and Figure-2.

Current R&D Highlights, Jan.-Mar. 2009 35


Figure.2 Actions of peripheral 5HT receptors on the cardiovascular system

Table-3 List of the main peripheral cardiovascular responses caused by 5-HT receptors and their
selective ligands
Receptor Agonist Antagonist Cardiovascular effect
5-HT1B/1D Sumatriptan GR127935 Reduce sympathetic drive (i.e. reduction in
noradrenaline release to the heart and
5-HT1B CP-93129 In Rats GR 55562 Vasoconstriction

5-HT1D PNU-109291 BRL15572 -----

5-HT2A DOI MDL 100907 Vasoconstriction, platelet aggregation and
Also has affinity for direct tachycardia in rats.
5-HT2C Adrenaline release from the adrenal

5-HT2B BW723C86 RS 127445 Release of NO, thus, vasodilation

36 Current R&D Highlights, Jan.-Mar. 2009

5-HT3 PBG Granisetron Reflex bradycardia and hypotension
Ondansetron Rabbit heart where it causes the release of
noradrenaline from sympathetic terminals
5-HT4 BMIU4 GR113808 Tachycardia (positive chronotropy) and
SB-204070 increase in atrial force (positive iontrophy)
5-ht5A/5B None None. SB-269970 Reduce sympathetic drive (i.e reduction in
does have good noradrenaline release, to the heart and
affinity, but is also a vasculature)
5-HT7 antagonist

5-HT7 None. 5-CT is often SB-269970 (also has Vasodilation

used, but it shows affinity for 5-
poor selectivity. ht5a/5b)
Newer agonists are SB-258719 Tachycardia in cats
AS19 and LP44, but
their selectivity is
not clear
Chronic diabetes mellitus is associated experimental animals due to more than one
with depressed heart functions and diabetic factor. The attenuation in the ability to
cardiomyopathy. It is characterized by generate contractile force has been suggested
decreased left ventricular developed pressure to be due to the depression in the ATPase
(LVDP), decreased rate of ventricular pressure activity of contractile proteins21,22 and
development (+dP/dt), decreased rate of alteration in the sarcolemmal membrane20,21.
ventricular pressure decline (-dP/dt) and The defects in cardiac relaxation have been
decreased heart rate. From our study, we have attributed to the depression in the sarcoplasmic
reported that type 1 diabetes produces decrease reticular calcium uptake22 and the sarcolemmal
in LVDP, +dP/dt, -dP/dt and heart rate. calcium exchange activities 23. It has also been
Treatment with sarpogrelate has been reported reported that cardiac mitochondria isolated
to produce significant increase in LVDP, from diabetic animals have reduced capacity to
+dP/dt, -dP/dt and heart rate. In addition, the accumulate calcium 20,21. All this evidence lead
diabetic rats showed increase in heart weight to the conclusion that condition of calcium
to body weight and left ventricle weight to overload may present be present in
body weight ratios indicating hypertrophy of mitochondrial cells in chronic diabetes 20,21. 5-
the heart. Sarpogrelate significantly decreased HT causes very strong smooth muscle cell
heart weight to body weight ratio indicating contraction that is considered to be associated
reduction in hypertrophy18. Circulating levels with cardiovascular diseases like hypertension
of 5-HT are increased in diabetics as well as (Frishman, et al, 1995)24. 5-HT causes an
patients with coronary artery disease as increase in [Ca2+]i of smooth muscle cells via
compared to the normal subjects. This increase 5-HT2 receptor through the release of calcium
in 5-HT levels may be due to release of 5-HT from intracellular stores as well as the influx of
from platelets as well as mast cells19. extracellular calcium 25,26. 5-HT induced influx
Sarpogrelate treatment restores the 5-HT2A may occur through both, voltage dependent
receptor sensitivity and reverses the inotropic and independent channels26. Chronic treatment
effects of 5-HT, thus improves the heart with 5-HT2A antagonist sarpogrelate may have
function. However, chronic hyperglycemia led to the suppression of this resultant calcium
may alter the hemodynamic responses in overload leading to improvement in cardiac

Current R&D Highlights, Jan.-Mar. 2009 37

function. following pre-treatment with the selective 5-
Role of 5HT in Obesity HT2C receptor antagonist, SB24208430;
although some reports do suggest the actions
It is well established that enhancing 5-HT of mCPP are not solely 5-HT2C receptor-
neurotransmission in the brain regulates mediated but also 5-HT1B receptor-mediated31.
feeding habits by inducing hypophagia. Another 5-HT2C receptor agonist, Ro60-0175,
Fenfluramine and D-fenfluramine, compounds also induces hypophagia32, although this
that stimulate 5-HT release from the synapse compound also interacts with 5-HT2A/2B
and block its reuptake, reduce the volume of receptors, the hypophagic response appears to
food intake in both rats and humans13, at least necessitate 5-HT2C receptor activation
potentially through the promotion of satiety23. due to prevention of the response by
Similarly, administration of the SSRI pretreatment with the selective 5-HT2C
antidepressant, fluoxetine, presumably also receptor antagonist, SB242084. It is reported
potentiating central 5-HT function, also results that serotonergic mechanism is involved in
in lower food intake in both rats and humans27. secretion of leptin and that both leptin and 5-
It is believed that distinct 5-HT receptor HT may interact for the regulation of food
subtypes are responsible for mediating the intake. From our laboratory we have reported
hypophagic response of this neurotransmitter, glucose and lipid lowering effect of fresh juice
with the primary candidates being the 5-HT1B of ginger is mediated through 5-HT
and 5-HT2C receptors. Evidence for the receptors33. Further evaluation of active
involvement of the 5-HT1B receptor is based fractions of ginger in goldthioglucose induced
largely on the ability of pharmacological obese mice suggests that ethyl acetate and
agents, including the selective 5-HT1B receptor methanolic fraction of Z. Officinale (ginger)
agonist, CP94, 253 and the nonselective 5- has beneficial effect in condition of obesity. In
HT1A/1B receptor agonist, RU24969, to reduce addition to decrease serum glucose, insulin and
food intake in rodents28,29. Similarly, evidence lipid levels it can also significantly retard gain
implicating the 5-HT2C receptor in the in body weight. Based on our data (Table-4),
regulation of feeding is supported by these beneficial effects, Z.Officinale can be
pharmacological studies. For instance, the considered as supplementary herbal therapy in
mixed 5-HT1B/2C receptor agonist, m- obese patients for prevention or treatment of
chlorophenylpiperazine (mCPP), induces obesity.
hypophagia in mice, which is blocked
Table: 4 Effects of ginger methanolic and ethyl acetate extracts on body weight, serum glucose and
insulin levels on goldthioglucose-induced obesity in mice34.
Groups Body weight (g/mice) Glucose (mg/dl) Insulin (U/ml)

Normal control (vehicle) 22.5 1.1 78.5 1.1 31.0 0.8

Obesity control (OB) (vehicle) 41.6 1.6a 156.7 1.7a 91.3 2.1a
b b
OB+ methanolic extract 32.5 1.1 124.4 2.5 75.0 1.5b

OB+ ethyl acetate extract 35.8 0.8b 128.7 2.1b 88.3 1.8b
N=6, values represent mean S.E.M. a Significantly different from normal control P<0.05. b Significantly different from obesity
control P<0.05.

38 Current R&D Highlights, Jan.-Mar. 2009

Conclusions antiatherosclerotic, antithrombotic and anti
From the forgoing discussion, it is evident anginal effect. It seems that sarpogrelate is an
that sarpogrelate is a specific 5HT2A receptor excellent drug for the treatment of peripheral
antagonist. Many experimental studies suggest vascular disease and can be an effective drug
that sarpogrelate has number of for the treatment of diabetes and associate
pharmacological effect namely, anti-platelet, cardiovascular complications.
Cell Cardiol 1981, 13: 303-309.
23. Rowland, N.E. et al., J.. Progr. Neurobiol. 1986, 27, 13
1. Lackovic Z, et al.,. J Neurochem 1990, 54: 143-147. 24. Frishman WH, et al.,. J Clin Pharmacol 1995, 35: 541-
2. Chen CC, et al., Res 1991, 552: 175-179. 72.
3. Holden RJ. Schizophrenia, Med Hypotheses 1995, 44: 25. Doyle VM, et al., Naunyn Schmiedebergs Arch
379-391. Pharmacol 1986, 333: 98-103.
4. Furman BL, et al., Diabetologia 1980, 19: 386-390. 26. Hirafuji M, et al., Res Commun Mol Pathol Pharmacol
5. Yamada J, et al.,. Life Sci 1995, 57:819-825. 1998, 99: 305-319.
6. Chaouloff F, et al., Eur J Pharmacol 1990a, 177: 107- 27. McGuirk, J. et al.,.. Int. J. Obesity 1990, 14, 361372.
110. 28. Lee, M.D. et al.. Eur. J. Neurosci. 2004, 19, 30173025.
7. Baudrie V, et al., DOI. Eur J Pharmacol 1992, 213:41- 29. Lucas, J.J. et al. J. Neurosci. 1989,18, 55375544.
46. 30. Kennett, G.A. et al. Neuropharmacology 1997, 36, 609
8. Laude D, et al., Naunyn-Schmiedebergs Arch 620.
Pharmacol 1990, 342: 378-381. 31. Schreiber, R. et al., J.. Progr. Neuro-Psychopharmacol.
9. Umrani DN, et al., J. Mol Cell Cardio. 2001; 33:A124. Biol. Psychiatry 2002, 26, 441449.
10. McCall RB, et al., Pharm Rev 1994, 46: 231243. 32. Clifton, P.G. et al. Psychopharmacology 2000, 152, 256
11. Sharma SK, et al., J Pharmacol Exp Ther 1999, 290: 267.
14751481. 33. Akhani SP, et al., J Pharm pharmacol 2004; 56 101.
12. Hara H, et al., Thromb Haemost 1991, 65: 415 34. Goyal RK, et al.,. Fitotherapia 2006, 77, 160-163.
420. 35. Hajduch E, et al., J Biol Chem 1999, 274: 13563-13568.
13. Blundell, J.E.. Appetite 1988, 7, 3956. 36. Yamada J, et al.,.. Life Sci 1989, 45:1931-1936.
14. Umrani DN, et al., Mol Cell Biochem 2003, 249: 5357. 37. Lechin F, et al.,. Acta Physiol Lat Am 1975, 25: 339-46.
15. Garvey W, et al., Am J Physiol 1993, 264: H837-H844. 38. Sugimoto Y, et al.,. Eur J Pharmacol 1996a, 307: 75-80.
16. Humphrey, P.P. et al.,. Trends Pharmacol. Sci. 1991, 12, 39. Weiss, O. Ueber die Wirkungen von Blutserum-
444446. Injectionen ins Blut. Archiv fu r die Gesamte
17. Fozard, J.R. J. Cardiovasc. Pharmacol. 1982, 4, 829838. Physiologie des Menschen und der Thiere LXV, 1896,
18. Temsah RM, et al.,. Can. J. physiol. pharmacol. 2001; 215230.
19. Van Den Berg EK, et al., Circulation 1989, 79:116-124.
20. Pierce GN, et al., Am J Physiol 1985a, 248: E170-E175
21. Pierce GN, et al., Can J Cardiol 1985b, 1: 48-54.
22. Penpparkgul S, et al., Sonnenblick EH, Scheuer J. J Mol

Current R&D Highlights, Jan.-Mar. 2009 39


System Biology Enables Novel Strategies for the

Management of Type 2 Diabetes
Alok Kumar Verma, Ram Raghubir and Ram Pratap*
Division of Medicinal and Process Chemistry,
Central Drug Research Institute, Lucknow
System biology is a new concept in systems.
biological sciences to understand complex Robustness consists of four basic
molecular networking of the system. A proper mechanisms, which ensure the robustness of
understanding of the failure of the inbuilt the system: system control, alternative means
robustness mechanisms inviting the disease of redundancy (or fail safe) and diversity,
state, may offer system-based approach for the
modularity and decoupling in which physical-
future drug design for the effective and safe level perturbation is isolated from functional
management of systemic diseases. level activities of the system. Robustness is
In perspective of the system biology, enhanced in biological systems as there are
diseases are viewed as breakdown of multiple means to achieve a specific function.
robustness and disease evolves when damage This encompasses redundancy, overlapping
to the mechanisms that maintain robustness function and diversity. Redundancy generally
can not be repaired. In general, robustness is refers to a situation, in which several identical,
manifested as adaptation to the dynamic or similar, components (or modules) can
environment and as stability against external replace with each other, when another
and internal disturbances. Living systems are component fails. This implies that drugs
generally robust against various perturbations, targeting such pathways are likely to have
such as mutation, toxin and environmental limited efficacy. Diversity, or heterogeneity,
changes, but can be extremely fragile to the represents the other extreme, whereby a
perturbations of high amplitude for which the specific function can be attained by different
system has not been optimized. The means available in a population of
mechanism that provide robustness and protect heterogeneous components. The biological
normal functions in a dynamic environment system has evolved decoupling mechanism for
may also be used to maintain abnormal states. its robustness like capacitors in electrical lines
When fundamental robustes mechanisms are decouple the voltage fluctuations. The
co-opted by the disease process as in cancer, biological systems have also evolved
then it becomes difficult to treat the disease. decoupling mechanisms for its robustness by
Drugs can be ineffective when the inherent assigning different functions to different cell
robustness of the system in patients, that is constituents, which is known as physical
being targeted, is compensated by redundant separation of various functions inside the cell
pathways. Also the side effects of drugs can be so that functional fluctuations in one part is not
the result of its interference at an unexpected transferred to another and also repairing
points of fragility (divergent point) of these mechanism e.g. heat shock proteins fix mis-

40 Current R&D Highlights, Jan.-Mar. 2009

folded proteins as a result of environmental affecting the supply of nutrients to the organs.
stress, which also decouples genetic variations Oxidative stress in human biology comes from
from the phenotype variations. System control variety of sources e.g. in aerobic cells,
introduces positive and negative feed back, incomplete reduction of oxygen in the
feed forward and other regularity loops to mitochondrial electron transport chain releases
maintain homeostasis of the system as well as superoxide anion, which on reaction with iron
bi-stable behaviors, which enables the system or copper produce the highly reactive and
to move between two stable states. damaging hydroxyl radicals into cytosol. Our
Positive feedback contributes to biological system utilizes oxidative stress to
robustness by amplifying the stimuli, often defend itself e.g. inflammatory cells, such as
producing bi-stability, so that the activation macrophages and neutrophils produce
level of a downstream pathway can be clearly hydrogen peroxide and hypochlorous acid as a
means of bactericidal activity. Diabetes results
distinguished from non-stimulated states, and
so that these states can be maintained. Positive owing to an imbalance between oxidative
feedback is also used in signal transduction stress and its defense mechanism for its
and the cell cycle to form switchlike behavior proliferation and hence convert excess plasma
of the system by amplification of stimuli, so glucose to keto-aldehyde, a highly reactive
intermediate called Amadori adduct, which
that it initiates transition and a new state of the
system is made that is more robust against ultimately reacts indiscriminately with proteins
noise and fluctuations of stimuli. under non-enzymatic conditions to produce
advanced glycation endproducts (AGEs). The
Negative feedback is the principal mode oxidative stress therefore could be one of the
of control that enables robust response to important target for interference. The system
perturbations. For example in relation to biology based analysis of diabetes led Kitano
obesity and diabetes, food intake and its et al (2004)1 to suggest that the TNF- and
disposition is controlled by anabolic and stress adiponectin loop may be the target for new
hormones. Leptin secreted by adipocytes and antidiabetic drugs, which the nature has
ghrelin by the stomach, are centrally regulated evolved for emergency supply of glucose to
by hypothalamus, a brain loci, controlling the brain. In ancient environment during
appetite. Hypothalmus also activate release of evolution, the TNF- and adiponectin loop was
stress hormone noradrenaline from adrenal evolved to impart insulin resistance so as to
glands to initiate thermogenesis to protect maintain glucose supply to the neuronal and
animals from cold. These negative feed back innate immune related cells and thus providing
mechanisms respond with perturbations for robustness against near-starvation levels of
adaptation to the dynamic environment and food supply by maintaining a higher blood-
hence can be utilized for drug interference in sugar level. So, the system has adapted the
diabetes and obesity. mechanism to provide robustness against low
Type-2 diabetes is a major manifestation level of glucose supply by a negative feed back
of metabolic syndrome, which is a highly loop where TNF- makes insulin resistant so
complex disease comprising obesity, insulin that glucose is not completely converted to
resistance, hyperlipidemia and hypertension. glycogen and is always available for brain and
Metabolic syndrome is a systemic disease immune cells to function. The phenomenon
affecting multiple organ systems through the has been taken over by the disease metabolic
narrowing of macro- and micro-vascular syndrome, where adipocytes releases cytokines
systems under the influence of the oxidative TNF- and IL6 to keep off glucose uptake.
stress provided in the system and thereby Besides TNF-, some other hormonal and
cytokines factors affect insulin sensitivity such

Current R&D Highlights, Jan.-Mar. 2009 41

as resistin and glucocorticoids and that these
may serve newer targets for diabetes. OH

In the light of the robustness and fragility HO OH

of the biological systems, Kitano et al (1994) NH HO OH

has analyzed diabetes in detail and categorized HO OH
OH Miglitol
it into energy supply, its utilization and O
maintenance of homeostatic status and their HO

failure leads to diabetes. This opens new vistas O

to understand the therapeutic measures and to HO


future designing strategies for developing OH


novel drugs. We will attempt a brief OH

Acarbose Voglibose
description of these categories and treatment
available and the targets currently being glucose levels and the long term effect of these
pursued in-view of the recent advancements in drugs is only a small reduction in blood. Since
molecular biology of the disease. alpha-glucosidase inhibitors prevent the
A. Food Intake, Absorption and Control degradation of complex carbohydrates into
Mechanism glucose, the undigested complex carbohydrates
The process of food intake can be move to the colon, where bacteria digests them
categorized under positive feed back in process causing gastrointestinal side effects such as
of energy intake, whereas negative feed back flatulence and diarrhoea.
loops regulate appetite by hormonal The appetite control mechanisms
messengers. The hormonal messengers however, may be exploited for the
controlling the food intake (appetite) are management of obesity. To control
leptin, secreted by adipocytes and ghrelin by hyperglycemic condition, the peptide
the stomach are controlled at the level of hormones called incretins have been targeted.
hypothalamus. The arrival of food in the duodenum stimulates
the release of polypeptides called glucagon-
After the ingestion of food, the
carbohydrate constituents are absorbed into the like peptide-1 (incretin) and glucose-dependent
system through their conversion to mono insulinotropic polypeptide (GLP). They
saccharides. Pancreatic amylase in the intestine enhance the ability of glucose to stimulate
degrades complex carbohydrates to oligo and insulin secretion by the pancreas and stimulate
disaccharides. Within the brush border of the the ability of the tissues to take up glucose
intestinal villi of small intestine, -glucosidase from the blood. GLP-1 is rapidly degraded in
enzymes break down the oligo- and vivo through the action of dipeptidyl peptidase
disaccharides to monosaccharides, which are IV (DPP-IV), which cleaves the N-terminal
absorbed through the mucosal border. two amino acids to give the inactive GLP-1
Competitive inhibition of these enzymes amide.
reduces the rate of absorption and hence A cell surface serine protease, DPP-IV is
postprandial hyperglycemia. -1, 4- ubiquitously expressed, with highest levels
glucosidase inhibitors such as acarbose, found in the kidney and the lower levels in
voglibose and miglitol are therefore used for liver and pancreas, where it rapidly terminates
the treatment of patients with diabetes the activity of GLP-1 by cleaving the N-
mellitus. terminal dipeptide (His-Ala) of GLP-1. DPP-
In diabetic patients, the short-term effect IV inhibitors, therefore stabilize endogenous
of these drugs is to decrease current blood GLP-1 at the physiological concentrations, and

42 Current R&D Highlights, Jan.-Mar. 2009

induce insulin secretion in a glucose- B. Control Mechanisms For Energy
dependent manner. They also stabilize other Storage:
The energy transport and storage
mechanism is primarily governed by the
hormone insulin forming a negative feed back
loop in glucose homeostasis. A primary
H metabolic action of insulin is to facilitate the

postprandial disposition of glucose via its
BMS-477118 (Saxagliptin)
actions on three key target tissues: suppression
O GSK 832093C (Denagliptin)
of glucose output from the liver and
stimulation of glucose uptake and metabolism
in skeletal muscle and adipose tissue. Defects
N N O N in insulin secretion and action on its target
tissues manifest diabetes. Reduced insulin
action and its resistance for glucose transport
in skeletal muscle and adipose tissue have
SYR-322 (Alogliptin) LAF 237 (Vildagliptin) therefore been targets of drug design for type 2
F diabetes.

F N Insulin-stimulated glucose transport in

skeletal muscle in type 2 diabetes is impaired
resulting in enhanced insulin secretion from
pancreatic -cells, the phenomenon is termed
MK0431(Sitagliptin) as hyper-insulinemia. Peripheral insulin
resistance combined with impairment of
incretins, including gastric inhibitory peptide insulin secretion results into hyperglycemia. At
and pituitary adenylate cyclase activating the end stage, changes in insulin signaling,
peptide. Further they reduce the antagonistic such as its inability to inhibit hepatic
and desensitizing effects of the fragments gluconeogenesis is accompanied by
formed by the truncation of the incretins. deterioration of pancreatic beta cell function
resulting in failure of hyper secretion of insulin
Several DPP-IV inhibitors have to compensate insulin resistance. Such a
progressed in clinical development, and their situation results in long term micro-vascular,
characteristics have recently been reviewed. neurological, and macro-vascular
These agents have consistently reduced blood complications including retinopathy,
glucose, predominantly post-prandially, and nephropathy, neuropathy and increased risk of
this appears to be associated with increases in cardiovascular diseases.
active circulating GLP-1 (and possibly other
incretins) as well as reductions in glucagon. a). Stimulation of insulin secretion:
Acutely, DPP-IV inhibitors seem to increase Glucose induced insulin secretion from
the insulin response to glucose. LAF- pancreatic -cells is the end result of a
237(Novartis) is a second generation DPP-IV complex cascade of actions initiated by ligand
inhibitor that lowers the blood sugar levels sensitive potassium sensitive ATP channels.
towards normal and prevented large Binding of glucose on the receptor brings
fluctuation after meals in type II diabetes. It is closure of the ATP-sensitive potassium
presently in phase III human clinical trials. channels. As a result the decrease in potassium
ion efflux leads to depolarization of the cell

Current R&D Highlights, Jan.-Mar. 2009 43

membrane, opening of voltage-gated Ca2+ hypoglycemia. Glimepiride has also been
channels, elevation of the cytoplasmic Ca2+ shown to increase insulin sensitivity of
concentration and stimulation of Ca 2+ ion peripheral tissues to insulin. Sulfonylureas do
dependent exocytosis of the insulin. The KATP not have a clinically significant effect on the
channel is a heteroctameric complex composed lipid profile.
of four inwardly rectifying K+ channel subunits H 3C O O O
(Kir6.2) and four sulfonylurea receptors H3C
N C HN H 2 C H2 C S NH C NH CH 3
(SUR1). Two isoforms of the receptor have H2 O
been indentified, SUR1 on pancreatic cells Glimepiride
and SUR2 on vascular smooth muscle and Cl
cardiac termed as SUR2B and SUR2A C
respectively. This KATP channel has been O
utilized to enhance insulin secretion from CH3 Glibenclamide
pancreatic cells in diabetic patients.
i) KATP closing by sulfonylurea stimulated
Second generation sulfonylureas as insulin
The first-generation agents include
acetohexamide, chlorpropamide, tolazamide, ii) KATP closing non-sulfonylurea stimulated
and tolbutamide. secretion:
The non-SU secretagogs include
H CH 3 O
H meglitinide, repaglinide and nateglinide. Like
H 3C S N C N Cl S N C N CH3
O O the sulfonylureas, the non-SU secretagogs
Tolbutamide Chloropropamide made available since 1998 lower plasma
glucose by increasing the release of insulin
H 3C S N C N
from functional pancreatic -cells. The
Tolazamide Acetohexamide mechanism is exactly the same as that of
First generation sulfonylureas as insulin secretogogs. sulfonylureas, except the non-SU secretagogs
are more selective as they lack affinity towards
The second-generation agents include SUR2A and SUR2B channels. Unlike
glimepiride, glipizide, and glyburide. The sulfonylureas, non-SU secretagogs have a very
second-generation agents are more potent and short half-life and duration of action, so they
in general have better pharmacokinetic and stimulate insulin secretion for brief episodes.
safety profiles. This mechanism only works if
Therefore, they are dosed with meals and are
insulin is present in the -cells. Sulfonylureas most helpful in decreasing postprandial
display more pronounced action in the hyperglycemia. Unlike sulfonylureas, non-SU
presence of glucose. The increased insulin secretagogs have decreased incidence of
flows into the portal veins to suppress the hypoglycemia. Compound BTS 67582 binds to
elevated basal rate of hepatic glucose the KATP channel at the site different from
production. One concern with these agents is sulfonylureas and is therefore effective in
the loss of efficacy over time, which may be sulfonylurea resistant animal models.
related to the potential to exhaust -cell
function. Because these agents increase plasma
levels of insulin, they may cause

44 Current R&D Highlights, Jan.-Mar. 2009


H3 C H2 H H O H 2 H
H H H2 2 H H2
CH 3
Repaglinide Nateglinide KAD-1229 (Meglitinide)

iii) KATP channel opener stimulated effect on the exocytotic machinery of -cells.
secretion: These compounds are at different phases of
MCC 134 opens potassium channels, development as novel oral insulinotropic
activates KATP channel on smooth muscle cells agents.
and inhibits SUR1 resulting in reduced insulin The imidazoline compounds such as KU
secretion. Therefore it is effective in 14R act via another putative imidazoline
hypertensive diabetic patients. NN 414 opens receptors on pancreatic islet. The classical
KATP channels on pancreatic -cells, thereby imidazoline receptors (I1 and I2) occur on
reduces insulin secretion. It also prevents smooth muscle cells. The imidazoline
glucose induced apoptosis of human islets. compound KU 14R causing insulin secretion
from pancreatic islet acts through another
O unknown imidazoline receptor on -cells,
NH 2
termed as I3.
CH 3 N
N N 3
N H H CH 3
N CH 3

MCC 134 NN 414 NH2

BTS 67582 O
iv) 2A - Adrenoceptor/ imidazoline receptor NH
antagonists as insulin secreting agents: N
The studies on the mechanism of action of O
prazosin, revealed that -2A adrenoceptors
cause stimulation of pancreatic sympathetic
nerve to inhibit the insulin release. This target O
H 3C N
H3 C
therefore led designing of drugs through its HN
interference. The scientists at Central Drug HN

Efaroxan RX 871024 KU 14R

Research Institute, prepared prazosin analog RX 801080

centpiperalone which exhibited significant v) Sodium dependent glucose transport pump

sugar lowering activity but was abandoned due inhibition:
to its minor nausea sensation in clinical
studies. However its mechanism of action In normal individuals, more than 99% of
could not be established. the plasma glucose that is filtered through
glomerulus of kidney is reabsorbed, resulting
Further studies towards the search of -2A in only less than 1% of the total filtered
adrenoceptors antagonist led discovery of glucose being excreted in urine. This re-
compounds such as RX 801080, KU 14R, absorption process is mediated by two sodium
Efaroxan and RX 871024. The mechanism of dependent glucose co-transporters (SGLTs):
RX 801080 revealed that its insulinotropic SGLT1, a low capacity, high-affinity
effect is mainly due to dual mechanisms: by transporter expressed in the gut, heart, and
closing KATP channel and activating voltage- kidney and SGLT2, a high-capacity, low-
gated Ca2+ channels secondly by its direct affinity transporter that is expressed mainly in

Current R&D Highlights, Jan.-Mar. 2009 45

the kidney. 90% of renal glucose re-absorption streptozotocin (STZ) rats. These findings,
is facilitated by SGLT2 residing on the surface combined with a favorable ADME profile,
of the epithelial cells lining the S1 segment of have prompted clinical evaluation of
the proximal tubule, while the remaining 10% dapagliflozin for the treatment of type 2
is likely to be mediated by SGLT1 localized on diabetes.
the more distal S3 segment of the proximal b). Desensitization of insulin resistance:
tubule. Humans with SGLT1 gene mutations
experience glucose-galactose mal-absorption, Glucose transport is thought to be rate-
resulting in frequent, watery diarrhoea and limiting for glucose uptake and metabolism by
dehydration, when on a glucose diet, skeletal muscle and adipose tissue. Insulin
confirming that SGLT1 is the major glucose mediated glucose transport could occur by
transporter in the small intestine. These either stimulating the activity of existing cell
individuals present with little or no glucosuria, surface glucose transport proteins or by
suggesting that SGLT1 is not the major translocation of an intracellular transporter
glucose transporter in the kidney. However, (glucose transporter iso-type 4, Glut 4) to the
since persistent renal glucosuria is the sole cell surface in response to insulin. In type 2
reported phenotype of humans with SGLT2 diabetes the insulinstimulated translocation of
gene mutations, selective inhibition of SGLT2 Glut 4 to the cell surface of muscle and fat
has been proposed to aid in the normalization tissue is defective and therefore requires
of plasma glucose levels in patients with intervention. In order to find points of
diabetes by preventing the renal glucose re- therapeutic intervention the understanding of
absorption process and promoting glucose insulin signaling pathway is essential.
excretion in urine. Selective SGLT2 inhibitors In the event of diabetic signaling cascade,
would be desirable, since gastrointestinal side the insulin first bind to an enzyme receptor
effects associated with SGLT1 inhibition referred as insulin receptor (IR) on the target
would be minimized. This mechanism is tissue. The protein has a ligand-binding
expected to be associated with a low risk of domain on the extracellular surface of the
hypoglycemia, because there is no interference plasma membrane and an enzyme active site
with the normal counter regulatory on the cytosolic side. The enzyme is a protein
mechanisms for glucose. kinase that phosphorylates Tyr residues in
specific target protein, known as insulin
Cl OEt receptor substance (IRS-1). Once the protein is
phosphorylated on Tyr residues of IRS-1, it
O carries the message to targets in the cytosol
HO and nucleus through the phosphorylation of
intermediate proteins involving Grb2, Sos and
Ras. Ras then activates protein kinase, Raf-1
OH which in turn activates MEK followed by
activation of MAPK. Activated MAPK moves
into nucleus and modulates the transcription of
Bristol-Mayers have recently developed insulin regulated genes. When Grb2 associates
the C-aryl glucoside (dapagliflozin) getting with PI3K, PI3K gets activated to convert PIP2
lead from natural product as a potent and to PIP3. PIP3 indirectly activates PKB, which
selective hSGLT2 inhibitor which reduced phosphorylates serine/threonine residues on
blood glucose levels in a dose-dependent its target proteins e.g. GSK3. Activated PKB
manner by as much as 55% in hyperglycemic triggers the movement of GLUT-4 from

46 Current R&D Highlights, Jan.-Mar. 2009

internal membrane vesicles to the plasma TNF- induced inflammatory changes in the
membrane. endothelial cells by blocking inhibitory NF-B
Insulin resistance is a central feature of the phosphorylation and NF-B activation. The
metabolic syndrome, leading to hyper- newly identified adipokine omentin increases
insulinaemia and involves multiple defects of insulin stimulated storage of glucose in
insulin receptor and post-receptor signaling. adipocytes and increases PKB phosphor-
Pathways that control non-genomic effects of rylation.
insulin appear to be more vulnerable to the Besides the above revelation in the
disruption. In the insulin resistance state, forward direction, the molecular level studies
insulin fails to induce normal GLUT-4 protein have also identified pathways which modulate
translocation in skeletal muscles, resulting in signaling pathways at insulin receptor
the hyperglycemic stage in the plasma. substrate-1. Protein tyrosine phosphatase-1B
Adipocytes play a regulatory role in the (PTP-1B) dephosphorylates tyrosine residues
development of insulin resistance as they can on the insulin receptor, which negatively
produce adipokines (hormones and cytokines) regulates insulin signaling and therefore
and also as they become saturated with their requires intervention. Serine phosphorylation
excess lipid storage capacity leading to the of IRS-1 catalyzed by protein kinase C (PKC),
abnormal distribution of lipids to other organs which itself get activated by inositol 1, 4, 5-
and tissues. Adipocytokines such as TNF- triphosphate, attenuates IRS-1 signaling
and IL-6 are pro-inflammatory factors activity via prevention of tyrosine
contributing to the development of insulin phosphorylation is another modifier of tyrosine
resistance. TNF- induces the serine kinase activity. Recent studies on c-Jun NH2
kinase iso-type 1 (JNK-1) suggest that this
phosphorylation of IRS-1 causing serine
phosphorylation of the insulin receptor kinase is also a mediator of insulin resistance
resulting in blockade of normal tyrosine as it phosphorylates Ser on IRS-1.
phosphorylation of the insulin receptor causing i) Metformin, a biguanidinide as insulin
interference with insulin signal transduction. sensitizer:
Further IL-6 and TNF- induce suppression of Metformin presents several mechanisms
cytokines signaling-3 (SOC-3) resulting in of action, but its primary mechanism for
inhibition of tyrosine phosphorylation of IRS-1 lowering plasma glucose is to decrease hepatic
and thus reduce the activation of Akt (PKB), gluconeogenesis. To some extent, it also
which finally results in reduction in the release improves insulin sensitivity of peripheral
of GLUT-4 from secretory vesicles. Leptin is tissues. It does this by increasing insulin-
an adipocyte hormone which decreases TG stimulated uptake and use of glucose. This is
synthesis, stimulates -oxidation and enhance shown by a reduction in fasting plasma
insulin secretion through modulation of glucose and insulin concentrations. It is not
various insulin targets including IRS-1, effective in the absence of insulin. Metformin
MAPK, ERK, p38 MAP kinase, PKB, P kinase
also decreases intestinal absorption of glucose.
and PI-3 kinase. Adiponectin increases insulin Metformin has been shown to decrease the
sensitivity by activation of AMPK and by low-density lipoprotein (LDL) levels and
increase in tyrosine phosphorylation of insulin triglycerides (TGL) by about 10% to 15% and
receptor. In liver it inhibits both the hepatic may slightly increase the high-density
gluconeogenesis enzyme and the rate of
lipoprotein (HDL) levels. The improvement in
endogenous glucose synthesis while in insulin sensitivity is a by product of these
muscles it increases glucose transport and alterations. Metformin has anorexigenic
increases fatty acid oxidation. It suppresses

Current R&D Highlights, Jan.-Mar. 2009 47

properties. It acutely and selectively stimulates in most tissues. PPAR regulates genes
p44/ p42 MAP kinase. Adverse effects of involved in fatty acid uptake and oxidation,
metformin therapy include gastrointestinal inflammation, and vascular function, whereas
distress, such as abdominal pain, nausea, and PPAR regulates genes involved in fatty acid
diarrhoea in up to half of patients. uptake and storage, inflammation and glucose
CH3 H homeostasis. Insulin resistance starts with
obesity, which resists anti-lipolytic effects of
N N NH2 insulin leading to increased plasma free fatty
acid levels and altered partitioning of FFA
between the adipose tissue, skeletal muscle,
and liver. This imbalance results in
NH NH intracellular accumulation of triglycerides and
fatty acid metabolites in muscle and liver.
Dysfunctional fat cells also produce excessive
ii) Stimulation of Peroxisome-proliferator- amounts of cytokines e.g. tumor necrosis
activated-receptor- (PPAR) led insulin factors-, interlukin-6 and resistin. The insulin
sensitization: sensitivity thus can be improved by selective
stimulation by PPAR ligands. This property
Adipocyte is a central player in the control
of energy balance and whole body lipid has been attributed to the direct effect of
homeostasis. Storage and release of fatty acids agonists on lipid metabolism in adipose tissue
and glycerol from the adipocyte impact overall and secondary effects on lipid and glucose
lipid homeostasis as well as hepatic and metabolism in liver and skeletal muscle.
peripheral glucose metabolism. Adipocytes PPAR a gonists promote adipocyte
also perform an important endocrine function differentiation and promote FFA uptake and
by secreting numerous cytokines, bioactive storage in subcutaneous adipose tissue. This
peptides, and complement factors. Upon reduces FFA levels, with associated reductions
secretion into the bloodstream, adipocyte in insulin resistance. PPAR is also believed to
derived signaling molecules act at distant sites increase the expression and translocation to the
to regulate energy homeostasis. The cell surface of the glucose transporters thus
peroxisome is a sub-cellular organelle, whose increasing glucose uptake into liver and
functions extend well beyond the removal of skeletal muscle cells and reducing plasma
molecular oxygen and later breakdown of glucose levels. PPAR agonists also restore
hydrogen peroxide, to include glycerolipid insulin sensitivity by decreasing TNF- and
synthesis, cholesterol biosynthesis and increasing adiponectin expression.
breakdown, and fatty-acid oxidation. O O
Peroxisome proliferator-activated receptors NH NH
(PPARs) are members of the nuclear receptor N N
family of ligand-activated transcription factors BRL-49653 Pioglitazone
that bind to fatty acids and their metabolites. O N CO2 H

The three PPARs (alpha, beta/delta, and O

gamma) are distributed differently in the O

various organs. PPAR is expressed mainly in O
CH 3
tissues, where active fatty acid catabolism S

occurs (e.g. liver, brown fat, kidney, heart, and O

skeletal muscle) and PPAR m ainly in white O
and brown adipose tissue. PPAR is expressed Ciglitazone Troglitazone

48 Current R&D Highlights, Jan.-Mar. 2009

The thiazolidinediones more specifically thermogenesis:
enhance insulin sensitivity, but they also Adipose tissue serves not only as a depot
potently promote adipocyte differentiation and for triglyceride storage but also as a dynamic
often increase total fat mass. For example endocrine organ involved in the control of
rosiglitazone and pioglitazone are effective energy balance. Adipocytes are responsible for
glucose-lowering drugs but have moderate the storage of fat and its breakdown (lipolysis)
effects on lipids resulting in increase of is primarily controlled by the sympathetic
adipocytes in patients with type 2 diabetes.
nervous system. Activation of -adrenergic
However, the L-tyrosine analogue farglitazar receptors decreases lipolysis and activation of
has robust effects on glucose, high-density -adrenergic receptors increases lipolysis.
lipoprotein as well as on triglycerides in They are members of the large family of G-
diabetic patients. protein-coupled receptors that regulate an
assortment of intracellular second messenger
O COOH systems, including cAMP, phospholipid
hydrolysis, ion fluxes, and mitogen-activated
N O protein (MAP) kinase cascades. 3-adrenergic
O receptor is expressed in white, brown as well
in skeletal tissue and its stimulation elevates
the levels of cAMP and thereby stimulation of
lipolysis and adipose specific genes. The
increased expression of uncoupling protein-1
in skeletal muscle and UCP-2, and - 3 in
C. Utilization of Stored Energy and Its adipose tissues uncouples the fatty acid
Control Mechanisms: oxidation from oxidative phosphorylation. The
As we have seen above that the diabetes is process increases heat production with a boost
a consequence of obesity which results from a in energy consumption rendering 3-adrenergic
chronic imbalance between energy intake and receptor agonist as potential anti-obesity
agents and through stimulation of lipolysis
energy expenditure. Energy expenditure
includes basal metabolism, physical activity sensitization of insulin action. Some of the 3-
and adaptive (non-shivering) thermogenesis.
Adaptive thermogenesis is regulated at least OH

two hormonal effectors: -adrenergic agents NH


and thyroid hormone. On stimulation by -

adrenergic hormone norepinephrine in HN HN
adipocytes it starts lipolysis of stored L-757, 793 LY 377604

triglycerides to release fatty acid (FA) and OH

glycerol into the blood, which are taken up by CH 3

skeletal muscle cells for FA based -oxidation.

AJ-9677 CP-331, 684
The fatty acid oxidation releases energy as OH

heat. These back up feed forward reactions CH3 O COONa

ensure energy supplies in case of emergency Cl

and their stimulation have therefore been the
target for glucose homeostasis in present day agonists under development are mentioned
life style utilizing high energy food. here. Encouraging data has emerged from
clinical studies of CL-316,243 a highly
i) 3- Adrenergic receptor stimulation led selective albeit rodent specific 3-adrenergic

Current R&D Highlights, Jan.-Mar. 2009 49

receptor agonist. It has been observed that it major contributor for insulin resistance, has
increases lipolysis, fat oxidation and insulin not yet been exploited. Adiponectin modulates
action in human. However due to its poor in a way to neutralize the effect of TNF- and
bioavailability it has been abandoned. At sensitizes insulin action which has not received
present the compound LY 377604 up in phase attention so far. The stimulation of
III trial. With regard to thyroid hormone thermogenesis by thyroid hormone and 3-
stimulation, tyrosine analogs have also been adrenergic system need further exploration to
prepared and one of these compounds obtain clinically useful molecules. The -cell
farglitazar, dual activators of PPAR- and apoptosis decreases the -cell mass and hence
PPAR- lowers lipids and improves insulin leads to defective insulin secretion which is
action and is in phase III clinical settings. mediated by interleukin-1 secreted from
Thus the several mechanistic aspect of macrophage. Anti-apoptotic molecules
directed to -cell may prevent the damage and
energy homeostasis including energy intake,
storage and its supply has been considered for should therefore enhance insulin level to
drug design. However, the area of adipocyte control type 2 diabetes. The subject therefore
cytokines e.g. tumor necrosis factor-, requires attention.
interlukin-6, IKK-, JNK-1 etc. which are
Subunits. J. Gen. Physiol. 114, 203-213 (1999). J.C.
Koster, Q. Sha, and C.G. Nichols.
Further Readings:
6. Dipeptidyl Peptidase-IV Inhibitors: Pharmacological
1. Metabolic syndrome and robustness tradeoffs. Diabetes, Profile and Clinical Use. Clinical diabetes 26 (2), 53-57
53 (Supplement 3) S6-S15 (2004). H. Kitano, K.. Oda, T. (2008). J. R. White.
Kimura, Y. Matsudoka, M. Csete, J. Doyle and M. 7. Insulin and Oral Antidiabetic Agents. Am. J. Pharm.
Muramatsu. Educ. 69 (5), Article 89, 1-11 (2005); M. S. Ahmed.
2. Novel strategies for the pharmacological management of 8. Therapeutic roles of peroxisome proliferator- activated
type 2 diabetes. Trends in Pharmacological Sciences receptor agonists. Diabetes 51, 2460-2470 (2005). B.
25(2), 86-91 (2004). A. Nourparvar, A. Bulatta, U. D. Staels and C. J. Fruchart.
Mario and R. Perfetti. 9. A cold inducible Co-activator of nuclear receptors linked
3. Lehninger Principles of Biochemistry, D.L. Nelson and to adaptive thermogenesis. Cell 92, 829-839 (1998). P.
M.M. Cox; Macmillan Worth Publishers Third Edition Puigserver, Z. Wu, W. C. Park, R. Graves, M. Wright and
2003. S. M. Bruce.
4. Dipeptidyl peptidase IV (DPP IV) inhibitors a newly 10. Discovery of Dapagliflozin: A potent, selective renal
emerging drug class for the treatment of type 2 diabetes. sodium-dependent glucose co-transporter 2(SGLT2)
Diabetes Vasc. Dis. Res. 3(3), 159165 (2006). Brian D. Inhibitor for the Treatment of Type 2 Diabetes. J. Med.
Green, Peter R. Flatt, Clifford J. Bailey. Chem, 51, 11451149 (2008). Meng et al.
5. Sulfonylurea and K1-Channel Opener Sensitivity of KATP
Channels Functional Coupling of Kir6.2 and SUR1

50 Current R&D Highlights, Jan.-Mar. 2009


Overview of Diabetes Mellitus Management

Dr Ashim Ghatak
Division of Clinical & Experimental Medicine
Central Drug Research Institute, Lucknow
The major goal in treating diabetes is to weight loss, exercise, and oral medications.
minimize any elevation of blood sugar Ideally, insulin should be administered in
(glucose) without causing abnormally low a manner that mimics the natural pattern of
levels of blood sugar. Type 1 diabetes is insulin secretion by a healthy pancreas;
treated with insulin, exercise, and a diabetic however, the complex pattern of insulin
diet. Type 2 diabetes is treated first with secretion by the pancreas is difficult to
weight reduction, a diabetic diet, and exercise. duplicate. Still, adequate blood glucose control
When these measures fail to control the can be achieved with careful attention to diet,
elevated blood sugars, oral medications are regular exercise, home blood glucose
used. If oral medications are still insufficient, monitoring, and multiple insulin injections
treatment with insulin is considered. throughout the day.
Adherence to a diabetic diet is an In the past, the insulin was being derived
important aspect of controlling elevated blood from animal sources, particularly cows and
sugar in patients with diabetes. The American pigs. Not only was there a problem with
Diabetes Association (ADA) has provided enough supply of insulin to meet the demand,
guidelines for a diabetic diet. The ADA diet is but beef and pork insulin also had specific
a balanced, nutritious diet that is low in fat, problems. Originating from animals, these
cholesterol, and simple sugars. The total daily types of insulin caused immune reactions in
calories are evenly divided into three meals. In some people. Patients would become intolerant
the past two years, the ADA has lifted the or resistant to animal insulin. With the
absolute ban on simple sugars. Small amounts acceleration of scientific research in the latter
of simple sugars are allowed when consumed half of the twentieth century, beef and pork
with a complex meal. insulin were replaced by human insulin. In
Weight reduction and exercise are 1977, the gene for human insulin was cloned,
important treatments for diabetes. Weight and through modern Recombinant technology,
reduction and exercise increase the body's human insulin is being manufactured in huge
sensitivity to insulin, thus helping to control amounts and is freely available Human insulin
blood sugar elevations. is now widely used.
Management of Type-I Diabetes Mellitus Insulin now comes in a variety of
Insulin is the mainstay of treatment for
preparations that differ in the amount of time
patients with type 1 diabetes. Insulin is also following injection until they begin to work
and the duration of their action. Because of
important in type 2 diabetes when blood
glucose levels cannot be controlled by diet, these differences, combinations of insulin are

Current R&D Highlights, Jan.-Mar. 2009 51

often used to allow for a more tailored regimen the most common types of insulin currently in
of blood sugar control. The table below lists use in the U.S. and their specific properties.
Table 1: Insulin Formulations Available[4,5]

Insulin Onset of action Peak Duration

Rapid acting (analog)

As part lisproglulisine 10-20 minutes15-30 1-3 hours.5-2.5 hours1-1.5 3-5 hours3-6.5 hours3-
minutes10-15 minutes hours 5 hours
Short-acting (human)

Regular 30-60 minutes 1-5 hours 6-10 hours

Intermediate (human)

NPH 1-2 hours 6-14 hours 16-24+ hours

Long-acting (analog)

detemirglargine 0.8-2 hours1.1 hours No significant peakNo Up to 24 hoursUp to 24

significant peak hours

Premixed (analog)

70% APS/30% aspart 10-20 minutes10-30 1-4 (2.4) hours1-6.5(2.6) Up to 24 hoursUp to 24

75% NPL/25% lispro minutes10-30 minutes hours0.8-4.8 (2.3) hours hoursUp to 24 hour
50% NPL/50% lispro

Premixed (human)

70% NPH/30% regular50% 30-60 minutes30-60 1.5-16 (4.4) hours2-5.5 Up to 18-24 hoursUp
NPH/50% regular minutes (3.3) hours to 18-24 hours

Range (mean)NPH = neutral protamine Hagedorn; APS = aspart protamine suspension; NPL = neutral protamine

Table 2: Currently Available Methods for Insulin Delivery

Device Advantages Disadvantages

Prefilled pen, eg, FlexPen Less wastage of pen contents vs Initially can be more expensive than
(Novo Nordisk, Bagsvaerd, vial/syringe Discreet Appears less vial/ syringe Cannot mix insulins
Denmark), Humalog Pen (Eli ''medical''Injection may be more Possibility of air bubbles
Lilly and Co, Indianapolis, comfortable than vial and syringe
Indiana), SoloSTAR (Aventis Less time consuming Refrigeration
Pharma Holding GmbH, not required Easy to use Accurate
Frankfurt, Germany) dosing Disposable

Reusable pen, eg, NovoPen Discreet Sturdier than prefilled pens As above Need to change cartridges

52 Current R&D Highlights, Jan.-Mar. 2009

(Novo Nordisk), HumaPen Injection may be more comfortable (time consuming and less convenient
MEMOIR (Eli Lilly and Co), than vial and syringeAccurate dosing than prefilled pens)
OptiClik (Aventis Pharma
Holding GmbH)

Dosers, eg, InnoLet (Novo Easy to use Accurate dosing Suitable As above Not currently available with
Nordisk) for patients with visual/ dexterity insulin analogs
problems Disposable

Insulin pump Uses only rapid-acting insulin (most Pump and supplies expensive
consistent profile) Most accurate Undetected interruptions in insulin
dosing Allows very flexible lifestyle delivery may occur, with possible
Closest to replacing body's own increased risk of ketoacidosisMay
insulin cause discomfort as worn
continuously Needs high patient
motivation, involvement, and
commitment to use

Jet injectors Needle-free Single component May May cause bruising Potential for
benefit patients with severe insulin- decreased amount of absorbed insulin
induced lipoatrophy Requires weekly cleaningRisk of
infection May be less comfortable
than needle-based devices Not suited
to intermediate- or long-acting

Table 3: Insulin Analog Formulations Available in Pen and Doser Devices

Device Insulin Manufacturer

Disposable (prefilled) pens

FlexPen Levemir, NovoLog, NovoLog Mix 70/30 Novo Nordisk

Lilly Prefilled Humalog, Humalog Mix 70/30, Humalog Mix 75/25, Humalog Mix Eli Lilly
Pen 50/50, Humulin N

SoloSTAR Lantus, Apidra Sanofi-Aventis

Durable (cartridge) pens

NovoPen 3 Levemir, NovoLog, NovoLog Mix 70/30 Novo Nordisk

NovoPen Junior Levemir, NovoLog, NovoLog Mix 70/30 Novo Nordisk

HumaPen Humalog, Humulin Eli Lilly


Current R&D Highlights, Jan.-Mar. 2009 53

HumaPen Humalog Eli Lilly

OptiClik Lantus, Apidra Sanofi-Aventis


InnoLet Novolin N, Novolin R, Novolin 70/30 Novo Nordisk

For example, a patient may take an insulin. The cartridges and needles are
injection of Lantus in the morning and evening disposed of when finished and new ones
to provide a baseline of insulin throughout a simply are inserted. In many cases, the entire
24-hour period. In addition, the same patient pen is disposed of. These insulin delivery
may take an injection of Humalog just before devices are less cumbersome than traditional
meals to cover the increase in carbohydrate methods.
load after eating. Insulin pump: The most recently
Different Methods of Delivering Insulin available advance in insulin delivery is the
There are now a variety of insulin insulin pump. In the U. S., MiniMed, Deltec
preparations and also there are various and Disetronic market the insulin pump. An
methods for administering insulin. insulin pump is composed of a pump reservoir
similar to that of an insulin cartridge, a battery-
Pre-filled insulin pens: In the past, insulin operated pump, and a computer chip that
was available only in an injectable form that allows the user to control the exact amount of
involved carrying syringes (which a few insulin being delivered. Currently, pumps on
decades ago were made of glass and required the market are about the size of a pager or
sterilization), needles, vials of insulin, and beeper. The pump is attached to a thin plastic
alcohol swabs. Needless to say, patients often tube (an infusion set) that has a cannula (like a
found it difficult to take multiple shots each needle but soft) at the end through which
day, and, as a result, good blood sugar control insulin passes. This cannula is inserted under
was often compromised. Many pharmaceutical the skin, usually on the abdomen. The cannula
companies are now offering discreet and is changed every two days. The tubing can be
convenient methods of delivering insulin. disconnected from the pump while showering
Both Novo Nordisk and Lilly have an or swimming. The pump is used for continuous
insulin pen delivery system. This system is insulin delivery, 24 hours a day. The amount
similar to an ink cartridge in a fountain pen. A of insulin is programmed and is administered
small pen-sized device holds an insulin at a constant rate (basal rate). Often, the
cartridge (usually containing 300 units). amount of insulin needed over the course of 24
Cartridges are available in the most widely hours varies depending on factors like
used insulin formulations, such as those listed exercise, activity level, and sleep. The insulin
in the table above. The amount of insulin to be pump allows for the user to program many
injected is dialed in by turning the bottom of different basal rates to allow for this variation
the pen until the required number of units is in lifestyle. In addition, the user can program
seen in the dose-viewing window. The tip of the pump to deliver additional insulin during
the pen consists of a needle that is replaced meals to cover the excess demands for insulin
with each injection. A release mechanism caused by the ingestion of carbohydrates with
allows the needle to penetrate just under the the meal.
skin and deliver the required amount of Over 50,000 people worldwide are using

54 Current R&D Highlights, Jan.-Mar. 2009

an insulin pump. This number is growing sensor, it does "request" a response from the
dramatically as these devices become smaller patient if there is a need for adjustments
and more user-friendly. Insulin pumps allow according to the patterns it is programmed to
for tight blood sugar control and lifestyle detect. The ultimate goal of this technology is
flexibility while minimizing the effects of low to "close the loop" by continuously sensing
blood sugar (hypoglycemia). At present, the what the body needs, and then responding by
pump is the closest device on the market to an providing the appropriate dose of insulin.
artificial pancreas. More recently, newer While this technology is a few more years in
models of the pump have been developed that the making, the strides in this direction
do not require a tubing, in fact - the insulin continue to grow.
delivery device is placed directly on the skin Inhaled Insulin Inhaled insulin, marketed
and any adjustments needed for insulin by Pfizer in 2006, was approved by the FDA.
delivery are made through a PDA like device
This inhaled form of insulin is called Exubera.
that must be kept within a 6 foot range of the The insulin is packaged in dry blister packs
insulin delivery device, and can be worn in a that are inserted into an inhalation device. This
pocket, kept in a purse, or on a tabletop when device lances the powder packs allowing the
working. insulin to enter a chamber that has a mouth
Probably the most exciting innovation in piece through which the user can inhale the
pump technology is the ability to use the pump insulin. Exubera has a peak of action similar to
in tandem with newer glucose sensing Humalog (rapid acting), and a duration of
technology. Glucose sensors have improved action similar to regular insulin (short acting).
dramatically in the last few years, and are an It can be combined with oral medication in
option for patients to gain further insight into patients with type 2 diabetes or used alone. In
their patterns of glucose response to tailor a patients with type 1 diabetes the insulin should
more individual treatment regimen. The be combined with a longer acting basal insulin
newest generation of sensors allows for a real such as glargine.
time glucose value to be given to the patient. The side effect profile of inhaled insulin is
The implantable sensor communicates
similar to other insulins, and the user must be
wirelessly with a pager-sized device that has a aware of hypoglycemia. In addition, since the
screen. The device is kept in proximity to the insulin is absorbed through the lungs, there
sensor to allow for transfer of data, however, it was initial concern regarding lung function.
can be a few feet away and still receive While there is a slight decrease in lung
transmitted information. Depending on the
function with the initial use of Exubera, this
model, the screen displays the blood glucose stabilizes quickly and returns to baseline of
reading, a thread of readings over time, and a aged matched controls when the Exubera is
potential rate of change in the glucose values. discontinued. Since this is still a new product,
The sensors can be programmed to produce a it is recommended that any patient starting on
"beep" if blood sugars are in a range that is inhaled insulin have lung function tests done
selected as too high or too low. Some can prior to starting treatment. If baseline values of
provide a warning beep if the drop in blood FEV1 (a measure of lung function) are < 70%,
sugar is occurring too quickly. Exubera is not given. After six months of use
To take things one step further, there is lung function tests are performed again; if
one particular sensor that is new to the market deterioration is noted, Exubera is discontinued.
that is designed to communicate directly with Exubera is not to be used in regular or
the insulin pump. While the pump does not yet intermittent smokers and patients requiring
respond directly to information from the

Current R&D Highlights, Jan.-Mar. 2009 55

very small doses of insulin. Nevertheless, in (for example, by surrounding the islet cells by
the right population, this is a great option. the patient's own cells and then implanting
Intranasal, Transdermal: Other routes for them) are underway. In addition, researchers
the delivery of insulin have also been tried. are exploring artificial barriers that can
Intranasal insulin delivery was thought to be surround the islet cells, provide protection
promising. However, this method was against rejection, and still allow insulin to
associated with poor absorption and nasal enter the bloodstream.
irritation. Transdermal insulin (skin patch Management of Type II Diabetes
delivery) has also yielded disappointing results Based on what is known, medications for
to date. Insulin in pill form is also not yet type 2 diabetes are designed to:
effective since the digestive enzymes in the gut
break it down. o Increase the insulin output by the pancreas.
o Decrease the amount of glucose released from the
Pancreas transplantation: Ultimately, the liver.
goal in the management of type 1 diabetes is to o Increase the sensitivity (response) of cells to
provide insulin therapy in a manner that o Decrease the absorption of carbohydrates from the
mimics the natural pancreas. Perhaps the intestine.
closest therapy available at this time is a o Slow emptying of the stomach to delay the
transplant of the pancreas. Several approaches presentation of carbohydrates for digestion and
to pancreatic transplantation are currently absorption in the small intestine.
o When selecting therapy for type 2 diabetes,
being studied, including the whole pancreas consideration should be given to:
and isolated islet cells (these groups of cells o The magnitude of change in blood sugar control
contain beta cells that are responsible for that each medication will provide.
insulin production). Data available from 1995 o Other coexisting medical conditions (high blood
pressure, high cholesterol, etc.)
indicates that almost 8,000 patients underwent o Adverse effects of the therapy
pancreatic transplantation. Most patients o Contraindications to therapy
undergo pancreatic transplantation at the time o Issues that may affect compliance (timing of
of kidney transplantation for diabetic kidney medication, frequency of dosing)
disease. o Cost to the patient and the healthcare system
It's important to remember that if a drug
Transplantation is not without risk. Both can provide more than one benefit (lower
the surgery itself and the immnosuppression blood sugar and have a beneficial effect on
that must occur afterward pose significant risks cholesterol, for example), it should be
to the patient. For these reasons, the kidney preferred. It's also important to bear in mind
and pancreas are usually transplanted at the that the cost of drug therapy is relatively small
same time. At present, there is disagreement compared to the cost of managing the long-
about whole pancreas transplantation in term complications associated with poorly
patients not currently requiring kidney controlled diabetes.
transplantation. The issue of whether the
benefits outweigh the risks in these patients is Varying combinations of medications also
under debate. There is also a chance that are used to correct abnormally elevated levels
diabetes will occur in the transplanted of blood glucose in diabetes. As the list of
pancreas. Selectively transplanting islet cells is medications continues to expand, treatment
an interesting alternative to whole pancreas options for type 2 diabetes can be better
transplantation. However, the concern over tailored to meet an individuals needs. Not
rejection remains. Attempts to disguise the every patient with type 2 diabetes will benefit
islet cells in tissues that the body won't reject from every drug, and not every drug is suitable
for each patient. Patients with type 2 diabetes

56 Current R&D Highlights, Jan.-Mar. 2009

should work closely with their physicians to with sulfonylureas.
achieve an approach that provides the greatest In a three month study, repaglinide
benefits while minimizing risks. dropped fasting blood glucose values by 61
Patients with diabetes should never forget mg/dL and post meal blood glucose values by
the importance of diet and exercise. The 100 mg/dL. Because repaglinide is short acting
control of diabetes starts with a healthy and given before meals, it is particularly
lifestyle regardless of what medications are beneficial in lowering blood glucose after
being used. meals and does not tend to lower fasting
Medications that increase the insulin glucose levels to the same degree. Repaglinide
output by the pancreas - sulfonylureas and has been used in combination with other
meglitinides : medications, such as metformin (Glyciphage),
with impressive results. In 83 patients with
Sulfonylureas - Historically, increasing type 2 diabetes, blood sugar control improved
insulin output by the pancreas has been the significantly with the addition of repaglinide to
major area targeted by medications used to Glyciphage.
treat type 2 diabetes. Medications that increase
the output of insulin belong to a class of drugs Repaglinide interacts with other
called sulfonylureas. Sulfonylureas primarily medications. Therefore, the doctor must be
lower blood glucose levels by increasing the aware of all other medications a patient is
release of insulin from the pancreas. Older taking before prescribing repaglinide. The
generations of these drugs include usual starting dose is 0.5mg before each meal
chlorpropamide and tolbutamide, while newer and can be increased to 4mg. The maximum
drugs include glyburide (DiaBeta), glipizide daily dose is 16mg. Repaglinide is used with
(Glucotrol), and glimepiride (Amaryl). These caution in people with kidney or liver
drugs are effective in rapidly lowering blood abnormalities. Since repaglinide increases
sugar but run the risk of causing hypoglycemia insulin levels, it has the risk of causing
(abnormally low and dangerous levels of blood abnormally low blood sugars. Blood sugars
sugar). In addition, they are sulfa-containing that remain severely low can result in
drugs and should be avoided by patients who sweating, tremors, confusion, and may lead to
are allergic to sulfa. coma and seizure. In addition, the use of
repaglinide has been associated with
Meglitinides - Repaglinide and Nateglinide: headaches, muscle and joint aches, along with
The class of drugs known as meglitinides is sinus infections in some individuals. This drug
relatively new. Meglitinides also work on the should not be used in pregnancy or by nursing
pancreas to promote insulin secretion. Unlike mothers. The dose may need to be adjusted in
sulfonylureas that bind to receptors on the older people, since the elderly may metabolize
insulin producing cells, meglitinides work (eliminate) medications at a slower rate. For
through a separate potassium based channel on more, please read the drug information on
the cell surface. Unlike the sulfonylureas repaglinide.
which last longer in the body, repaglinide and
nateglinide are very short acting, with peak Nateglinide has essentially the same
effects within one hour. For this reason, they profile of side effects and interactions as
are given up to three times a day just before repaglinide. The major benefit of Nateglinide
meals. Since these drugs also increase is that the starting dose of 120mg does not
circulating insulin levels, they may cause need to be adjusted upward, but rather remains
hypoglycemia, but the literature suggests this constant. These medications are also relatively
is less frequent than the hypoglycemia seen safe to use in people with impaired kidney

Current R&D Highlights, Jan.-Mar. 2009 57

function.. Pioglitazone and rosiglitazone are
Biguanides: Medications that decrease the thiazolidinediones approved for use in the
amount of glucose produced by the liver : A India. While they are sister compounds to
class of drugs called biguanides has been used Rezulin, extensive studies have failed to show
for many years in Europe and Canada. In 1994, that they are associated with any liver
the FDA approved the use of the biguanide problems. Both Pioglitazone and rosiglitazone
metformin (Glyciphage) for the treatment of act by increasing the sensitivity
(responsiveness) of cells to insulin. They
type 2 diabetes in the U.S. Glyciphage is
unique in its ability to decrease glucose improve the sensitivity of muscle and fat cells
production by the liver. Briefly, because to insulin. These drugs have been effective in
metformin does not increase insulin levels, lowering blood sugars in patients with type 2
when used alone, it does not usually cause diabetes, Pioglitazone and rosiglitazone act
within one hour of administration and are
hypoglycemia. In addition, metformin has an
effect whereby it tends to suppress appetite, taken once daily. It is important to note that it
which may be beneficial in diabetics who tend takes up to six weeks to see a drop in blood
to be overweight. Metformin may be used by glucose levels with these drugs and up to 12
itself or together with other oral drugs or weeks to see a maximum benefit. Pioglitazone
and rosiglitazone have been approved as first
insulin. It should not be used in patients with
kidney impairment and should be used with line therapy in diabetes and for use in
caution in those with liver impairment. The combination with other drugs. Both drugs may
older biguanides that preceded metformin were be used in patients taking other oral drugs as
associated with a serious condition called well as those using insulin.
lactic acidosis, a dangerous acid build up in the While reported liver problems with these
blood resulting from accumulation of the drug agents are mild (and reversible with
and its breakdown products. While metformin discontinuation of the drug), most physicians
is safer in this regard, it is recommended that choose to follow an earlier recommendation to
the drug be discontinued for 24 hours before do blood tests to detect liver injury every two
any procedure involving the intravenous months or so during the first year of therapy.
injection of dyes (such as for some x-ray Recently this recommendation has been
studies of the kidney) or surgery is performed. removed. If at any point the liver tests increase
The dyes may impair kidney function and to three times the normal upper limit, the drug
cause a build up of the drug in the blood. should be stopped.
Metformin can be restarted after these
The most important contraindications to
procedures once the patient is urinating these medications include any type of liver
normally. disease, and heart failure. Fluid retention can
Medications that increase the sensitivity of be of particular concern in patients with signs
cells to insulin: The class of drugs known as or symptoms of heart failure and in those with
thiazolidinediones lowers blood glucose by ejection fractions of less than 40% which
improving target cell response to insulin (that indicates poor function of the heart. While the
is, increasing the sensitivity of the cells to reports are three to eight pounds, clinical
insulin). Troglitazone (Rezulin) was the first of experience shows up to 12-15 pounds of
this class in the U.S. Because of severe toxic weight gain can occur. Usually the majority of
liver effects, troglitazone has been taken off this is fluid, but an absolute body weight gain
the market. Sister compounds are now can also occur. This is likely to be dose-
available with a better safety profile. These dependent and, therefore, the increases in
drugs include pioglitazone and rosiglitazone. weight may be greater with higher doses of

58 Current R&D Highlights, Jan.-Mar. 2009

drug. Weight gain is more pronounced in doubt that the uses for this class of medications
patients who are also taking insulin. In general, will expand.
the ankle swelling and puffiness due to the Pioglitazone is used for the treatment of
accumulation of fluid can be controlled with type II diabetes along with a healthy diabetic
the addition of a diuretic such as diet, regular exercise, weight control, smoking
spironolactone (Aldactone) furosemide reduction, and careful monitoring of blood
(Lasix) does not work as well) or by glucose. Pioglitazone may be used alone or in
reducing the dose. On occasion, patients may
combination with metformin, a drug in a
be symptomatic enough from fluid retention to different class of anti-diabetic drugs, that also
warrant withdrawal of the drug. Some recent lowers blood glucose. Since it requires
studies have suggested an association between naturally-secreted insulin to be effective,
pioglitazone and rosiglitazone and untoward pioglitazone is not recommended in type I
cardiac events, for example, heart attacks,
diabetes where the amount of insulin is very
though this association is controversial. low or absent. Nevertheless, pioglitazone is
Regardless of the controversy, it is well approved for treating type II diabetes in
established that pioglitazone and rosiglitazone combination with insulin as well as another
should be avoided in patients with class of anti-diabetic drugs, the sulfonylureas.
symptomatic heart failure or heart failure.
Dosing- Pioglitazone is prescribed once daily
Another newer concern is an association in doses ranging from 15 to 45 mg.
of treatment with a small increase in the Pioglitazone may be taken any time of the day,
frequency of fractures of the distal long bones with or without meals. If a dose is missed on
of the arms and legs. At present, this does not one day, two doses should not be taken the
translate into fractures of the hip and spine,
next day to make up for the missed dose.
which would be clinically more worrisome.
More data is needed to make a definitive Drug Interactions: To date, no formal
statement about cause and effect at this time. studies to evaluate drug interactions of
pioglitazone with other drugs have been
As an aside, Pioglitazone and conducted. However, since another
rosiglitazone have an added benefit of thiazolidinedione that is similar to pioglitazone
changing cholesterol patterns in diabetes. HDL may reduce the effectiveness of oral
(or good cholesterol) increases with these contraceptives (potentially leading to
medications, and triglycerides often decrease. pregnancy), caution should be used when
While there is some controversy regarding using pioglitazone with an oral contraceptive.
what happens to bad cholesterol (LDL) levels,
there is a suggestion that Pioglitazone may be Clinical studies using pioglitazone 15-
superior in changing lipid profiles than 45mg did not reveal changes in blood levels
rosiglitazone. In this population of diabetics for the following drugs: glipizide, digoxin,
that is already at an increased risk for heart warfarin or metformin. In addition, the clotting
disease, an improvement in cholesterol profile of blood did not appear to be changed enough
is beneficial. As more and more data becomes by pioglitazone to require alterations in the
available, there is mounting evidence that this doses of the blood thinner, warfarin.
class of drugs may provide direct benefits to Pregnancy- There are no adequate studies of
the heart and large blood vessels and may pioglitazone in pregnant women. Pioglitazone
actually be valuable in preventing the may be used in pregnancy if the physician
progression of diabetes in high-risk individuals feels the potential risks are justified. Nursing
by reducing inflammation and by decreasing Mothers: It is unknown if pioglitazone is
clotting factors. As time goes on, there is no secreted in breast milk. Therefore, the safety to
Current R&D Highlights, Jan.-Mar. 2009 59
a nursing infant when the mother is taking well as insulin. Since it requires naturally-
pioglitazone is unknown. secreted insulin to be effective, rosiglitazone is
Side Effects and Precautions-The most not recommended for use in type I diabetes
common side effects seen in clinical trials with where the amount of insulin is very low or
pioglitazone alone or in combination with absent.
sulfonylureas, metformin, or insulin were Dosing- Rosiglitazone may be taken once or
upper respiratory tract infection, headache, twice daily, with or without meals. Daily doses
sinusitis, muscle aches, tooth disorders, range from 4 to 8 mg either with or without
hypoglycemia, and sore throat. In addition, other antidiabetic medications. Studies do not
fluid accumulation (edema) occurred in less demonstrate additional effects when more than
than 5% of patients taking pioglitazone alone 8mg per day are taken.
but 15% of patients taking pioglitazone and Drug Interactions- Rifampin decreases the
insulin (as compared with 2% and 7% of blood concentration of rosiglitazone by
patients receiving placebo, respectively). Fluid increasing its breakdown in the liver.
accumulation can lead to heart failure. Therefore, use of rifampin may decrease the
To date, no formal studies to evaluate effect of rosiglitazone.
drug interactions of pioglitazone with other Gemfibrozil increases the concentration of
drugs have been conducted. Nevertheless, rosiglitazone in the blood by reducing its
because it interacts with the liver enzymes that breakdown. Therefore, rosiglitazone may
eliminate some other drugs, there is the increase the side effects of rosiglitazone.
potential for pioglitazone to increase the
elimination of such drugs as erythromycin, Pregnancy- There are no adequate studies of
calcium channel blockers (e.g., Cardizem), rosiglitazone in pregnant women. Nursing
cisapride (Propulsid), corticosteroids, Mothers: It is unknown if rosiglitazone is
cyclosporine, tracrolimus, trizolam (e.g., secreted in breast milk. Therefore, the safety of
Halcion), trimetrexate, and HMG-CoA rosiglitazone to nursing infants also is
reductase inhibitors (e.g., Lipitor). This would unknown.
reduce their effectiveness. Side Effects and Precautions- The most
Since another thiazolidinedione common side effects seen with rosiglitazone
antidiabetic drug has been associated with liver alone or in combination with metformin are
injury, it is recommended that periodic upper respiratory tract infection, haedache,
monitoring of liver-related side effects and back pain, hyperglycemia, fatigue, sinusitis,
liver function be done in patients taking diarrhea and hypoglycemia. Rosiglitazone has
pioglitazone. Side effects while taking been shown to cause mild to moderate
pioglitazone which may be due to liver injury accumulation of fluid (edema) and can lead to
include nausea, vomiting, abdominal pain, heart failure. Patients who already have heart
fatigue, anorexia (loss of appetite), or dark failure. may develop worsening symptoms
urine. Blood liver tests also are recommended with rosiglitazone. In addition, anemiamay
during pioglitazone therapy. occur with rosiglitazone alone or combined
with metformin. Rosiglitazone also causes
Rosiglitazone, combined with diet, increasing amounts of weight gain with
exercise, weight control and cessation of increasing doses.
smoking is used for treating type II diabetes.
Rosiglitazone may be used alone or in A review of the studies of rosiglitazone
combination with other types of anti-diabetic led the FDA to conclude that the medication
drugs such as metformin or sulfonylureas as might increase the risk of heart attacks and

60 Current R&D Highlights, Jan.-Mar. 2009

angina, but left the association as inconclusive. work at other sites, such as sulfonylureas.
Additionally, there isn't enough evidence that Clinical studies have shown statistically better
the risk of heart attack and angina is any control of blood glucose in patients treated
greater with rosiglitazone than with other oral with Precose and a sulfonylurea compared to
medicines used in the treatment of diabetes. the sulfonylurea alone. arcabose is currently
Uses: Rosiglitazone is an anti-diabetic used alone or in combination with a
drug (thiazolidinedione-type, also called sulfonylurea.
"glitazones") used with a proper diet and Arcabose is taken three times a day at the
exercise program to control high blood sugar beginning of meals. The dosage varies from 25
in patients with type 2 diabetes (non-insulin- to 100mg with each meal. The maximum
dependent diabetes). Rosiglitazone works by recommended dose is 100mg three times a
helping to restore your body's proper response day. At doses greater than this, reversible
to insulin, thereby lowering your blood sugar. abnormalities in liver tests may be seen.
Effectively controlling high blood sugar helps Because of its mechanism of action, arcabose
prevent heart disease, strokes, kidney disease, has significant gastrointestinal side effects.
blindness, and circulation problems, as well as Abdominal pain, diarrhea, and gas are
sexual function problems (impotence). common and are seen in up to 75% of patients
Rosiglitazone is used either alone or in taking Arcabose. For this reason, arcabose is
combination with other anti-diabetic administered using a low initial dose that is
medications (e.g., metformin, sulfonylureas, increased over weeks depending on the
insulin). patient's tolerance. Most of the gastrointestinal
Medications that Decrease the symptoms tend to subside over the course of a
few weeks although some patients report
Absorption of Carbohydrates from the
Intestine persistent problems.

Before being absorbed into the New Medications that Affect Glycemic
bloodstream, carbohydrates must be broken Control
down into smaller sugar particles, such as Symlin (pramlintide): Symlin is the first in
glucose, by enzymes in the small intestine. a new class of injectable, anti-hyperglycemic
One of the enzymes involved in breaking medications for use in patients with type 2 or
down carbohydrates is called alpha type 1 diabetes treated with insulin.
glucosidase. By inhibiting this enzyme, Pramlintide, the active ingredient in Symlin, is
carbohydrates are not broken down as a synthetic analog of human amylin, a
efficiently and glucose absorption is delayed. naturally occurring neuroendocrine hormone
Acarbose: The alpha glucosidase inhibitor synthesized by pancreatic beta cells that helps
available in the India. is arcabose (Multibay). control glucose control after meals. Amylin,
In clinical trials with over 700 patients, the use similar to insulin, is absent or deficient in
of arcabose was associated with a reduction in patients with diabetes. When used with insulin,
hemoglobin Alc values (a well known this compound can improve glycemic control
measurement of average blood sugars over the and has additional benefits that cannot be
preceding three months) that was significantly realized with insulin alone.
greater than the use of placebo (no treatment). According to published data, Symlin
However, as a single agent, arcabose is not as reduces post meal blood sugar peaks, reduces
effective as the other medications for diabetes. glucose fluctuations throughout the day,
Since arcabose works in the intestine, its enhances satiety (the sensation of fullness)
effects are additive to diabetic medications that leading to potential weight loss, and lowers

Current R&D Highlights, Jan.-Mar. 2009 61

mealtime insulin requirements. Studies have IV. So, if you could make a substance like
shown it improves A1C beyond the effect of GLP-1 that was not so easy to breakdown, this
insulin alone. would have potential benefit; thus, the studies
Symlin is taken just prior to meals, three began. Ultimately, after modifying this
times a day. It is given in injection form and is hormone, exenatide (with the trade name
used for: Type 2 diabetes, as an additional Byetta) was developed. Byetta is the first in a
treatment in patients who use mealtime insulin new class of drugs for the treatment of type 2
diabetes called incretin mimetics. Byetta has
therapy and have failed to achieve desired
glucose control despite optimal insulin been shown to have many of the same effects
therapy, with or without a concurrent on sugar regulation as GLP-1, so it mimics the
sulfonylurea agent and/or metformin. Type 1 body's natural physiology for self-regulating
diabetes, as an additional treatment in patients blood sugar. Namely, it slows the release of
glucose from the liver, slows stomach
who use mealtime insulin therapy and who
have failed to achieve desired glucose control emptying thereby regulating delivery of
despite optimal insulin therapy. nutrients to the intestine for absorption, and
works centrally in the brain to regulate hunger.
Symlin is considered a therapy option in
patients with insulin-using type 2 or type 1 Byetta is indicated as additional therapy to
diabetes, that are unable to achieve adequate improve control of blood sugars in patients
glycemic control despite individualized insulin with type 2 diabetes who are taking metformin,
management. Insulin-using patients with type a sulfonylurea, or a combination of metformin
2 diabetes may also be taking a concurrent and a sulfonylurea but who have not achieved
sulfonylurea agent and/or metformin. adequate sugar control. It enhances the way the
insulin producing beta cells in the pancreas
The major side effect of Symlin is nausea, work. Insulin secretion increases only when
and this can be reduced with a slow, steady, blood sugars are high and decreases as blood
increase in dose. The other major side effect is sugars approach normal. In addition to
hypoglycemia (dangerously low levels of enhancing the normal physiology of the beta
blood sugar). To avoid this, the dose of cell, Byetta suppresses glucose release from
mealtime insulin should be cut in half when the liver, slows stomach emptying and the
starting Symlin. Of note is the degree of absorption of nutrients including carbohydrate,
weight loss seen with Symlin therapy. Studies and reduces intake of food.
for up to six months show weight loss of
greater than six pounds more than placebo Just like Symlin, Byetta is given by
(inactive pills). For more, please read the drug injection, but it is given twice a day (usually
information on pramlintide (Symlin). before breakfast and dinner meals). It comes in
a disposable pen form and is available in two
Byetta (exenatide)- Byetta (exenatide) is a doses. The goal is to start with the lower dose
new medication on the market that has it's for a month or so and then move up to the
origins in an interesting place--the Gila higher dose if needed and if tolerated. Similar
monster's saliva. Scientists studying this small to Symlin, the main side effect is nausea, most
lizard noted it could go a long time without likely due to its effects on stomach emptying.
eating. They found a substance in it's saliva This medication is temperature sensitive and it
that slowed stomach emptying, thus making was recommended that the pens be stored at
the lizard feel fuller longer. This substance was 36-46 degrees F. Recently, this has changed,
similar in nature to a gut hormone found in with a recommendation that unopened pens be
humans known as GLP-1. GLP-1 is broken refrigerated, and once opened, the pens can be
down in the body by an enzyme called DPP- left at room temperature. The risk of

62 Current R&D Highlights, Jan.-Mar. 2009

hypoglycemia is still a possibility with Byetta, pill form. While Byetta has a significant
especially when used in combination with weight loss profile, DPP-IV inhibitors so far
sulfonylureas. Your physician may choose to have had no effect on weight.
decrease the dose of some of your other Combination Medications
medications when initially evaluating how you
respond to Byetta. Glyburide/ metformin, rosiglitazone/
metformin, glipizide/ metformin, and
Similar to Symlin, weight reduction is pioglitazone/metformin are four relatively new
seen with Byetta in the majority of patients. combination pills in varying strengths are in
This makes it particularly suitable for the the market to treat diabetes.
typical patient with type 2 diabetes who is also
overweight. For more, please read the drug The benefit to these combination drugs is
information pamphlet on exenatide (Byetta). that there are fewer pills to take, hopefully
leading to better compliance. While they work
A longer acting from of Byetta is currently well, it is preferable to give patients individual
being considered for approval by the FDA. medications until we know what doses are
This would allow for the same benefits (and working, and then switch to a combination pill
side effects) without need for such frequent once the patient has been stable on the doses of
injections. DPP-IV inhibitors. GLP-1 in the individual medications for a period of time.
body is broken down by an enzyme called DPP
IV. Logically, you can either make a synthetic A Final Word
GLP-1 that is not broken down by this enzyme These last few years have been an exciting
(for example, Byetta) or you could try to stop time in diabetes care. Many agents for the
the enzyme that breaks down the GLP-1 your treatment of type 2 diabetes are under
body already makes. Hence, the new class of development and the options for insulin
drugs called DPP IV inhibitors. They do just therapy continue to grow and methods for
that, that is, they inhibit this enzyme from insulin delivery continue to become more
breaking down GLP-1. This allows GLP-1 refined. While research continues to expand in
already in the blood to circulate longer. There these areas, one thing remains constant.
are a number of companies working on this Achieving the best blood sugar control
class of drug and the FDA just approved the possible remains the ultimate goal in both type
first drug in this class made by Merck and 1 and type 2 diabetes. We now know, beyond a
called Januvia. Januvia can be used in doubt, that good blood sugar control
combination with certain other medications minimizes the long-term complications of
and must be dose adjusted in patients with diabetes, including blindness, nerve damage,
poor kidney function. For more, please read and kidney damage. Finally, a healthy lifestyle
the Januvia pamplet. can do nothing should remain the
These drugs have essentially the same side cornerstone of management for diabetes.
effect profile as Byetta; however, they are in .

Current R&D Highlights, Jan.-Mar. 2009 63

News & Views
mmol/l. In the United States normal fasting
blood glucose is considered to be below 5.6
mmol/l and normal concentrations after an oral
two hour glucose tolerance test to be below 7.8
(BMJ, 337 , p. 255 (August 2,2008))
57 Million Americans Should be Treated
for Prediabetes Raised Blood Glucose Concentration
and Diagnosis of Diabetes
Some 57 million US residents have
prediabetes, and almost 24 million, 8% of the Diagnosis of diabetes is usually based on
population, already have diabetes, says the the clinical symptoms and fasting blood
American Association of Clinical glucose results. A further fasting plasma
Endocrinologists. glucose (FPG) or oral glucose tolerance test
(OGTT) should be arranged to confirm the
Speaking at a meeting in Washington, DC, diagnosis; this is usually advisable unless the
the endocrinologists said that doctors need to symptoms are convincing. If the patient is of
identify people with prediabetes and treat them south Asian origin, OGTT is appropriate, as
by recommending changes to lifestyle, and using FPG alone in this group can miss
exercise such as diet, and prescribing drugs if diabetes. If it was a random sample, arrange a
necessary. Otherwise the human and financial fasting test. In the context of cardiovascular
cost would be huge, they warned. In a risk assessment, all concentrations 6.1
consensus statement they said that prediabetes" mmol/l from a random sample should be
raises short term absolute risk of type 2 followed up in this way. If the fasting sample
diabetes five to six fold. Complications of result is <6.1 mmol/l then the asymptomatic
diabetes begin early in the progression from patient could simply be given lifestyle advice,
normal glucose tolerance to diabetes, and some particularly if the risk of diabetes is low. If the
people with prediabetes already have sample suggests impaired fasting glycaemia
microvascular changes and end organ damage. then follow up with a further fasting sample or
Most of these people have not had diabetes OGTT. OGTT is better if there are risk factors
diagnosed, and primary care doctors will need or a raised clinical . suspicion of diabetes.
to identify and treat most of them, the panel
said. In either case withhold advice on dietary
modification until the follow-up fasting test or
People with prediabetes have blood OGTT, to avoid masking the diagnosis:
glucose levels that "are not normal but not Clearly agree the follow-up arrangements to
diabetic. This should not be an area of benign discuss the results and give advice, as
neglect," said Alan Garber, chairman of the boroerline glucose test results can easily go
organisation's task force on prediabetes and a unnoticed.
professor at Baylor College of Medicine in
Houston, Texas. Such people have more risk "Impaired glucose regulation" covers
of cardiovascular disease, blindness, kidney impaired glucose tolerance (IGT) and impaired
problems, and amputations and are likely to go fasting glycaemia (IFG). IGT can be identified
on to develop diabetes, he said. only under standardised conditions of
carbohydrate challenge and not from random
Dr Garber informed that people with samples. Both IGT and IFG are risk factors for
prediabetes had fasting blood glucose diabetes, but IGT carries greater
concentrations of 5.6-6.9 mmol/l and two hour cardiovascular risk. The implications for care
glucose tolerance test concentrations of 7.8-11 under current UK policy are the same for

64 Current R&D Highlights, Jan.-Mar. 2009

News & Views
either condition: assessment and reduction of the sensor's interstitial fluid readings and the
overall cardiovascular risk (recognising the 1.5 more reliable" self monitored glucose readings.
times greater risk in those with IGT) and A lag exists between changes in blood
annual blood glucose testing (FPG or OGTT) glucose levels and those of interstitial fluid,
to identify the development of diabetes. A and readings from interstitial fluid are slightly
range of interventions may reduce progression lower than those from blood. This is of
to diabetes. particular concern at times of rapidly changing
Lifestyle interventions seem at least as blood glucose levels and in hypoglycaemia.
effective as drugs, whose exact role is still The National Institute for Health and Clinical
unclear. Targeting of such patients for risk Excellence has yet to appraise the technology.
factor control has great potential for prevention Real time continuous glucose monitoring
of cardiovascular disease. displays the most recent glucose reading and
The continuous glucose monitor used by alerts the user when a preset glucose range is
Murphy and colleagues can be thought of as breached. The advantages of rapid response,
diabetology's answer to cardiology's:2.1, hour particularly to hypo glycaemia, are evident but
electrocardiography monitor. It is used as an in practice there are problems with false
investigative tool, is attached to the patient alarms; the temptation to give extra insulin so
(usually for 7:2 hours), and requires the user to often that it accumulates, causing
return to hospital for its removal. The data are hypoglycaemia; the temptation not to validate
downloaded and examined for abnormal with self monitored blood glucose readings;
glucose levels and trends. and the psychological morbidity of being
The sensor is inserted through the attached to a device for a defined period.
(BMJ, 337 , p. 873 (October11, 2008))
abdominal wall, so that its glucose oxidase tip
lies within subcutaneous tissue, where it Novo Nordisk to Give Free Insulin to
measures the giucose level of interstitial fluid, Kids
not of bloud. The sensor is wired to a palm Novo Nordisk plans to start distributing
sized monitor, which can be clipped to
free insulin to all diabetic children below
clothing. The sensor cannot be disconnected, poverty line in India.
even temporarily-for example, when
showering. The monitor captures and stores The $6.9-billion Danish pharma major is
the average glucose measurement every five also conducting human trials of six new drugs
minutes, yielding 288 readings in 2.1, hours. I in its 55 centres in India and plans to launch
GLP-1 - Liraglutide insulin drug globally by
The patient is taught .to key in the times 2009. The company has, however, dropped its
of food, exercise, insulin, and symptoms of inhaler insulin, Aerx, due to high costs and less
hypo glycaemia. The device also requires at efficiency compared to an injected drug.
least four self monitored blood glucose
readings to be entered each day for calibration, With over 40 million diabetic patients,
obtained by finger prick. India has the single largest share among
countries in the world diabetic population of
The device used by Murphy and over 200 million. About 11% urban population
colleagues does not give "real time" readings; and 4.5% rural population is diabetic. But only
both patient and professional are unaware of a fraction of the patients get diagnosed and
the measurements until the end of the 3-7 day among those which get diagnosed, even a
period of recording, determined by the life of smaller fraction is able to afford treatment.
the sensor. The data are then downloaded.
Software ensures adequate correlation between Novo Nordisk has around 60% market

Current R&D Highlights, Jan.-Mar. 2009 65

News & Views
share by volume in India. Eli Lilly, Aventis, could result in patients not receiving the
Pfizer, Wockhardt, Biocon, and Zenotech Labs expected dose, said the regulator. Caraco has
are some other major players in this market. initiated the recall. The FDA said the recall
Novo Nordisk has also announced the launch was valid nationwide and 22,156 bottles of the
of its mobile clinic here for free diagnosis of drug were in circulation in the US.
diabetics. The van is equipped with blood In November 2007, the FDA had asked
glucose monitoring systems for diabetes Ranbaxy Laboratories to withdraw its
screening and detection, weight check, body
Gabapentine tablets 600 mg from the US
mass index platforms and patient education market for excessive impurity specification.
audio-visuals. Metformin Hydrochloride, a bio-equivalent of
(The Economic Times, 8.2.2008)
Bristol Myers Squibb's Glucophage, was
Eli Lilly Drops Inhaled Insulin launched by Caraco in the US in February
Programme 2002.
(Business Standard, 25.3.2008)
Eli Lilly & Co has announced it will
terminate development of an inhaled insulin Avesthhgen Launches Bioactive to
treatment for diabetes, which it was Control Blood Sugar
conducting in partnership with Alkermes Inc, Avesthagen has launched its first
after deciding that product's commercial clinically-validated bioactive - 'Teestar' aimed
potential was not strong. at controlling blood sugar. The company has
Lilly's decision marks the third setback in brought out its product as a dietary supplement
recent months for inhaled insulin formulations, and in crackers (biscuit) form.
once deemed potential I blockbuster products
Dr. Morawala-Patell said, "The company
because of their greater convenience than has used two of its patented technologies to
standard injectable insulin. Cambridge, develop Teestar - 'ADEPT', a database that
Massachusetts-based Alkermes, which makes brings together traditional medicine and
the alcohol addiction drug Vivitrol, said Lilly modem systems biology, created under World
has the right to terminate its license to the
Bank-funded SPREAD project; and 'MetaGrid
inhaled treatment, Air Insulin, at its discretion. - an algorithm that enables comprehensive
(The Economics Times, 9.3.2008)
constituent profiling of plant extracts and
US FDA Asks Caraco Pharma to Recall thereby helps to maintain batch-to-batch
Diabetes Drug reproducibility of the bioactive. Teestar is the
first of the seven bioactives and will be
The US Food and Drug Administration
(USFDA) has asked Caraco Pharmaceutical followed by more' which are in the pipeline.
Laboratories, the US subsidiary of Sun Our goal is to incorporate, tasty, life-enhancing
Pharmaceuticals Industries, to withdraw many natural ingredients into our lifestyle."
batches of its generic Metformin The research and development (R&D) for
Hydrochloride tablets used for treating 'Teestar' was carried out on the lines of
diabetes, citing efficacy and quality issues. pharmaceutical actives, wherein the bioactivity
According to a USFDA Class II withdrawl and safety are proven at different levels. This
announced on March 19, Caraco will have to was prepared' from a single Indian plant
withdraw seven lots of Metformin mentioned in Ayurveda using the firm's
Hydrochloride in bottles of 100, 500 and 1000 technologies.
(Chemical Weekly, 13.5.2008, p. 138)
tablets each. The withdrawal was necessitated
by undersized and oversized tablets; which

66 Current R&D Highlights, Jan.-Mar. 2009

News & Views
Aventis Pharma Launches Disposable (NPPA) has increased the prices of 19
Insulin Pen imported insulin-based medicines.
Aventis Pharma has launched a new pre- The decision is in response to requests
filled disposable insulin pen for diabetic made by importers Eli Lilly and Pfizer, who
patients as it expects to increase its market wanted an increase in the prices of specific
share to 9 per cent with the launch. brands on the grounds that the rupee had
"SoloSTAR, a disposable insulin pen is to depreciated against the dollar, leading to an
be used for the treatment of hyperglycemia in increase in the import cost. The price revision
people with type 1 or type 2 diabetes and is covers 13 brands of Eli Lilly and six of Pfizer.
now available in Chandigarh, Punjab, Haryana The NPPA has also approved minor price
and Himachal Pradesh," Aventis Pharma reduction for two insulin-based medicines
Senior Director Susheel Umesh said. imported by Sanofi Aventis. The price revision
"This pen is designed in a very convenient is in the range of 2-5 per cent. Thus, a 3 ml
manner to enable patients carry it easily, catridge of Eli Lilly's human insulin injection
especially while travelling," he added. may now cost just over Rs 211, instead of
around Rs 205. The Indian anti-diabetic
Currently, the market for insulin stood at medicine market is estimated at over Rs 1,000
Rs 460 crore and it is growing at a rate of 80 crore.
per cent. (Business Standard, 9.7.2008)
(Financial Express 16.5.2008)
Diabetes Drugs Need Long-Term
Lifestyle Modification Can Delay Cardiovascular Safety Data
All drugs in development for type 2
Lifestyle changes can make a big diabetes should undergo long-term safety trials
difference. Drinking less alcohol, eating more to rule out an excessive cardiovascular risk, the
vegetables and exercising can prevent or delay US FDAs advisors recommended.
the onset of diabetes. Diet and exercise
reduced the incidence of diabetes by about The recommendations, if adopted, would
43% over 20 years among 577 high-risk mark a paradigm shift in diabetes drug
Chinese adults, the researchers reported in the development likely to result in longer, larger
journal Lancet. At the end of the 20 years, and costlier clinical studies. Diabetes drugs
80% of those who changed what they ate and would join nonsteroidal anti-inflammatories as
exercised more had diabetes, compared with one of the few categories of medicines for
93% who, made no changes, said Guangwei Li which long-term CV safety data are required.
of the China-Japan Friendship Hospital in The FDAs endocrinologic and metabolic
Beijing and Ping Zhang at the US Centers for drugs advisory committee voted 14 to two in
Disease Control and Prevention. The findings favour of requiring sponsors to conduct a long-
came as part of a series of studies addressing term trial, or provide other equivalent
new research about diabetes, which affects 246 evidence, to rule out an unacceptable CV risk
million adults worldwide, and accounts for 6% even in those drugs for which no adverse
of all global deaths. signal has been detected during traditional
(The Times of India, 24.5.2008) Phase II/III development. Most panellists
NPPA Increases Price of 19 Imported agreed such studies, at least in part, should be
Insulin Drugs conducted before approval.

National Pharmaceutical Pricing Authority Several endorsed the idea of conducting a

multi-year "screening" study to rule out an

Current R&D Highlights, Jan.-Mar. 2009 67

News & Views
unacceptably high, albeit- undefined, vice-president for evaluation research at the
cardiovascular risk, with completion of a American Board of Internal Medicine.
three- to five-year outcomes study after (Scrip, 9.7.2008, p. 6)
approval. It was also suggested that Phase III
India Seeks 17% Rise in Sale of Diabetic
trials could be extended to collect the several
tears' worth of necessary CV safety data, or
that a Phase III programme could be India, which is home to the largest
prospectively designed to allow for diabetic population in the world, has recorded
aggregation of long-term safety data sufficient a 17% rise in the anti-diabetic drug segment.
for approval, with a confirmatory study after The segment recorded sales of Rs 1,695 crore
licensing. Still others raised the spectre of in the 12 months to August 2008 compared to
beginning a long-term CV study before Rs 1,402 crore in the corresponding period last
approval, but using interim safety results as the year, according to ORG IMS data.
basis for licensing. Such long-term studies
should enrol patients at high risk of CV events, The segment's contribution to the Indian
and there should be independent adjudication pharmaceutical market as of June 2008 was
of CV events in all diabetes drug studies, the also higher at 5.1 % compared to 4.6% in the
panel said. Some currently marketed diabetes corresponding period up to June 2007. With
agents also should undergo long term CV changing consumption patterns and more
safety testing, particularly newer, on patent sedentary lifestyles in India; industry sources
agents and those for which there are little CV expect this to at least double in the coming
data. year. A study by Decision Resources, a
research based consulting organisation, shows
The panellists recommended against
that the prevalence of type 2 diabetes in India
requiring that diabetes drugs demonstrate a
is among the highest in the world with more
cardiovascular benefit for approval. Instead,
they affirmed continued use of reduction in than 28-million cases in 2007. The prevalence
HbAlc as a well-established surrogate for of type 2 diabetes is expected to grow more
approval based upon the microvascular rapidly in India than in any other nation,
benefits that result from controlling glucose. climbing to more than 60 million cases by
10 classes of therapies are available for 2017. Type 2 diabetes is the most common
treating diabetes, all of which were approved form of diabetes. In type 2 diabetes, either the
on the basis of efficacy in lowering HbAlc. body does not produce enough insulin- or the
However, there is no conclusive evidence that cells ignore the insulin.
any of the marketed individual drugs or "WHO's Burden of Disease report states
treatment regimens confers a macrovascular that diabetes is going to grow by 40% in
benefit, the FDA said. Rather than focusing on developed countries, but by 70% in developing
cardiovascular benefit, the committee said it countries. Apart from this rise, there are so
was more important not to increase CV harm.
many undiagnosed people,'" said International
Patients with type 2 diabetes have a two-to
Diabetes Federation vice-president SM
fourfold increased risk of cardiovascular
Sadikot. A study by Mr Sadikot has shown that
mortality compared to those without the
by 2030, the number of rural people suffering
from diabetes will equal those in urban areas.
"The current pre-approval process is Oral diabetic medication generated revenues of
insufficient to rule out CV risk in a disease Rs 1,183 crore in the last year while insulin
where CV morbidity and mortality are so posted sales of Rs 51-1 crore, according to an
prevalent;' said panellist Dr Eric Holmboe, ORG-IMS report. The top players in this
68 Current R&D Highlights, Jan.-Mar. 2009
News & Views
segment include Abbott, USV, Sanofi Aventis, how the formation of insulin-producing cells
Sun Pharma, Nicholas Piramal and Wockhardt. during embryonic development can be
The number of companies looking to enter mimicked by directing stem cells in culture, a
this therapeutic area is also on the rise. "Lots statement said. Besides developing cell therapy
of companies are "looking at entering the for the treatment of insulin-dependent diabetes,
chronic illness space. With a slowing down of the collaboration will in the long term focus on
acute illnesses in larger cities and towns and a cure for type 1 diabetes.
the change in lifestyles, companies who have a (The Economic Times, 27.10.2008)
presence in anti-infectives are also entering the
anti-diabetic space," said Alok Dalal, analyst Too Little Sleep may Raise Diabetes
with Religare. Trying to break into the chronic Risk
illness segment is easier when compared to A good night's sleep may help lower your
CNS (central nervous system) segment, he risk of developing type 2 diabetes, researchers
added. The UK is the first to have taken a step say.People averaging less than six hours of
in this direction. "There are 170 million shuteye during the work week over a period of
diabetic people in the world today and India years were shown to have nearly five times the
accounts for 27% of that. We plan on working chance of developing the disease compared to
with different organisations and countries to those who averaged six to eight hours of sleep,
combat this, India being one of them," said according to research scheduled to be
Ann Keen, UK under secretary of state for presented Wednesday at an American Heart
health, at a diabetes conference in Mumbai. Association conference in Palm Harbor, Fla.
Sujay Shetty, associate director at "This study supports growing evidence of the
PricewaterhouseCoopers, said, "Chronic association of inadequate sleep with adverse
diseases like diabetes are going to be a big health issues. Sleep should be assessed in the
clinical setting as part of well-care visits
market going forward. This segment's
throughout the life cycle," study lead author
contribution to the overall pharmaceutical
Lisa Rafalson, a research assistant professor at
market is going to increase."
the University at Buffalo in New York, said in
(The Economic Times, 18.10.2008) a news release issued by the association. The
study, in which 1,455 people reported on their
Novo Nordisk Enters Pact for Insulin
sleep habits, compared fasting glucose levels
from Stem Cells on people over a six-year period. The results
Novo Nordisk, stem cell biotechnology were based on adjustments made for age, body
firm Cellartis and Swedens Lund University mass index, glucose and insulin
concentrations, heart rate, high blood pressure,
Stem Cell Center have announced a
family history of diabetes and symptoms of
collaborative research agreement to develop depression. The study found no significant
insulin-producing cells from human stem cells. difference in fasting glucose levels or risk of
Novo Nordisk will have exclusive rights to developing type 2 diabetes between those who
further develop and commercialise potential averaged six to eight hours of sleep during
products for the treatment of diabetes while weeknights and those who averaged more than
Cellartis has the rights to further develop and eight hours a night. "Our findings will
hopefully spur additional research into this
commercialise certain other products resulting
very complex area of sleep and illness,"
from the technologies developed under the Rafalson said.
collaboration. Research will be conducted into (Health Day News, March 11, 2009)

Current R&D Highlights, Jan.-Mar. 2009 69

News & Views
Abnormal Heart Rhythm Boosts Death cardiovascular risk factors, such as blood
Risk for Diabetics pressure and cholesterol, controlled more
In people with diabetes, there's a strong aggressively," Patel advised."This is a separate
association between abnormal heart rhythm, or issue from rate and rhythm control [or the use
atrial fibrillation, and increased risk of other of anticoagulants to prevent thromboembolic
heart-related problems and death, according to events], which is the usual therapeutic focus in
a study that included 11,140 patients with AF. These issues are important,
but we believe our data suggest that
people.Researchers found that participants
who had atrial fibrillation (AF) at the start of heightened awareness and management of
the study were 61 percent more likely to die overall cardiovascular risk is also important."
from any cause, 77 percent more likely to die (Health Day News, March 12, 2009)
from cardiovascular causes such as a heart Plasma Fetuin-A Levels and the Risk of
attack or stroke, and 68 percent more likely to Type 2 Diabetes
develop heart failure or other problems such as
stroke.But the study also found that the risk of Type-2 diabetes represents a major global
developing complications or dying was lower public health threat and, together with obesity,
if doctors gave more aggressive treatments to constitutes an important contributor to the
diabetic patients with AF. In this study, predicted decline in life expectancy. The
treatment involved a combination of the blood pathophysiology of Type 2 diabetes is
pressure lowering drugs perindopril and complex: In addition to impaired insulin
indapamide."Active treatment produced secretion from -cells, reduced insulin
similar relative benefits to patients with and sensitivity was found to play a predominant
without AF. However, because of their higher role in the pathogenesis of the disease. Several
risk at the start of the study, the absolute circulating proteins have been shown to be
benefit associated with active treatment was involved in the regulation of insulin sensitivity
greater in patients with AF than without. We such as adiponectin retinol binding protein 4
estimate that five years of active treatment and fetuin-A (former name for the human
would prevent one death among every 42 protein 2-Heremans-Schmid glycoprotein,
patients with AF and one death among 120 AHSG). Fetuin-A is an endogenous inhibitor
patients without AF," noted study leader of the insulin-stimulated insulin receptor
Professor Anushka Patel, director of the tyrosine kinase. Administration of fetuin-A to
Cardiovascular Division at The George rodents inhibited insulin-stimulated styrosine
Institute for International Health at the phosphorylation of the insulin receptor and
University of Sydney in Australia.The insulin receptor substrate-1 in rat liver and
researchers also found that the association skeletal muscle. In addition, fetuin-A knockout
between AF and deaths from cardiovascular mice exhibited increased insulin sensitivity
disease was much stronger in women than in and were resistant to the adipogenic effect of a
men. Women with AF were twice as likely to high-fat diet, supporting the hypothesis that
die as women without AF, while men with AF fetuin-A is involved in the pathophysiology of
were 50 percent more likely to die than men insulin resistance in rodents.
without AF.The findings were published In agreement with these data, we and
March 12 in the European Heart Journal."This others have recently shown that high levels of
study informs clinicians that AF is a marker of circulating fetuin-A are associated with insulin
greater risk of cardiovascular events and resistance in humans, suggesting that fetuin-A
mortality among diabetics, both men and may represent a novel mechanism involved in
women. Such patients should have their the pathophysiology of type 2 diabetes. In the

70 Current R&D Highlights, Jan.-Mar. 2009

News & Views
present study, we investigated whether 20 min 3 days a week. Another important
circulating fetuin-A predicted the incidence of dimension is the time spent in sedentary
type 2 diabetes, independently of established occupations; in the Nurses Health Study, the
risk factors, in the large European Prospective number of hours spent sedentary was related
Investigation into Cancer and Nutrition with incident diabetes even after adjusting for
(EPIC)-Potsdam Study. total physical activity.
(Diabetes, 57, October 2008, p.2762)
Physical activity may decrease the risk of
Physical Activity and Insulin Sensitivity diabetes by increasing insulin sensitivity.
Physical activity is now recognized as a Insulin sensitivity has been shown to increase
major component of type 2 diabetes with physical activity, as assessed by
prevention; cohort studies have documented questionnaire. Objective assessment of
the lower risk of incident diabetes even for physical activity is now possible with
everyday activities such as walking. In a post unobtrusive accelerometer-based motion
hoc analysis of the Finnish Diabetes sensors. The aim of this study was to describe
Prevention Study, walking for exercise for at the relationship between insulin sensitivity, as
least 2.5 h a week in comparison with less than measured by the gold standard
1 h was associated with a 63-69% lower risk of hyperinsulinemic-euglycemic clamp, and
incident diabetes. Physical activity is a habitual physical activity assessed by
complex behavior characterized by intensity, accelerometer; total activity, activity intensity,
duration, and frequency/ Various consensus and time spent in light and sedentary activities.
(Diabetes, 57, October 2008, p.2613)
groups recommend physically active lifestyles
for adults, with an accumulation of at least 30
min of moderate-intensity aerobic physical
activity 5 or more days a week or vigorous-
intensity aerobic physical activity for at least

Dear Readers
We are happy to receive your encouraging response to our
journal. We shall, however, appreciate receiving your critical
comments and suggestions for further improvements. We are
always looking forward to your specific contributions on
various aspects of the journal. The contributions shall be
duly acknowledged.

Current R&D Highlights, Jan.-Mar. 2009 71

R & D Highlights

Cell-based Treatments for Diabetes

Type 1 diabetes mellitus (TlDM) is a post-transplantation period so, to ensure a
single-cell disorder in which insulin-secreting successful outcome, islet transplantation
-cells in pancreatic islets of Langerhans are protocols replace up to 106 primary human
irreversibly destroyed by an autoimmune islets per recipient. A single transplantation
assault, resulting in potentially fatal metabolic may therefore require islets from up to four
dysfunction as a consequence of insufficient donor pancreases. At present, the only suitable
circulating levels of insulin. Since the isolation source of human islets for clinical use is from
of insulin in 1920s the main therapeutic pancreases of heart-beating, brain-dead donors.
approach to T1DM has been insulin This type of organ donor is rare, so current
replacement, but excursions in blood glucose protocols for human islet transplantation are
associated with intermittent insulin delivery unlikely to make a widespread therapeutic
led to a high risk of long-term complications, impact on T1DM, with ~ 105 potential
causing increased morbidity and mortality. recipients in the UK and ~ 106 in the USA.
Recent clinical trials, however, have This clinical need is therefor driving research
demonstrated that transplantation of human into alternative sources of functionally
islets of Langerhans can offer a cure for competent, insulin-secreting -cells as
TlDM. There are extant problems with current substitutes for donor islets in transplantation
transplantation protocols, but the success of therapy.
islet transplants is proof-of-concept that cell- A number of different cells/tissues have
based treatments for T1DM can be effective. been proposed as potential starting material
This review will focus on one major from which to generate transplant material,
impediment to the widespread uptake of
transplantation therapy for TlDM, which is the BOX 1
very limited availability of suitable transplant Potential Sources of -cells for Transplantation Therapy
material. A number of potential sources of material for cell-based therapy of
diabetes have been investigated over the past decade. This lists some
An adult human pancreas contains of the more promising candidates.

approximately 106 islets (~2 x 109 -cells), but o insulin-secreting cell lines
these comprise only a minor part of total o engineered non--cells/gene therapy
o islets/l3-cells from other species
pancreatic tissue (2-3%) so islets for o tissue stem cells
transplantation must be isolated from whole pancreas
bone marrow
pancreas by enzymatic digestion, which is an liver
inefficient process. The clinical symptoms of neural
o embryonic stem cells
diabetes do not usually become apparent until
and some of these are shown in Box 1. The
60-80% of the -cell mass is lost, suggesting
physiological properties required of substit'!te
that glycaemic control can be maintained on
-cells have been considered in detail
20-40% of normal -cell mass. Current
elsewhere but it is worth considering briefly
evidence suggests that a significant fraction of
two essential attributes of such cells. First,
transplanted islets are lost in the immediate
they must be able to synthesise and store

72 Current R&D Highlights, Jan.-Mar. 2009

R & D Highlights
insulin, and to release it in sufficient amounts advantage of using the patient's own tissue as a
to maintain plasma glucose in a narrow range starting material (e.g. fibroblasts), but these
(5-8 mM) in the face of sporadic food intake. engineered cells lack the stimulus recognition
Too much insulin is as potentially lethal as too and response elements that are expressed by
little insulin, so the cells must be able to authentic -cells. Their insulin secretory
respond rapidly to changes in plasma glucose responses are therefore unregulated and are not
in either direction. Pancreatic -cells have responsive to physiologically relevant stimuli
evolved complex stimulus-response coupling such as post-prandial changes in blood
mechanisms to monitor and respond to glucose. There may be some therapeutic
changes in nutrients, hormones and benefit to people with diabetes in having a
neurotransmitters and substitute -cells will low, maintained basal delivery of insulin via
require similar mechanisms to enable a tightly genetically engineered non--cells, but this
regulated release of insulin in response to would at best be an adjunct to, rather than' a
environmental cues. Second, the proliferative replacement for, conventional insulin therapy.
capacity of the replacement cells must be The remainder of this review will therefore
tightly regulated to avoid post-transplantation focus on areas that we consider most likely to
expansion of -cell mass leading to the generate the quantities of cells required for
development of hyperinsulinaemic transplantation while maintaining
hypoglycaemia. This is not a problem when differentiated function - islets from non human
using authenic -cells/islets derived from species and the de novo generation of
human donors because they have an functional -cells from stem cell populations.
exceedingly low proliferative capacity, but it is -Cells from other Species:
a potential drawback when using cells Xenografts to Treat Type 1 Diabetes
generated in vitro from proliferative precursor
populations. Using islets of Langerhans from other
species is an obvious way of providing the
This combination of highly specialised large amounts of functional tissue required for
secretory function and controlled proliferative transplantation therapy of diabetes. Most effort
capacity is a challenging target, and some
in this area has been directed towards using pig
ofthe suggested starting materials (Box 1) fail islets because: (i) Western countries have pre-
to meet one or other of these criteria and so existing facilities for high-throughput
will not be considered in detail in this review. breeding, rearing and slaughtering of pigs
For example, transformed cells derived from (porcine pancreas as a by-product of pork
human -cells offer the potential of generating
production was a source of insulin for treating
in vitro the (thousands of) billions of cells TIDM for many years before recombinant
required for transplantation therapy, and human insulin became widely available); (ii)
insulin-secreting cell lines can be engineered high islet yields can be obtained from porcine
to produce regulated secretory responses. Such pancreas using techniques similar to those for
cells show unregulated proliferation and form human islet isolation; and (iii) pigs are
insulinomas in vivo, and so are unlikely to amenable to genetic modification to make
offer any therapeutic benefit in the foreseeable human insulin or to protect against immune
future. Another suggested source of assault. Two important impediments have
replacement -cells is to engineer non--cells however restricted the widespread use of pig
to make insulin, and this has been done in a islets in humans. First, the hyperimmune
variety of cell types including fibroblasts, response to xenografts has proved difficult to
skeletal muscle, neuroendocrine, kidney and avoid. Numerous attempts to hide the
ovarian cells. This approach has the potential transplanted xenografts from the host immune

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system by islet encapsulation have largely physiological circumstances such as pregnancy
failed to maintain islet viability and insulin and obesity. The origins) of these new -cells
secretory responses over the prolonged periods is important when considering how to expand
required of. transplanted islets. Second, the the -cell mass in or ex vivo. Recent lineage
demonstration that porcine endogenous tracing studies in mice suggest that, under
retroviral (PERV) sequences in the porcine most circumstances including .acute pancreatic
DNA may become activated on regeneration, new -cells arise by a slow but
xenotransplantation raised the possibility of uniform self-renewal of existing -cells.
novel viral infections in humans receiving Bone marrow-derived stem cells
porcine islet implants. Until recently, these
drawbacks made it unlikely that Bone marrow (BM) contains
xenotransplantation would find any major hematopoietic stem cells and mesenchymal
clinical application in the treatment of TIDM. stem cells, both of which exhibit considerable
but several recent developments have placed it developmental plasticity. An initial report that
back in the spotlight. BM stem cells could engraft into pancreatic
islets in vivo and differentiate to an insulin-
Stem Cells as a Source of Substitute - expressing phenotype could not be confirmed
Cells by other groups. More recent reports suggest
The recent explosion of interest in the that BM stem cells reversed experimental
therapeutic potential of stem cells for single diabetes in vivo by enhancing the regeneration
cell disorders such as T1DM has generated and survival of endogenous -cells rather than
much research activity in this area. The article repopulating the islets with trans-differentiated
will focus on recent advances in the generation -cells.
of functional -cells from stem cell Liver progenitor cells
populations, using a broad classification of
stem cells as either tissue stem cells, which are Early studies demonstrating that the
multi potent progenitor cells found in fetal and experimental overexpression of pancreatic
adult tissues, or as embryonic stem cells, transcription factors in hepatic cells in vivo
which are pluripotent, undifferentiated cells produced insulin-expressing cells generated a
generated from the inner cell mass of a great deal of interest in the potential of liver
developing blastocyst and which have the cells as a source of replacement -cells. Liver
potential to differentiate into any tissue in the is relatively accessible for biopsy and has the
embryo. capacity to regenerate and so is a clinically
attractive option for autologous grafting of
Tissue stem cells liver-derived cells in patients with T1DM.
Tissue stem cells are usually considered to Neural stem cells
be lineage-restricted, and to mature into the
differentiated cells of the host tissue/organ, but The use of neural stem cells as -cell
evidence is emerging of trans-differentiation precursors has not been much explored.
into other types of tissue, suggesting that Subpopulations of neurons express functional
disparate tissues may offer sources of elements that are characteristic of -cells,
progenitor cells that have the potential to including ATP-dependent K+ channel SUR1
become insulin-expressing cells. and Kir6.2 subunits, voltage-operated Ca2+
channels, GLUT2 glucose transporters and the
Pancreatic stem cells pancreatic form of glucokinase, and the
The -cell mass increases during developmental pathways of -cells and
development, and changes with (patho) neurons show similarities with many

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transcription factors (e.g. PDX-l, nkx2.2, each of the potential sources of -cells has
nkx6.1, neurogenin-3, NeuroDl/Beta2, Pax4, specific individual advantages and
Pax6 and Isl1) regulating both processes. disadvantages, the balance of which will
Other tissue stem cells eventually determine its clinical usefulness.
Porcine islets have the great advantages of
There have been sporadic reports that being fully functional primary islets, and of
progenitor/stem cells from other tissues can be being available in large numbers, but these are
induced to differentiate intoinsulin-expressing balanced by persistent problems with immune
cells, including cells localised to intestinal rejection and fears of PERV infection in the
epithelium, dermis, spleen, salivary gland and recipient. If these problems can be
blood monocytes. These studies have not convincingly overcome xenotransplantation
always proved to be reproducible, and have may become an effective alternative to human
been reviewed elsewhere islet transplantation. The concept of
Embryonic stem cells autologous grafting of insulin-secreting cells
derived from the patient's own tissue stem cells
Embryonic stem (ES) cells have great (particularly bone marrow or liver) is very
potential in cell/organ replacement therapies attractive, but the early promise of tissue stem
because of two intrinsic properties. First, ES cells in experimental animals has not yet
ce\ls can produce cells of all three embryonic translated into clinically useful material
germ layers (pluripotent). Second, ES cells can because of problems with restricted
proliferate indefinitely in viir.o if they are proliferative capacity, low levels of insulin
maintained in their initial undifferentiated expression and poor, or non-existent, insulin
state, so they are capable of produdng the large secretion. Embryonic stem cells have the
numbers of cells required for transplantation required proliferative capacity, and recent
therapies. Initial attempts to differentiate ES studies have demonstrated the differentiation
cells to insulin-expressing cells used mouse ES of hES cells to an insulin-secreting phenotype
(mES) cells, as did many subsequent studies, without using clinically unacceptable genetic
because mES cells are much easier to obtain modification. It remains to be seen whether
and use than human ES(hES) cells, and current experimental protocols can be refined
because they are not subject to the ethical and and scaled-up to generate enough cells for
legal constraints that accompany hES cells. transplantation therapy, and whether
Concluding Remarks purification methods of sufficient stringency
can be devised to allow the transplantation of
Transplantation therapy offers a novel
the differentiated -cells while ensuring the
treatment for diabetes and the potential gains, absolute exclusion of potentially teratogenic
both clinical and commercial, are enormous. hES cells. For almost a century the only
The availability of unlimited amounts of available treatment for TIDM has been the
functionally competent graft material would administration of exogenous insulin to
allow islet transplantation to evolve from a
suppress hyperglycaemia. It is now a real
restricted, experimental treatment to a more possibility that the next decade will see the
widespread applicability, much as has widespread application of cell-based therapies
happened for other organ transplantation to cure this disorder.
procedures in the past. The problems (Based on the article written by Peter M Jones;
associated with graft immunogenicity and Monica L Courtney; Christopher J Burns and Shanta
autoimmune destruction of engrafted material J Persaud and published in the Drug Discovery Today,
are common to all sources of replacement - Vol. 13 (19-20), October 2008, p. 888)
cells, and beyond the scope of this review, but

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Adipose tissue transplantation may be a nuclear fractions of kidney was prepared for
potential treatment for diabetes, athero- the quantification of oxidative-nitrosative
sclerosis and nonalcoholic steatohepatitis. stress (lipid peroxidation, superoxide
Sanal, Madhusudana Girija et al. dismutase, catalase, non protein thiols, total
Medical Hypotheses nitric oxide), tumor necrosis factor-alpha
Adipose tissue is critical in energy (TNF-[alpha]), tissue growth factor-1beta
homeostasis. Adipose tissue buffers the lipids (TGF-[beta]1), p65 subunit of NF[kappa][beta]
and energy rich compounds which are pumped and caspase-3.Key findings
into the blood stream soon after meals. It After 8 weeks of STZ injection, the rats
senses, signals other organs like liver and brain produced significant alteration in renal
about the energy reserves via adipokines. function, increased oxidative-nitrosative stress,
Adiponectin, the most abundant adipokine has TNF-[alpha], TGF-[beta]1, caspase-3 activity
insulin sensitizing, anti-inflammatory
in cytoplasmic lysate and active p65 subunit of
antiatherogenic and antisteatotic effects. NF[kappa][beta] in nuclear lysate of kidney of
Adipose tissue dysfunction is accompanied by diabetic rats. Interestingly, co-administration
abnormal lipid distribution and storage which of tocotrienol significantly and dose-
contributes to diseases like diabetes, dependently prevented biochemical and
nonalcoholic fatty liver disease and
molecular changes associated with diabetes.
atherosclerosis. Obesity and lipodystrophy are Tocotrienol (100 mg/kg) was demonstrated to
associated with dysfunctional adipocytes. Pre- be more effective than [alpha]-tocopherol (100
adipocytes are easy to isolate and culture. A mg/kg). Moreover, diabetic rats treated with
personalized depot specific liposuction to insulin-tocotrienol combination produced more
remove the inactive adipocytes followed by pronounced effect on molecular parameters as
adipocyte repopulation could be useful in the compared to their respective groups. Taken
treatment of these diseases. (Scienedirect) together, the data reveal that tocotrienol
Attenuation of diabetic nephropathy by modulates the release of profibrotic cytokines,
tocotrienol: Involvement of NFkB signaling oxidative stress, ongoing chronic inflammation
pathway. and apoptosis and thus exerts a marked
Kuhad, Anurag et al. renoprotective effect. (Scienedirect)
Life Sciences An update on preventive and
Diabetic nephropathy is a serious regenerative therapies in diabetes mellitus.
complication for patients with diabetes Reimann, M. et al.
mellitus. Approximately 30-40% of patients
Pharmacology & Therapeutics
with type I and 15% with type II diabetes Type 1A (immune-mediated) and type 2
mellitus develop end stage renal disease. The diabetes mellitus are two of the most common
study was designed to evaluate the impact of severe chronic illnesses, affecting over 230
tocotrienol on renal function and reno- million people worldwide with an estimated
inflammatory cascade in streptozotocin- global prevalence of 5.1%. Although type 1
induced diabetes. Streptozotocin (STZ)- and type 2 diabetes differ greatly in modes of
induced diabetic rats were treated with pathogenesis, these illnesses share a common
tocotrienol (25, 50 and 100 mg/kg), [alpha]- pathology and consequences characterized by
tocopherol (100 mg/kg) or with vehicle form loss of functional beta-cell mass and
5th to 8th weeks. After 8 weeks, urine albumin subsequent dysregulation of carbohydrate and
excretion, urine output, serum creatinine, lipid metabolism. Since therapy for diabetes
blood urea nitrogen, creatinine and urea and the associated complications poses
clearance were measured. Cytoplasmic and enormous public health and economic burdens,

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novel preventive and regenerative therapies produced significant increase in transfer
have emerged in the past decade with the aim latency which was coupled with enhanced
to preserve beta-cell mass and delay the onset acetylcholinesterase activity, increased
of diabetes. The goal of this review is to oxidative-nitrosative stress, TNF-[alpha], IL-
provide a comprehensive overview of current 1[beta], caspase-3 activity and active p65
efforts in the fight against diabetes, and subunit of NF[kappa][beta] in different regions
attempt to document all strategies that have of diabetic rat brain. Interestingly, co-
emerged in clinical studies within the past 25 administration of tocotrienol significantly and
years. First, strategies to identify individuals at dose-dependently prevented behavioral,
risk, ranging from whole-genome scans to biochemical and molecular changes associated
autoantibody screening, will be discussed. with diabetes. Moreover, diabetic rats treated
Second, novel approaches to prevent or delay with insulin-tocotrienol combination produced
the onset of disease will be covered. Particular more pronounced effect on molecular
focus is given on emerging strategies for parameters as compared to their per se groups.
individuals at risk for type 1 diabetes that Collectively, the data reveal that activation of
target T-cell regulation and induction of NF[kappa][beta] signaling pathway is
tolerance, while new pharmaceutical concepts associated with diabetes induced cognitive
in combination with lifestyle interventions are impairment and point towards the therapeutic
discussed within the scope of type 2 diabetes potential of tocotrienol in diabetic
prevention. Lastly, important efforts to halt encephalopathy. (Scienedirect)
disease progression with emphasis on beta cell Can blood glucose self-monitoring
regeneration are presented. (Scienedirect) improve treatment outcomes in type 2
Suppression of NF-[ ][ ] signaling diabetes?
pathway by tocotrienol can prevent diabetes Varanauskiene, Egle et al.
associated cognitive deficits. Diabetes Research and Clinical Practice,
Kuhad, Anurag et al. 82(Suppl.2), S112 (Dec., 15, 2008)
Pharmacology Biochemistry and Behavior Increased cardiovascular risk in diabetes
The etiology of diabetes associated cannot be attributed to the higher prevalence of
cognitive decline is multifactorial and involves classic risk factors.Importance of postprandial
insulin receptor down regulation, neuronal hyperglycemia. Most of the cardiovascular risk
apoptosis and glutamatergic neurotrans- factors have shown to be directly related to the
mission. The study was designed to evaluate degree of postprandial glycemia (PPG). PPG
the impact of tocotrienol on cognitive function should be recognized as a marker for the
and neuroinflammatory cascade in strepto- increased risk of cardiovascular
zotocin-induced diabetes. Streptozotocin- disease.Assessment of targets for glycemia
induced diabetic rats were treated with control. Two important methods available--
tocotrienol for 10 weeks. Morris water maze self-monitoring of blood glucose (SMBG)
was used for behavioral assessment of reveals immediate hour-to-hour blood glucose,
memory. Cytoplasmic and nuclear fractions of while long-term glycemia is assessed by
cerebral cortex and hippocampus were HbA1c. Reducing PPG and glycemia
prepared for the quantification of excursions is as important as lowering fasting
acetylcholinesterase activity, oxidative- plasma glucose and HbA1c
nitrosative stress, tumor necrosis factor-alpha levels.Effectiveness of SMBG. SMBG plays a
(TNF-[alpha]), interleukin-1beta (IL-1[beta]), key role in diabetes care, and has proven to be
NF[kappa][beta] and caspase-3. After effective for insulin treated type 2 diabetic
10 weeks of streptozotocin injection, the rats patients. Debate continues on the effectiveness

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R & D Highlights
of SMBG in non-insulin treated type 2 biomaterials are described using a combination
diabetes. Whether non-insulin treated type 2 of natural polyelectrolytes, with particles
diabetic patients benefit from SMBG, a large- formulated through nanoemulsion dispersion
scale randomized controlled trial with the followed by triggered in situ gel complexation.
follow-up period to investigate long-term Biomaterials meeting these criteria include
effects should be carried out. A general alginate, dextran, chitosan, and albumin in
recommendation is that insulin treated patients which alginate/dextran forms the core matrix
perform SMBG at least three times per day. complexed with chitosan and albumin coat.
SMBG frequency for non-insulin users should Smaller size and higher albumin-based acid-
be individualized to treatment regimen and protective formulation was orally administered
level of control. to diabetic rats and glucose reduction and
Mutations in C2orf37, encoding a physiological response analyzed. Insulin
encapsulation efficiency was 90, 82, and 66%
nucleolar protein, cause hypogonadism,
alopecia, diabetes mellitus, mental for uncoated, chitosan-coated, and albumin-
retardation, and extrapyramidal syndrome. chitosan-coated alginate nanospheres,
Alazami, Anas M. et al. respectively. The choice of coating polymer
The American Journal of Human seems to influence insulin release profile and
to be crucial to prevent peptic digestion.
Genetics, 83(6), 684 (Dec., 12, 2008)
Hypogonadism, alopecia, diabetes Physiological response following oral delivery
mellitus, mental retardation, and showed that insulin albumin-chitosan-coated
extrapyramidal syndrome (also referenced as alginate nanospheres reduced glycemia", 72%
Woodhouse-Sakati syndrome) is a rare of basal values. Albumin serves as an
autosomal recessive multisystemic disorder. important enteric coating providing acid- and
We have identified a founder mutation protease protection enabling uptake of active
consisting of a single base-pair deletion in drug following oral' dosage.
C2orf37 in eight families of Saudi origin. Diabetes mellitus type 1 is a generalized
Three other loss-of-function mutations were disorder of glucose metabolism that is
subsequently discovered in patients of generally attributed to an absence of insulin
different ethnicities. The gene encodes a secretion. The unique treatment remains
nucleolar protein of unknown function, and the periodic insulin
cellular phenotype observed in patient Reduced serum resistin levels in
lymphoblasts implicates a role for the diabetic patients: Study from western India.
nucleolus in the pathogenesis of this disease.
Mahadik, Sujata R. et al.
Our findings expand the list of human Diabetes and Metabolic Syndrome:
disorders linked to the nucleolus and further Clinical Research and Reviews
highlight the developmental and/or Resistin is an adipocyte-derived peptide
maintenance functions of this organelle. that might play a role in obesity and insulin
Polyelectrolyte biomaterial interactions resistance (IR); however, its role in humans is
provide nanoparticulate carrier for oral largely unknown. The aim of the study was to
insulin delivery. elucidate the role of serum resistin and explore
Catarina Pinto Reis et al. its relationship with inflammatory marker C-
Drug Delivery. 15: 127-139, 2008 reactive protein (CRP) and adipocytokine
Nanospheres are being developed for the (leptin, adiponectin) in Indian diabetic
oral delivery of peptide-based drugs such as patients. A total of 171 subjects including 41
insulin. Mucoadhesive, biodegradable, controls, 41 obese and 89 Type 2 diabetes
biocompatible, and acid-protective mellitus (T2DM) patients were recruited in this

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cross-sectional study. Fasting serum resistin, Oxidative stress pathway genes and
leptin, adiponectin, insulin and CRP were chronic renal insufficiency in Asian Indians
measured by enzyme immunoassay. The with Type 2 diabetes.
relation between these variables was studied Tiwari, Arun K. et al.
by univariate and multiple regression analysis. Journal of Diabetes and its
Serum resistin levels were significantly Complications, 23(2), 102 (2009)
reduced in non-obese treated T2DM patients. There are significant regional variations in
In the correlation analysis after controlling for prevalence of diabetes and diabetic chronic
age and BMI authors found that resistin is renal insufficiency (CRI) in India. Oxidative
significantly associated with leptin (0.687, stress plays an important role in the
p < 0.002) and CRP (0.549, p < 0.018) in only development of diabetic complications. To
control females and with CRP (0.642, determine the importance of the
p < 0.01) in T2DM female patients. In multiple polymorphisms in the genes involved in
linear regression analysis resistin was maintenance of cellular redox balance, we
independently predicted by the leptin performed a case control study in subjects
(p < 0.01) and leukocyte (p < 0.004) in from south and north India. Successive cases
controls, treated T2DM patients. Reduced presenting to the study centers with Type 2
resistin and leptin levels in non-obese treated diabetes of >2 years duration and moderate
T2DM and significant association between CRI (n=194, south India 104, north India 90)
these two in control and treated T2DM suggest diagnosed by serum creatinine >=2 mg/dl after
interplay between these two adipocytokines. In exclusion of nondiabetic causes of CRI were
addition, the weak association of resistin with compared with diabetes subjects with no
diabetes indicates that it may be playing an evidence of renal disease (n=224, south India
indirect role in the pathogenesis of T2DM. 149, north India 75). Twenty-six
(Scienedirect) polymorphisms from 13 genes from the
Pregnancy and diabetes scenario oxidative stress pathway were analyzed using
around the world: India. polymerase chain reaction-restriction fragment
Seshiah, Veerasamy et al. length polymorphism. Genes included were
International Journal of Gynecology & superoxide dismutases (SOD1, 2, 3),
Obstetrics, 104(Suppl. 1), S35 (Mar., 2009) uncoupling proteins (UCP1, 2), endothelial
Women with gestational diabetes mellitus nitric oxide synthase (NOS3), glutathione-S-
(GDM) are at an increased risk of developing transferases (GST) (M1, T1, P1), vascular
diabetes in the future, as are their offspring. endothelial growth factor (VEGF),
GDM is not only of clinical relevance, but is paraoxonase (PON) 1 and 2, and nicotinamide
also an important public health issue. A adenine dinucleotide phosphate reduced,
community-based prospective study showed oxidase p22phox. Genes were tested for their
that the prevalence of GDM was 13.9%. association with CRI using [chi]2 test. In south
Authors also observed that the frequency of Indian (SI) subjects there was significant
GDM varied across urban, semi-urban, and allelic and genotypic association of the wild-
rural areas. Based on multiple logistic type allele in SOD2 (Ala9Val; P=.002 and
regression analysis and taking the 3 areas into P=.013, respectively), UCP1 (-112 T>G,
consideration, family history of diabetes, age P=.012 and P=.009; Ala64Thr, P=.015 and
greater than or equal to 25 years, and body P=.004), NOS3 (Glu298Asp, P=.002 and
mass index greater than or equal to 25 were P=.009) and GSTP1 (Ile105Val, P=.003 and
found to have a significant independent P=.004) genes with development of CRI. None
association with GDM (P < 0.001). of these observations were replicated in the
north Indian (NI) subjects. A genotypic but not

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allelic association was observed for two China, India, and Korea.
markers, VEGF (-460 T>C) and PON1 Mohan, Viswanathan et al.
(Arg192Gly) among NI diabetic CRI subjects. Diabetes Research and Clinical
The nonreplication of association suggests Practice,83(1), 106(Jan., 2009)
differential genetic susceptibility of the two The efficacy and safety of sitagliptin as
populations to diabetic chronic renal monotherapy were evaluated in Chinese,
insufficiency. In the SI diabetic subjects, Indian, and Korean patients with type 2
oxidative stress pathway genes might be an diabetes inadequately controlled by diet and
important predictor for the development of exercise. In a randomized, placebo-controlled,
diabetic complications. Further, the association double-blind, 18-week trial, 530 patients with
of wild-type alleles may suggest that they HbA1c >=7.5% and <=11.0% (mean baseline
confer greater survival ability to comorbid 8.7%) received sitagliptin 100 mg once daily
complications and may be nephroprotective. or placebo. Compared with placebo, sitagliptin
Poor vitamin D status may contribute significantly (p < 0.001) reduced mean HbA1c
to high risk for insulin resistance, obesity, (-1.0%), fasting plasma glucose (-1.7 mmol/L),
and cardiovascular disease in Asian Indians. and 2-h postprandial glucose (-3.1 mmol/L),
McCarty, Mark F and a significantly (p < 0.001) greater
proportion of sitagliptin-treated versus
Medical Hypotheses, 72(6), 647 (2009)
Asian Indians are highly prone to insulin placebo-treated patients achieved HbA1c <7%
resistance syndrome, obesity, diabetes, and (20.6% versus 5.3%, respectively) at study
coronary disease. At any given BMI, they tend end. Efficacy of sitagliptin was demonstrated
to have more body fat and more central fat in each country. Sitagliptin was generally well-
than other groups - yet their insulin resistance tolerated. Clinical adverse events (AEs) were
is disproportionately high relative to their body reported in 23.3% and 15.2% of sitagliptin-
composition. They are also tend to have very treated and placebo-treated patients,
poor vitamin D status, even in UV-drenched respectively. The difference was primarily due
India, primarily owing to highly pigmented to increased gastrointestinal AEs in the
skin and a cultural tendency to avoid direct sun sitagliptin group, most of which were mild and
exposure. The resulting up-regulation of resolved on study drug. Serious AEs,
parathyroid hormone (PTH) arguably may play discontinuations due to AEs, and drug-related
a role in their high risk for insulin resistance AEs occurred with a low incidence in both
and associated pathologies. There is suggestive groups. No hypoglycemia was reported. In
evidence that moderate elevations of PTH may conclusion, of the study, sitagliptin
promote insulin resistance, weight gain, monotherapy for 18 weeks significantly
hypertension, left ventricular hypertrophy, and improved glycemic control and was well-
the acute phase response, while increasing risk tolerated in patients with type 2 diabetes from
for ischemic arrhythmias and cardiovascular China, India, and Korea.
mortality. Controlled studies should assess the Low bodyweight Type 2 diabetes in
impact of optimal vitamin D supplementation, India: Clinical characteristics and
with or without added calcium, on risk factors pathophysiology.
associated with insulin resistance in Asian Das, Sidhartha et al.
Indians, as well as in other highly pigmented Diabetes and Metabolic Syndrome:
urbanized ethnic groups that are at high risk Clinical Research and Reviews, 3(1),60 (2009)
for insulin resistance and obesity. Low body weight Type 2 DM/Type 2
Efficacy and safety of sitagliptin in the DM-lean is a distinct clinical entity that is
treatment of patients with type 2 diabetes in neither related clinically or pathophysio-

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logically to LADA nor former fruste of Type 16(23), 10085 (Dec., 1, 2008)
1DM, having absence of markers for Retinopathy is a major cause of blindness
autoimmune destruction of [beta]-cells and in the Western world, while cataract is one of
good insulin and C-peptide reserve for a the three major causes of blindness worldwide.
prolonged period of life. They constitute an Diabetes is one of the major risk factor in
independent variant of Type 2 DM with retinopathy and cataract. The prevalence of
inherent peculiarities of insulin kinetics in the blindness in India is 15 per 1000 while cataract
liver along with altered profile and behaviour alone accounts for 80% of this blindness.
of key enzymes related to carbohydrate Diabetes induced cataract is characterized by
metabolism which are marked by excess an accumulation of sorbitol which is mediated
extraction of insulin in hepatic bed, by the action of a key enzyme aldose reductase
hyperactive cytochrome system and non- (AR). Non-enzymatic glycation (binding of
supressible glucokinase activity. These glucose to protein molecule) induced during
peculiarities are reflected in the peripheral diabetes appear to be the key factor for AR
circulation as states of low circulating levels of mediated sugar-induced cataract. Finger millet
insulin, hyperglycemia, dyslipidemia without polyphenols (FMP) being a major anti-diabetic
low high density lipoprotein cholesterol and antioxidant component, we have evaluated
(HDLc), raised triglycerides (Tg), low levels them for AR inhibiting activity. Phenolic
of plasma homocysteine and BMI below 19 constituents in FMP such as gallic,
make these diabetics less prone to develop protocatechuic, p-hydroxy benzoic, p-
macrovascular disease. Peripheral neuropathy coumaric, vanillic, syringic, ferulic, trans-
and the consequences of poor glycemic control cinnamic acids and the quercetin inhibited
such as increased succeptibility to infections cataract eye lens effectively, the latter was
and endothelial dysfunction manifesting as more potent with an IC50 of 14.8 nM.
proteinuria dominate the clinical picture. In Structure function analysis revealed that
view of more of infective complications and phenolics with OH group at 4th position was
coexistent severe hyperglycemia (glucose important for aldose reductase inhibitory
toxicity) many of these diabetics may not property. Also the presence of neighboring O-
respond to OHA adequately at the initiation of methyl group in phenolics denatured the AR
therapy. However, due presence of insulin activity. Finger millet seed coat polyphenols
resistance and good []-cell reserve for insulin, (SCP) has been found to inhibit AR reversibly
despite of lean habitus, most of them respond by non-competitive inhibition. These results
well to OHA for long periods of life, as may thus, provide a stronger evidence for the
be comparable with any other phenotype of potentials of FMP in inhibiting
Type 2 diabetes. The insulin resistance cataractogenesis in humans.
observed in Type 2 DM-lean is not consequent Prevalence of diabetes mellitus and
to anthropometric parameters like central other abnormalities of glucose tolerance in
obesity and WHR as these diabetics are lean young adults aged 20-40 years in North
with poor fat depot and thus it could be an India (Kashmir Valley).
integral part of the pathogenic mechanism of Zargar, Abdul Hamid et al.
Type 2 DM per se. Diabetes Research and Clinical Practice,
Inhibition of aldose reductase from 82(2), 276 (Nov., 2008)
cataracted eye lenses by finger millet To assess the burden of type 2 diabetes
(Eleusine coracana) polyphenols. mellitus (T2DM) and other abnormalities of
Chethan, S. et al. glucose tolerance in young-adult (20-40 years)
Bioorganic & Medicinal Chemistry, men and non-pregnant women. prevalence of

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diagnosed T2DM, undiagnosed T2DM and analysis.
other abnormalities of glucose tolerance High prevalence of type 2 diabetes
studied in 3032 subjects from Kashmir Valley mellitus in affluent urban Indians.
of India. The study included a questionnaire, Boddula, R et al.
anthropological measurements, blood Diabetes Research and Clinical Practice,
sampling, and a standard OGTT. Eight (0.3%) 81(2), e4 (Aug., 2008)
of surveyed subjects were previously The highest prevalence of type 2 diabetes
diagnosed to have diabetes. Of 3024 subjects
mellitus in developing countries occurs in the
screened, prevalence of diabetes, impaired upper socio-economic group, but this has not
glucose tolerance (IGT), and impaired fasting been well documented in Indians. The age and
glycemia was 2.5%, 2.0%, 11.9% and 26.7%, sex standardized prevalence of diabetes in
respectively. Overall, age-adjusted prevalence 1112 affluent adult Indian subjects was 21.1%.
of T2DM (known plus unknown), IGT, IFG
This is the highest prevalence of diabetes
(WHO) and IFG (ADA) was 2.4% (95% CI: reported from India.
1.9-3.0), 1.6% (95% CI: 1.3-2.2), 11.1% (95%
CI: 10.0-12.3), and 25.2% (95% CI: 23.7- Global diabetes landscape--type 2
26.8), respectively. The difference in diabetes diabetes mellitus in South Asia:
prevalence was significant by age, habitat, Epidemiology, risk factors, and control.
family history of diabetes and BMI. The ratio Gupta, Rajeev et al.
of known-to-unknown diabetes was 1:10. This Insulin, 3(2), 78 (Apr., 2008)
is the first large scale study from North India Type 2 diabetes mellitus (DM) is a new
on prevalence of type 2 diabetes in the younger epidemic in South Asia and is the result of
age group of 20-40 years. Abnormal glucose societal influences and changing lifestyles.
tolerance including undiagnosed T2DM is Epidemiologic studies suggest that the
common in young adults. prevalence of DM has increased exponentially
in urban and rural populations. This study was
Synthesis and elucidation of absolute conducted to determine trends in the
stereochemistry of salaprinol, another prevalence of DM in various countries in
thiosugar sulfonium sulfate from the
South Asia. We performed an extensive,
ayurvedic traditional medicine Salacia systematic MEDLINE search for primary
prinoides. articles that reported on the epidemiology of
Tanabe, Genzoh et al. DM in South Asia. Additional articles were
Tetrahedron, 64(43), 10080 (Oct., 20, obtained from personal collections and
references cited in the primary articles. No
Synthesis and elucidation of absolute formal meta-analysis was performed because
stereochemistry of salaprinol (3) isolated from of differing methodologies and diagnostic
the root and stems of Salacia prinoides, which criteria. Epidemiologic studies conducted in
has been used for the treatment of diabetes in India during the 1960s and 1970s, using
India, Sri Lanka, and Southeast Asia countries, random and postload blood glucose
is described. Compound 3 and its 2'-epimer, estimations, reported DM in 1% to 4% of
epi-salaprinol (epi-3) were synthesized via the urban populations and 1% to 2% of rural
coupling reaction of a cyclic sulfate, 2-O- populations. More standardized epidemiologic
benzylglycerol 1,3-cyclic sulfate (5), with a studies in adults since the late 1980s reported
thiosugar, 1,4-dideoxy-1,4-epithio-d-arabinitol DM in 5% to 15% of urban populations, 4% to
(6), as the key reaction, and S configuration of 6% of semiurban populations, and 2% to 5%
the asymmetric center in the side chain of 3 of rural populations. A significantly increasing
was elucidated by the X-ray crystallographic trend has been observed in urban populations

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(exponential trend R2 = 0.74), whereas the population was 47%, GAD65 antibodies was
increase is slower (R2 = 0.29) in rural positive in 42 (41.2%) and IA-2 in 21 subjects
populations. The diabetes scenario is similar in (20.6%). A total of 14.7% (n = 15) TIDM
other South Asian countries. Current subjects showed both GAD65 plus IA-2
prevalence rates are 5% to 16% in urban areas autoantibody positivity. Comparison between
and 2% to 8% in rural areas. Risk factors for GAD65 positive and GAD65 negative groups
DM in this region are increasing sedentariness, showed younger age of onset, low BMI and
dietary excess, obesity (especially high waist- decreased C-peptide. GAD65 positivity alone
to-hip ratio), low birth weight, and genetic was associated with 6.39 times risk, IA-2
influences. DM is a major public health autoantibodies positivity with 5.4 times risk of
problem in South Asia. The prevalence is developing TIDM. Risk increased to 7.6 times
higher in urban areas than in rural areas and is of control population, when both
increasing. Population-based measures to autoantibodies were positive. Prevalence of
control the epidemic of DM include avoidance autoantibodies in TIDM and control group is
of adiposity through enhanced physical much less than that of western population
activity and regulated calorie intake. A suggesting heterogeneous nature of a young
comprehensive national chronic care program diabetic population with substantial percentage
is needed. of patients having non-immune type 1B
Prevalence of autoantibodies and risk diabetes. Despite low positivity, islets cell
estimation of development of youth onset autoimmunity plays dominant role in young
type 1 diabetes in northern India. TIDM of north India.
Ahmad, Jamal et al. Impact of metabolic abnormalities for
Diabetes and Metabolic Syndrome: beta cell function: Clinical significance and
Clinical Research and Reviews,2(1), 59 (Feb., underlying mechanisms.
2008) V. Grill et al.
Autoantibodies to islet cell antigens such Molecular and Cellular Endocrinology,
as insulin (IAA), the 65-kDa isoform of 297, 86-92 (2009)
glutamate decarboxylase (GAD65) and the It is firmly established that poor metabolic
protein tyrosine phosphatase (PTP) like control in diabetes inhibits beta cell function.
antigen IA-2 are markers of the autoimmune Chronic hyperglycaemia is probably the most
process preceding type 1 diabetes (T1DM) and important factor, exerting both primary
may help to predict the rapid decrease in negative effects (by glucose per se and/or
residual [beta]-cell function. The present metabolites) and secondary ones (by beta cell
investigation was undertaken to evaluate the exhaustion). Dyslipidemia in diabetes
relation between GAD65 and IA-2 in children aggravates the glucose effects both by
with newly diagnosed T1DM and to compare inducing insulin resistance and by direct
the frequency and levels of autoantibodies with effects on beta cells. Much experimental and
clinical characteristics. A total of 102 T1DM some clinical evidence indicates that therapies
subjects (age at onset <30 years; mean that promote beta cell rest such as early and
duration of disease 6.7 2.8 years) from north intensive insulin treatment and K-ATP channel
India were characterized by serological blockers can be beneficial.
determination of the islet cell antibodies, Proteomics in diabetes research.
GAD65 and IA-2. One hundred and two age Tea Sundsten et al.
and sex matched non-diabetic subjects of the Molecular and Cellular Endocrinology,
non-diabetic parents served as control. 297, 93-103 (2009)
Prevalence of autoantibodies in diabetic Both type 1 and type 2 diabetes mellitus

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are heterogeneous diseases with alterations in metabolic impairment inducing an epigenetic
many genes and their products. Not all programming of the pancreas (decreased beta-
transcriptional alterations lead to protein cell neogenesis and/or proliferation) which is
changes, which makes it very important to, in transmitted to the next generation; and (iii)
conjunction with mRNA expression studies, loss of beta-cell differentiation due to chronic
also address changes in cellular protein levels. exposure to hyperglycemia/hyperlipidemia,
Various proteomic techniques are available for inflammatory mediators, oxidative stress and
measuring many protein changes to perturbed islet microarchitecture.
simultaneously. Many proteomic studies have Oscillatory control of insulin secretion
been performed in the context of diabetes Anders Tengholm et al.
research, with the aims of both describing the Molecular and Cellular Endocrinology,
healthy tissue and to unravel the complex 297, 58-72 (2009)
pathophysiology behind the disease. In
Pancreatic -cells possess an inherent
addition, effects on proteins induced by ability to generate oscillatory signals that
different treatments have also been trigger insulin release. Coordination of the
investigated using proteomic approaches. In secretory activity among -cells results in
this paper the field of diabetes proteomics pulsatile insulin secretion from the pancreas,
today will be reviewed. Findings from
which is considered important for the action of
proteomic studies investigating pancreatic the hormone in the target tissues. This review
islets and -cells as well as serum, fat, skeletal focuses on the mechanisms underlying
muscle and liver are described. oscillatory control of insulin secretion at the
The GK rat beta-cell: A prototype for level of the individual -cell. Recent studies
the diseased human beta-cell in type 2 have demonstrated that oscillations of the
diabetes? cytoplasmic Ca2+ concentration are
B. Portha et al. synchronized with oscillations in -cell
Molecular and Cellular Endocrinology, metabolism, intracellular cAMP concentration,
297, 73-85 (2009) phospholipase C activity and plasma
Increasing evidence indicates that membrane phosphoinositide lipid
decreased functional beta-cell mass is the concentrations. There are complex
hallmark of type 2 diabetes (T2D) mellitus. interdependencies between the different
Nowadays, the debate focuses on the possible messengers and signalling pathways that
mechanisms responsible for abnormal islet contribute to amplitude regulation and shaping
microenvironment, decreased beta-cell of the insulin secretory response to nutrient
number, impaired beta-cell function, and their stimuli and neurohormonal modulators.
multifactorial aetiologies. This review Several of these pathways may be important
illustrates to what extend the GotoKakizaki pharmacological targets for improving
rat, one of the best characterized animal pulsatile insulin secretion in type 2 diabetes.
models of spontaneous T2D, has proved be a Growth hormone signaling in
valuable tool offering sufficient commonalities pancreatic -cellsCalcium handling
to study these aspects. Authors have proposed regulated by growth hormone
that the defective beta-cell mass and function Fan Zhang et al.
in the GK model reflect the complex Molecular and Cellular Endocrinology,
interactions of multiple pathogenic players: (i) 297, 50-57 (2009)
several independent loci containing genes Deficiency in insulin secretion is a
responsible for some diabetic traits (but not fundamental part in the pathogenesis of all
decreased beta-cell mass); (ii) gestational forms of diabetes, determined by impaired

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secretory function and inadequate -cell mass. control of whole body metabolic homeostasis,
Growth hormone (GH) is a multifunctional the regulation of the enzyme by upstream
hormone, involved in cellular metabolism, kinases, and its molecular structure. These new
mitogenesis and differentiation. In pancreatic studies and earlier work arguably propel
islets, GH is involved in maintaining -cell AMPK, and perhaps related family members
mass, stimulating islet hormone production into a super league of potential therapeutic
and insulin secretion, and, therefore, plays a targets for maladies including diabetes, cancer,
role in maintaining normal insulin sensitivity heart disease, and obesity. In this article
and glucose homeostasis. The intracellular authors have discussed some of these recent
events that convey the GH signal into various advances, focussing on the role of this and
cellular responses remain incompletely related enzymes in the control of pancreatic -
understood. In this review, we discuss GH cell function and glucose homeostasis.
signaling in the -cells, with emphasis on Ca2+
Mitochondrial dysfunction in
handling and insulin secretion regulated by pancreatic -cells in Type 2 Diabetes.
human GH (hGH). hGH-stimulated rise in Hindrik Mulder et al.
[Ca2+]i is dependent on extracellular Ca2+ and Molecular and Cellular Endocrinology,
is mediated by Ca2+-induced Ca2+ release 297, 34-40 (2009)
(CICR) in the -cell. This process is triggered
Mitochondrial metabolism controls insulin
by hGH-stimulated activation of the non- secretion from the pancreatic -cell. Type 2
receptor tyrosine kinases JAK2 and c-Src, Diabetes evolves when the -cells fail to
which causes tyrosine phosphorylation of release appropriate amounts of insulin, causing
RyRs, resulting in sensitization of CICR. The metabolic dysregulation and hyperglycemia. It
rise in [Ca2+]i elicited by hGH is associated is attractive to assume that mitochondrial
with an enhanced insulin secretion, effects that dysfunction plays a decisive role in these
are mediated mainly through the prolactin processes. Indeed, while being a rare
receptor. These mechanisms indicate that a rise condition, genetically determined dysfunction
in [Ca2+]i elicited by activation of PRLR is of mitochondria causes a Type 2 Diabetes-like
JAK2-dependent and is associated with syndrome. Here, In this article authors have
enhanced insulin secretion. In contrast, GH reviewed what is known about mitochondrial
receptor-mediated increase in [Ca2+]i is JAK2- dysfunction in the -cell in Type 2 Diabetes.
independent and is dissociated from insulin The focus is on observations in humans but
secretion. relevant studies in animal models of the
The AMP-regulated kinase family: disease are discussed. A particular emphasis is
Enigmatic targets for diabetes therapy. placed on changes in metabolic enzymes and
Guy A. Rutter et al. function in -cell mitochondria and how
Molecular and Cellular Endocrinology, altered structure of the organelle appears to
297, 41-49 (2009) facilitate its function. These molecular
AMP-activated protein kinase (AMPK) is processes are subject to tight genetic as well as
a widely conserved Ser/Thr-specific protein epigenetic control. Variations and implications
kinase, homologous to Saccharomyces of these mechanisms are reviewed. The
cerevisiae Snf1, and involved in nutrient emerging picture is that alterations in
sensing in lower organisms. In 2003, authors mitochondria may be a culprit in the
reviewed the role of this enzyme in glucose pathogenetic processes culminating in Type 2
homeostasis in mammals. In the subsequent 5 Diabetes. Such processes may prove to be
years, dramatic strides have taken place in our targets for therapeutic interventions in the
understanding of the role of AMPK in the disease.

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The importance of RNA binding Regulation of beta cell replication
proteins in preproinsulin mRNA stability Ying C. Lee et al.
Rikard G. Fred et al. Molecular and Cellular Endocrinology,
Molecular and Cellular Endocrinology, 297, 18-27 (2009)
297, 28-33 (2009) Beta cell mass, at any given time, is
A dynamic production of insulin is governed by cell differentiation, neogenesis,
necessary for proper glucose homeostasis. In increased or decreased cell size (cell
order to generate enough insulin available for hypertrophy or atrophy), cell death (apoptosis),
exocytosis in response to the demands of the and beta cell proliferation. Nutrients,
organism, the level of preproinsulin mRNA in hormones and growth factors coupled with
the pancreatic -cell needs to fluctuate. In their signalling intermediates have been
animal models for type 2 diabetes the contents suggested to play a role in beta cell mass
of preproinsulin mRNA are lowered, which regulation. In addition, genetic mouse model
might suggest that an impaired metabolism of studies have indicated that cyclins and cyclin-
preproinsulin mRNA contributes to the dependent kinases that determine cell cycle
development of glucose intolerance and progression are involved in beta cell
diabetes. Thus, it is of importance to replication, and more recently, menin in
understand the mechanisms by which association with cyclin-dependent kinase
preproinsulin mRNA levels are regulated. inhibitors has been demonstrated to be
Although extensively studied, there are aspects important in beta cell growth. In this review,
of the regulation of insulin gene expression authors highlight some aspects of cell cycle
that still remain enigmatic. Our understanding regulation in relation to beta cell replication.
of insulin gene transcription has improved The role of cell cycle regulation in beta cell
considerably the last 20 years, but less effort replication is mostly from studies in rodent
has been invested into the control of models, but whether these findings can be
preproinsulin mRNA stability. The extended to human beta cells remains to be
preproinsulin mRNA has a long half-life and shown.
changes in preproinsulin mRNA stability, Genetic dissection of type 2 diabetes.
induced by glucose, are likely to be regulated Martin Ridderstrale et al.
through specific mechanisms. Recent findings Molecular and Cellular Endocrinology,
indicate that the polypyrimidine tract-binding 297, 10-17(2009)
protein (PTB), also named hnRNP I, by Compared to the successful probing of
binding to the 3-UTR (untranslated region) of genetic causes of monogenic disorders,
the preproinsulin mRNA molecule, stabilizes dissecting the genetics of complex polygenic
the messenger, thereby participating in the diseases has until recently been a fairly slow
glucose-induced increase in preproinsulin and cumbersome process. With the
mRNA. Both recent findings pertinent to PTB introduction of whole genome wide
function in general, and on the specific role of association studies (WGAS) the situation
PTB on the production of insulin in -cells dramatically changed in 2007. The results
have been discussed in the review. The from several recent WGAS on type 2 diabetes
putative co-operativity between PTB and other (T2D) and obesity have identified at least
proteins in the control of preproinsulin mRNA eighteen genes consistently associated with
stability, and review -cell signaling events T2D. Many of the genes implicate pancreatic
that may control the mRNA stabilizing effect
beta-cell function in the pathogenesis of T2D
of PTB. whereas only one clearly associate with insulin
resistance. The identified genes most likely

86 Current R&D Highlights, Jan.-Mar. 2009

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merely represent the tip of the iceberg in the examined the effect of insulin on the
explanation behind T2D. Refined tools will transcriptional activity of NF-B, which
have to provide a more complete picture of the mediates the expression of a variety of
genetic complexity of T2D over the next few inflammation/coagulation-related genes using
years. In addition to common variants hepatocyte cell lines in vitro. Authors found
increasing susceptibility for the disease, rare that insulin (1 nM) alone caused minimal
variants with stronger effects, copy number increase in NF-B-mediated transcription. On
variations, and epigenetic effects like DNA the other hand, when cells were
methylation and histone acetylation will simultaneously treated with proinflammatory
become important. Nevertheless, today we are cytokines such as TNF, the following dual
able for the first time to anticipate that the effect of insulin was observed: short-term (6 h)
genetics of a complex disease like T2D really suppressive, and long-term (36 h or later)
can be dissected. stimulatory effects. The former effect was
Fetal programming of glucoseinsulin transient and appears to be mediated by the
metabolism phosphatidylinositol 3 kinase (PI3K) signaling
R. Huw Jones et al. pathway. The latter effect, in contrast, was
Molecular and Cellular Endocrinology, more pronounced, enhancing the TNF-
stimulated NF-B-dependent transcription by
297, 4-9 (2009)
Epidemiological studies have shown a link more than sevenfold. This positive effect was
between poor fetal growth and increased risk NF-B-specific, and was eliminated by
of developing type 2 diabetes. These mitogen-activated protein kinase (MAPK)
observations are highly reproducible in many inhibitors. Altogether, our data suggest that
populations worldwide although the insulin has short-term anti-inflammatory but
mechanisms behind them remain elusive. The long-term proinflammatory effects. From a
Thrifty Phenotype Hypothesis was proposed clinical standpoint, this implies that low basal
to explain the underlying causes of these and periodically high plasma insulin is
relationships. Animal models of poor beneficial, whereas a sustained rise in plasma
intrauterine nutrition have been utilised to help insulin, as often seen in patients with obesity,
to define the causal factors and identify the may induce atherothrombotic disorders,
molecular mechanisms. Programmed changes because of the NF-B-mediated
in beta cell function and insulin action have overexpression of proinflammatory/ proco-
been a common feature of animal models of agulant/ antifibrinolytic proteins in the liver.
poor intrauterine nutrition. Fundamental Inhibition of DPP-4: a new therapeutic
underlying mechanisms are starting to emerge, approach for the treatment of type 2
including changes in the epigenotype and diabetes.
mitochondrial function Pratley, Richard E. et al.
Insulin exhibits short-term anti- Current Medical Research and Opinion
inflammatory but long-term (2007), 23(4), 919-931.
proinflammatory effects in vitro. A review. Background: Glucagon-like
Yasumasa Iwasaki et al. peptide-1 (GLP-1) and glucose-dependent
Molecular and Cellular Endocrinology, insulinotropic polypeptide (GIP) are hormones
298, 25-32 (2009) secreted by the enteroendocrine cells of the gut
Although insulin is indispensable for in response to the ingestion of nutrients. These
maintaining glucose homeostasis, it is still incretin hormones, so called because they
controversial whether or not a high increase insulin secretion, are key modulators
concentration of insulin is deleterious. Authors of pancreatic islet hormone secretion and, thus,

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glucose homeostasis. The glucoregulatory English language were evaluated and selected
effects of incretins are the basis for new based upon consideration of their originality,
therapies currently being developed for the relevance, and frequency of citation. Findings:
treatment of type 2 diabetes mellitus (T2DM). DPP-4 inhibitors are a new class of
Drugs that inhibit dipeptidyl peptidase-4 antidiabetogenic drugs that provide
(DPP-4), a ubiquitous enzyme that rapidly comparable efficacy to current treatments.
inactivates both GLP-1 and GIP, increase They are effective as monotherapy in
active levels of these hormones and, in doing
patients inadequately controlled with diet and
so, improve islet function and glycemic control exercise and as add-on therapy in combination
in T2DM. Scope: In this review, we briefly with metformin, thiazolidinediones, and
describe (1) the role of pancreatic islet insulin. The DPP-4 inhibitors are well
dysfunction in the onset and progression of tolerated, carry a low risk of producing
T2DM, (2) the rationale for developing drugs
hypoglycemia, and are wt.-neutral. The long-
that enhance incretin activity, (3) the evidence term durability of effect on glycemic control
that inhibition of DPP-4 is effective in and -cell morphol. and function remain to be
ameliorating islet dysfunction and improving established. Conclusions: Islet cell
glycemic control in T2DM, (4) the efficacy, dysfunction is central to the pathogenesis of
safety, and tolerability of DPP-4 inhibitors as
T2DM. Incretin-based therapies, including
monotherapy and in combination with other GLP-1 analogs and DPP-4 inhibitors, have
antidiabetic agents, and (5) the potential utility been shown to restore glucose homeostasis and
of DPP-4 inhibitors relative to existing oral improve glycemic control. The DPP-4
antidiabetic agents and newer antidiabetic inhibitors, which can be used as monotherapy
drugs in the pipeline. The review is based upon or in combination with other antidiabetic
MEDLINE literature searches (1966-August drugs, are a promising new treatment option,
2006) and abstrs and presentations from the esp. for patients with early-stage T2DM and
American Diabetes Assocn. Scientific Sessions more severe hyperglycemia.
(2002-2006) and the European Assocn. for the
Study of Diabetes Annual Meetings (1998-
2006). Basic science, preclin., and clin.
studies and review articles published in the

Views expressed in the journal are those of the authors and the
Editorial Board/Publisher takes no responsibility for the same. We are
a secondary abstracting service and the veracity of information is of
the source quoted and not our primary responsibility.

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Risk Factors and Complications of Diabetes

Introduction diagnosis and then at regular intervals over the
Diabetes is a complex metabolic condition next 10 years. It was found that there was a
that requires meticulous management and a marked decrease in iGFR in the first year of
global approach. Poor management and control diagnosis of type 2 diabetes, followed by a
of diabetes often lead to poor disease subsequent more modest rate of decline in
outcomes. The management of diabetes and its iGFR.
complications presents an increasing challenge Cardiovascular Disease
to healthcare systems throughout the world. Cardiovascular disease is the main cause
New findings regarding complications of of mortality in patients with diabetes, and risk
diabetes, their prevalence and incidence, and reduction is an important goal in the treatment
risk factors involved were discussed at the of diabetes. In individuals, little is known
Annual Professional Conference of Diabetes about the importance of progressive change or
UK, held March 5-7, 2008, in Glasgow, U.K. variability over time in risk factors for
Various risk factors associated with atherosclerotic vascular disease. Data have
diabetes includediabetic nephropathy, shown a significant increase for major
cardiovascular disease, diabetic neuropathy, cardiovascular events and procedures in
diabetic retinopathy, hypoglycemia, metabolic subjects with type 2 diabetes..
syndrome, musculoskeletal disease hypo- Endothelial dysfunction, carotid intima-
glycemia, chronic liver diseases and coronary media thickness (CIMT) and lipoprotein
heart disease. abnormalities are factors contributing to
Diabetic Nephropathy cardiovascular disease. One study found that
Diabetes and hypertension are major risk abnormalities in flow-mediated dilatation and
factors for the development of end-stage renal CIMT are present in young type 1 diabetic
disease. Increased albumin excretion is seen in patients and correlate well with lipoprotein
the early stage of diabetic nephropathy before abnormalities. The PREDICT study measured
the coronary artery calcification score (CACS)
the glomerular filtration rate decreases.
Microalbuminuria, macroalbuminuria and end- and found it to be a powerful predictor of
stage renal disease are all associated with an cardiovascular events in asymptomatic patients
increased risk of death. People with chronic with type 2 diabetes.
kidney disease have a greater risk of Both metabolic syndrome and type 2
developing cardiovascular disease and diabetes are associated with a high
diabetes, as seen in a multiethnic population. cardiovascular risk due to clustering of
Patients with type 2 diabetes are at risk of atherothrombotic risk factors such as insulin
developing chronic kidney disease. The resistance, dyslipidemia, hypertension,
isotopic glomerular filtration (iGFR) rate was hypercoagulability and dysglycemia. Insulin
measured in type 2 diabetic patients at resistance in type 2 diabetic patients may be

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responsible for hypertension and dyslipidemia. Individuals with features of metabolic
It was found that prehypertension is associated syndrome and an increased risk of
with obesity but not specifically with insulin cardiovascular disease are found to have
resistance or metabolic syndrome. Although reduced functional vasodilatory reserve and
the majority of type 2 diabetic patients are this impaired response may contribute to
obese, the body mass index was found to be a decreased insulin sensitivity and glucose
poor discriminator of cardiovascular risk in uptake by muscle. Oxidative stress markers
these patients. such as whole-blood reduced glutathione and
Ischemic heart disease (IHD) is the most the ratio of reduced and oxidized glutathione
frequent macroangiopathic complication and may be integrally related in the etiology of the
the main cause of death in subjects with type 2 vasculopathy exhibited by type 2 diabetic
diabetes. Myocardial infarction often occurs in patients. Another interesting survey suggested
that arterial function deteriorates more rapidly
type 2 diabetic patients with no previous
cardiac symptoms. Diabetes is an important in mothers with gestational diabetes and
determinant of death after acute myocardial continues to do so postpartum, despite
infarction (AMI) and adversely affects the resolution of glucose intolerance.
outcome after AMI. Another study found Angiogenesis occurs within
hypertension to be a risk factor for IHD in a atherosclerotic plaques and a study
Scottish type 1 diabetic population and high- investigated the effects of thrombin on key
density lipoprotein (HDL) was found to have a aspects of angiogenesis such as cell
protective effect against cardiovascular proliferation, vascular tubule formation and
disease. expression of pro- and antiangiogenic
regulators. The investigators found that
Endothelial dysfunction leads to
atherosclerosis, which is the leading cause of thrombin stimulates vascular smooth muscle
macrovascular complications and death in cell proliferation, but attenuates endothelial
patients with type 2 diabetes. Investigations cell-mediated growth of vascular tubules and
within the endothelium have been limited by branching of new vascular structures.
access until the recent development of a new Osteoprotegerin, an anti resorptive agent
technique to sample cells from a forearm vein in bone, is present in the systemic vasculature.
in humans. It is normally high after menopause as a
Type 2 diabetes is associated with compensatory mechanism for excessive bone
increased vascular superoxide levels and turnover. The level of osteoprotegerin is also
impaired endothelial function. Researchers high in type 2 diabetic patients. The earlier rise
from Glasgow examined the effect of diabetes and loss of the normal postmenopausal rise
on vascular superoxide production in patients may represent an underlying premature
undergoing coronary artery bypass graft. They vascular inflammatory process in diabetic
concluded that reduced superoxide production patients.
in patients with type 2 diabetes may be Adiponectin is an adipocytokine with
attributable to increased use of modifiers of the favorable metabolic and vascular effects. High
angiotensin system and oral hypoglycemic adiponectin levels are consistently associated
agents. Thus, other factors such as impaired with a lower diabetes risk. However, evidence
smooth muscle function and reduced from studies linking total adiponectin and
endothelial nitric oxide generation may be vascular disease indicate no clear association.
responsible for impaired endothelium Diabetic Neuropathy
dependent vasorelaxation in diabetes.
Neuropathy in diabetic patients is a major
90 Current R&D Highlights, Jan.-Mar. 2009
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source of morbidity. The pathogenesis of surrogate measure of somatic neuropathy and
diabetic neuropathy remains poorly found to be useful in diagnosing and following
understood. Diabetic peripheral neuropathy is the progression of diabetic neuropathy in
a common and debilitating consequence of relation to risk factors. A study from London
diabetes. There are established risk factors for revealed that Contact Heat Evoked Potential
the development of peripheral neuropathy in Stimulator, which is a practical, rapid and
patients with diabetes, such as poor glycemic noninvasive clinical tool, can be used to evoke
control and hypertension. Increasing subject recordable potentials for the diagnosis of
height was found to be associated with an small-fiber neuropathy. Another study
increased long-term risk of developing suggested that mRNA for neuron-specific
neuropathy in type 1 diabetic patients who enolase may be a useful marker for diabetic
participated in the DCCT follow-up study. In neuropathy .
type 1 diabetic patients, the additional
Autonomic neuropathy is another
diagnosis of celiac disease appears to lead to important complication of diabetes that is
poorer nerve conduction even when associated with increased mortality. However,
controlling for glycemic control. it is often not diagnosed until advanced
Depression may be a major confounder of symptoms occur. Spectral analysis of heart rate
outcomes in clinical trials in diabetic variability is a novel technique that detects
peripheral neuropathy. Subjects with even autonomic dysfunction in diabetes in the very
moderate levels of depression are more likely early stages. It can also be used as a measure
to have higher baseline pain scores and to of peripheral neuropathy, as well as a marker
respond favorably to any intervention, whether of long-term risk. Spectral analysis of heart
placebo or active. rate variability and baroreceptor sensitivity in
Although there is an increased propensity combination may detect early autonomic
for the development of carpal tunnel syndrome dysfunction in young adults with type 1
in people with diabetes, the basis for this has diabetes.
not been established. Increased upregulation of Diabetic Retinopathy
hypoxia-inducible factor 1 (HIF-1), Digital retinal screening was performed in
vascular endothelial growth factor (VEGF) and both type 1 and type 2 diabetic patients to
vascular endothelial growth factor receptor 2 measure the prevalence of diabetic retinopathy.
(VEGFR2), suggestive of increased hypoxia The prevalence rate for diabetic retinopathy in
and vascular permeability, was found in type 2 diabetic patients on oral hypoglycemic
diabetic patients with established carpal tunnel drugs appeared to be lower than in other
syndrome. population studies. Visual acuity was well
In an animal study, glycation adducts were preserved and type 2 diabetic patients
found in the extracellular matrix of the sciatic receiving insulin were at high risk of diabetic
nerve of streptozotocin-induced diabetic rats, retinopathy, particularly maculopathy. A
which may contribute to decreased retrospective analysis found that the
regeneration of sensory neurons, leading to prevalence of sight-threatening maculopathy is
peripheral neuropathy. highest in eyes with sight-threatening diabetic
The accurate quantification of diabetic retinopathy and negligible in eyes with screen-
neuropathy is important to define at-risk negative retinopathy.
patients and anticipate deterioation. Corneal A study from London indicated that sleep-
confocal microscopy is a rapid, noninvasive disordered breathing, which is quite common
technique that has been shown to be a reliable in type 2 diabetic patients, plays an etiological

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role in diabetic retinopathy. Another study group of investigators reported that patients
mentioned that sleep-disordered breathing may with IAH had a 3-fold higher incidence of
play a role in metabolic syndrome via the severe hypoglycemia, a 2-fold increase in mild
inflammatory pathway. biochemical hypoglycemia and a 7-fold
Hypoglycemia increase in the incidence of episodes of
asymptomatic hypoglycemia compared to type
Hypoglycemia is a common adverse event 1 diabetic patients with normal awareness. In
of diabetes treatment and remains a major contrast, IAH in insulintreated type 2 diabetic
barrier to achieving optimal glycemic control patients is less common as a clinical problem.
in both type 1 and type 2 diabetic patients, However, those with IAH have, an increased
particularly those who are on insulin. risk of both mild and severe hypoglycemia .
Hypoglycemic episodes may compromise the
patients' quality of life. Bedtime blood glucose Metabolic Syndrome
is a significant risk factor for nocturnal The metabolic syndrome increases
hypoglycemia in type 1 diabetic subjects and cardiovascular risk in type 2 diabetes.
these subjects did not show any rebound Abdominal adiposity is considered a major risk
hyperglycemia following nocturnal factor for type 2 diabetes, metabolic syndrome
hypoglycemia. Gill et al. found that all the and cardiovascular diseases. This is supported
nocturnal hypoglycemic episodes in patients by Yang et al., who found that visceral
with type 1 diabetes were associated with adiposity remains a strong and significant
tachycardia and a subgroup appeared prone to determinant of insulin resistance in WHO
develop bradycardia, which may be grade III obesity. Neck circumference rather
responsible for sudden death. than subcutaneous fat is a more reproducible
Researchers documented a wide range of and precise measurement in this severely obese
Q-T lengthening following inhaled salbutamol cohort. An association between increased
in type 1 diabetic patients. These results can be central obesity and lower serum adiponectin
compared with the responses during and an intimate relationship between
experimental hypoglycemia to establish it as a triglycerides and insulin resistance were found
screening test for those at risk of abnormal in schizophrenic patients treated with
cardiac repolarization leading to fatal cardiac clozapine. Changes in waisthip ratio over time
arrhythmias during severe nocturnal may result in abnormal glucose handling and
hypoglycemia. routine measurement of this parameter is
necessary in this group of patients. Another
Type 1 diabetic patients are likely to be study suggested that plasma triglycerides and
unaware of hypoglycemia because of the albumin:creatinine ratio are associated with
impairment of the protective neurohumoral type 2 diabetes in morbid obese subjects.
counterregulatory responses to impending
hypoglycemia due to repeated hypoglycemic Musculoskeletal Disease
episodes. Impaired awareness of hypoglycemia Early detection of microvascular and
(IAH) is thought to affect approximately 25% macrovascular complications in subjects with
of subjects with type 1 diabetes. Despite diabetes could prevent fatal outcomes.
improvements in insulin therapies, intensi- Locomotor disease is found in 57% of patients
fication of insulin regimens and innovative with type 1 diabetes. Capsulitis invariably
patient education, a survey of a large hospital- coexisted with other upper limb abnormalities
based clinical population confirmed that 19.5% and predicted the presence of retinopathy
of type 1 diabetic patients continue to have and/or neuropathy. The mean glycosylated
IAH. Two different studies from the same hemoglobin (HbA1c) was also higher

92 Current R&D Highlights, Jan.-Mar. 2009

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inpatients with shoulder problems and these Cardiovascular risks in these patients were
results are very similar to those found in type 2 high, with the coexistence of other risk factors.
diabetic patients. Another study found that the Ethnic Variation
presence of diabetic peripheral neuropathy,
retinopathy and nephropathy was significantly The incidence of diabetes and its
higher in patients with limited joint mobility. complications varies in different ethnic
Therefore, all diabetic patients should be populations. A cross-sectional survey revealed
clinically examined for upper limb locomotor higher plasma glucose, serum leptin, Yon
disease and limited joint mobility, and if Willebrand factor, tissue plasminogen
present, they should be evaluated further for activator and fat mass-bioimpedence in South
other diabetic complications. Asian children compared with Europeans,
which make an important contribution to the
Other Risk Factors differences in insulin resistance observed in
Chronic liver disease is a major cause of these populations (50). Another similar study
morbidity and mortality. Up to 75% of subjects found higher mean truncal skinfold thickness,
with type 2 diabetes have nonalcoholic fatty HbA 1 c, fasting insulin and triglycerides, and
liver disease at diagnosis. A secondary-care lower HDL cholesterol in South Asian children
prevalence study revealed that 20% of patients compared with age-adjusted white Europeans.
with diabetes had elevated alanine In a study it was found that the prevalence of
aminotransferase (AL T), -glutamyl- microvascular complications such as
transpeptidase (GGT), or both. An audit found retinopathy, nephropathy and neuropathy and
that a significant proportion of both men and mean HbA 1 c are significantly higher and the
women with poor glycemic control have use of metformin, sulfonylureas and insulin is
abnormal lipid profiles associated with a very significantly lower in India compared to
high risk of cardiovascular disease. Mauritius and the UK. Poor glycemic control
Coronary heart disease (CHD), diabetes in South Asian subjects with type 2 diabetes
and chronic kidney disease together are and chronic disease comorbidity may be
considered a 'deadly trio' and an audit by the responsible for the increased risk of mortality
Deadly Trio Project found that 90% of the and morbidity. Although a higher proportion
patients were not receiving the optimal of South Asians were found to have poor
standard care (47). This project identified men glycemic control, the prevalence of obesity,
at high risk of CHD mortality, including all smoking and hypertension was lower in this
with known diabetes, and ensured that all will group than in non-South Asians. Therefore,
be offered appropriate treatment (48). Another there may be important opportunities for the
similar study from Spain found that type 2 early prevention of type 2 diabetes and other
diabetic patients who are not well controlled microvascular and macrovascular compli-
with two or more oral antidiabetic drugs have cations in this high-risk ethnic group.
(Based on the Conference Report published in Drugs
altered metabolic profiles, with HbA 1 c levels
of the Future 2008, 33(5): 463-468)
in the range requiring immediate intervention.

Future risk of diabetes in mother and common pregnancy complication with

child after gestational diabetes mellitus. increased maternal and perinatal morbidity.
Damm, Peter et al. However, significant long-term morbidity also
International Journal of Gynecology & exists for the mother and offspring. Women
Obstetrics with previous GDM have a very high risk of
Gestational diabetes mellitus (GDM) is a developing overt diabetes, primarily type 2

Current R&D Highlights, Jan.-Mar. 2009 93

R & D Technology
diabetes, later in life. Moreover, the risk of the Hcys was correlated to BMI and inversely
metabolic syndrome is increased 3-fold in associated to HDL-C among the non-diabetics.
these women. Their offspring have an 8-fold Further studies are needed to test the
risk of diabetes/prediabetes at 19-27 years of hypothesis in diabetics with disease
age. Thus, GDM is part of a vicious circle complications. (ScienceDirect)
which increases the development of diabetes in Efficacy and safety of exenatide in
the coming generations. (ScienceDirect) patients of Asian descent with type 2
diabetes inadequately controlled with
Fasting homocysteine levels in a cross- metformin or metformin and a
section of Saudi adults with type 1 diabetes sulphonylurea.
mellitus. Gao, Yan et al.
Al-Attas, Omar S. et al. Diabetes Research and Clinical Practice,
Diabetes and Metabolic Syndrome:
83(1),69 (Jan., 2009)
Clinical Research and Reviews Patients taking metformin (MET) alone or
Studies have shown homocysteine to be with a sulphonylurea (SU) were randomly
an independent risk factor for atherosclerosis assigned to exenatide 5 []g then 10 []g
and CVD in both diabetic and non-diabetic twice-daily for 4 and 12 weeks, respectively,
subjects. However, the association between the
or placebo. The primary endpoint was baseline
levels of homocysteine and type 1 diabetes to endpoint HbA1c change. 466 patients (age
mellitus remains a controversial one. A study 54 9 years, weight 68.7 11.2 kg, BMI
was conducted with the aim to test this in a 26.3 3.3 kg/m2, and HbA1c 8.3 1.1%;
cross-section of the Saudi type 1 diabetics mean S.D.) were enrolled in the full analysis
against non-diabetics to establish the set. Endpoint HbA1c reduction (mean [95%
relationship of homocysteine with regards to CI]) with exenatide was superior to placebo (-
type 1 diabetics and non-diabetics. A total of 1.2 [-1.3, -1.1]% vs. -0.4 [-0.5, -0.2]%,
97 subjects (41 males, 56 females) participated p < 0.001). More exenatide- than placebo-
in this cross-sectional study done at the treated patients achieved HbA1c <=7% (48%
diabetic clinic of King Abdul-Aziz University vs. 17%, p < 0.001). At endpoint, weight
Hospital Diabetic Centre, Riyadh, KSA. They reduction was greater with exenatide (-1.2 [-
were divided according to the presence of type 1.5, -0.9] kg) than placebo (-0.1 [-0.3, 0.2] kg),
1 DM. Glycemic and lipid parameters were p < 0.001. Nausea, generally mild-to-
measured using routing procedures. Hcys was moderate, was the most common adverse event
measured using photometric assay. Among with exenatide (25% vs. 1% with placebo).
males, Hcys levels were significantly lower The incidence of symptomatic hypoglycaemia
among the diabetic subjects (p-value 0.03). with exenatide and placebo were 36% and 9%,
Females with type 1 diabetes however have respectively (p < 0.001). Hypoglycaemia rates
higher total cholesterol levels than their control (events/patient-year) for patients taking
counterparts (p-value 0.003). Among the exenatide with MET or MET and SU were 1.8
control group, gender and HDL-cholesterol (0.9, 3.7) and 4.7 (3.5, 6.5), respectively.
exhibited significant inverse relationships with Exenatide treatment improved glycaemic
hcys (p-values 0.028 and 0.032, respectively) control in Asian patients with T2D and had a
and a strong positive association with body similar safety profile as in non-Asian patients.
mass index (p-value 0.034). Among the
diabetic group, only age was significantly Prevalence and pattern of cardiac
associated with Hcys (p-value 0.009). In the autonomic dysfunction in newly detected
Arab population, hcys is decreased in IDDM type 2 diabetes mellitus.
subjects compared to non-diabetic subjects. Jyotsna, Viveka P. et al.

94 Current R&D Highlights, Jan.-Mar. 2009

R & D Technology
Diabetes Research and Clinical Practice, and a significantly (p < 0.001) greater
83(1), 83 (Jan., 2009) proportion of sitagliptin-treated versus
Cardiac autonomic functions were placebo-treated patients achieved HbA1c <7%
assessed in 145 consecutive recently detected (20.6% versus 5.3%, respectively) at study
type 2 diabetics. Ninety-nine healthy persons end. Efficacy of sitagliptin was demonstrated
served as controls. Criteria for normalcy were, in each country. Sitagliptin was generally well-
heart rate variation during deep breathing tolerated. Clinical adverse events (AEs) were
>=15 beats/min, deep breathing expiratory to reported in 23.3% and 15.2% of sitagliptin-
inspiratory R-R ratio >=1.21, Valsalva ratio treated and placebo-treated patients,
>=1.21, sustained handgrip test >=16 mm of respectively. The difference was primarily due
mercury, cold pressor test >=10, BP response to increased gastrointestinal AEs in the
to standing <=10 mm of mercury and 30:15 R- sitagliptin group, most of which were mild and
R ratio on standing >=1.04. An abnormal test resolved on study drug. Serious AEs,
was defined as the above parameters being discontinuations due to AEs, and drug-related
<10 beats/min, <1.21, <1.21, <=10 mm of AEs occurred with a low incidence in both
mercury, <10, >=30 mm of mercury and groups. No hypoglycemia was reported. In the
<=1.0, respectively. A borderline test was study, sitagliptin monotherapy for 18 weeks
defined as, heart rate variation during deep significantly improved glycemic control and
breathing 11-14, sustained handgrip test 11- was well-tolerated in patients with type 2
15 mm of mercury, BP response to standing diabetes from China, India, and Korea.
11-29 mm of mercury and 30:15 R-R ratio on Immediate impact of a diabetes training
standing 1.01-1.03. Parasympathetic programme for primary care physicians--
dysfunction was found in 44.2% and An endeavour for national capacity building
sympathetic dysfunction in 51.9% diabetics. for diabetes management in India.
Among healthy controls, these figures were Murugesan, N. et al.
11.9% and 22.1%, respectively. Cardiac Diabetes Research and Clinical Practice,
autonomic function was normal in 7.8% 83(1), 140 (Jan., 2009)
patients and 32.5% healthy controls. India faces a huge burden from diabetes.
Efficacy and safety of sitagliptin in the National capacity for management of diabetes
treatment of patients with type 2 diabetes in has to be strengthened by improving
China, India, and Korea. knowledge of physicians treating diabetes,
Mohan, Viswanathan et al. especially in semi urban and rural areas. A
Diabetes Research and Clinical Practice, training programme was formulated and
83 (1), 106 (Jan., 2009) conducted at national level, as a step towards
The efficacy and safety of sitagliptin as this goal. Physicians from 6 states of India
monotherapy were evaluated in Chinese, (n = 3023, M:F 2311:712), aged 30-55 years,
Indian, and Korean patients with type 2 with service of >=3 years, (government
diabetes inadequately controlled by diet and n = 1720, private n = 1303, semi urban and
exercise. In a randomized, placebo-controlled, rural areas (n = 1581:1442)) were trained in
double-blind, 18-week trial, 530 patients with diabetes care in 5-day workshops between
HbA1c >=7.5% and <=11.0% (mean baseline March 2004 to December 2006. Impact of
8.7%) received sitagliptin 100 mg once daily training was assessed by pre- and post-training
or placebo. Compared with placebo, sitagliptin knowledge scores, feedback on usefulness of
significantly (p < 0.001) reduced mean HbA1c training modules, prioritizing activities to be
(-1.0%), fasting plasma glucose (-1.7 mmol/L), introduced in their practice and methods to be
and 2-h postprandial glucose (-3.1 mmol/L), used for raising public awareness on diabetes.

Current R&D Highlights, Jan.-Mar. 2009 95

R & D Technology
The training significantly improved knowledge cardiovascular risk in Asian Indians with
on treatment, complications, pathophysiology T2DM. The absence of relationship between
and diagnosis of diabetes (p < 0.001). The CRP and IMCL needs to be explored further in
participants considered information on a study using a large sample size.
preventive aspects of diabetes and foot care as Risk factors for developing
highly educative. Patient education and team- osteomyelitis in patients with diabetic foot
training were considered important in diabetes wounds.
management. Interest was evinced in raising
Lavery, Lawrence A et al.
public awareness about the disease. Well- Diabetes Research and Clinical Practice
planned short training programmes are useful Osteomyelitis worsens the prognosis in
in improving knowledge and in creating the diabetic foot, but predisposing factors
enthusiasm to improve diabetes care and remain largely undefined. In a prospectively
awareness. followed cohort authors assessed risk factors
Proton magnetic resonance for developing osteomyelitis. Consecutive
spectroscopy and biochemical investigation persons with diabetes who presented to a
of type 2 diabetes mellitus in Asian Indians: managed-care diabetes disease management
observation of high muscle lipids and C- program were enrolled. The patients
reactive protein levels. underwent standardized assessments and
Sinha, Sanjeev et al. monitored for all foot complications, defined
Magnetic Resonance Imaging, 27(1), 94 infections by criteria consistent with
(Jan., 2009) International Working Group guidelines, and
Authors report the determination of defined osteomyelitis as a positive culture
intramyocellular lipids (IMCLs) of the soleus from a bone specimen. 1666 persons were
muscle of patients with type 2 diabetes enrolled, 50% male, mean age 69 years. Over a
mellitus (T2DM) using proton magnetic mean of 27.2 months of follow-up, 151
resonance spectroscopy. In addition, the patients developed foot infections, 30 (19.9%)
various anthropometric and biochemical of which involved bone. Independent risk
profiles of these patients were determined, factors for osteomyelitis were: wounds that
including estimation of C-reactive protein extended to bone or joint (relative risk
(CRP), an inflammatory marker of coronary [RR] = 23.1), previous history of a wound
heart disease, and insulin resistance prior to enrollment (RR=2.2), and recurrent or
[Homeostasis Model Assessment (HOMA- multiple wounds during the study period
IR)]. The estimated CRP level and the IMCL (RR = 1.9). In this study population, managed
content in these patients were correlated with in a specialized diabetic foot care center, the
body mass index, percentage of body fat, other results suggest that independent risk factors for
measures of abdominal obesity, serum developing osteomyelitis are deep, recurrent
lipoproteins, fasting and post-oral glucose load and multiple wounds. These results may help
clinicians target their efforts at diagnosing foot
serum insulin levels and other surrogate
osteomyelitis to the highest risk patients.
markers of insulin resistance. The IMCL
content (P=.04), CRP (P=.008) and insulin
resistance (P=.0007) were significantly higher Inter-relationship between low-density
in T2DM patients compared to healthy lipoprotein phenotype and carotid intima-
controls. However, IMCL content did not media thickness in North Indian type 2
correlate with values of fasting insulin, diabetic subjects.
HOMA-IR or CRP in either group. These Ahmad, Jamal et al.
findings have strong implications of increased Diabetes and Metabolic Syndrome:

96 Current R&D Highlights, Jan.-Mar. 2009

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Clinical Research and Reviews VPT is well known for normal subjects, but
Diabetic dyslipidemia is characterized by not for diabetic subjects. This is a pilot study
a preponderance of small dense LDL which is to evaluate and plot the law of mobility for
highly atherogenic. The aim of this study was VPT among DM subjects. Authors used
to examine the interrelationship between LDL biothesiometer to find the VPT of several areas
Phenotype and atherosclerosis; to determine in upper and lower extremities for normal and
the factors determining LDL phenotype; and diabetic subjects. VPT of normal and diabetic
evaluate LDLc:apo-B ratio as a surrogate for subjects for different foot areas from proximal
the assessment of LDL phenotype in a group to distal is evaluated for 30 subjects. All the
of North Indian Type 2 diabetic subjects. 285 subjects are screened for peripheral artery
diabetic subjects attending the outpatient occlusive disease with ankle brachial pressure
Endocrine Clinic were subjected to detailed index (0.9 or above). VPT values of different
anthropometry and fasting serum lipid and areas are arranged in a proximal to distal order
apo-B was measured. The carotid intima- for the analysis. VPT values monotonically
media thickness (IMT) was determined using a decrease from proximal to distal areas.
high resolution B-mode Ultrasonography. Vierodt's law of mobility holds well for normal
LDLc:apo-B ratio was taken as a surrogate subjects in both feet areas. The law of mobility
index for LDL size. 29.5% patients with does not hold good for the DM subjects in one
normal triglyceride levels and 52.1% patients or both feet areas. The VPT value of diabetic
with normal LDLc levels showed the presence subjects reveals that the law of mobility do not
of small dense LDL or Phenotype B as holds good for diabetic subjects in foot areas.
estimated by the LDL cholesterol/apo-B ratio. Though the number of subjects is small, all the
The mean IMT in Phenotype B group was subjects defied the law.
higher (0.88 mm vs. 0.68 mm). Triglycerides Comparison of the glycemic control of
was the most important predictor variable the normo- and hypertensive Chinese
predicting carotid IMT (R2 = 0.15, patients with type 2 diabetes in a general
[beta] = 0.376) as well as LDL phenotype B outpatient clinic in Hong Kong.
(R2 = 0.28, [beta] = 0.561). Triglycerides and Go, Echo T.T. et al.
HDLc contribute independently to the Diabetes and Metabolic Syndrome:
variability in LDL particle size, and LDL Clinical Research and Reviews
particle size was associated with preclinical To describe and compare glycemic control
atherosclerosis as determined by carotid IMT between normo- and hypertensive type 2
in North Indian Type 2 diabetic subjects. LDL diabetic Chinese patients in outpatient setting.
cholesterol/apo-B ratio serves as an easy This retrospective cross-sectional study was
clinical tool to determine the elevated small performed by retrieving the records of 548
dense LDL. . (ScienceDirect)
Chinese type 2 diabetic patients. HbA1c [less,
Vibration perception threshold and the double equals] 6.5% was regarded as glycemic
law of mobility in diabetic mellitus patients. good control. Linear and logistic regressions
Manivannan, M et al. were used to compare mean HbA1c levels and
Primary Care Diabetes (In Press) the proportions with good glycemic control
Diabetic neuropathy is a family of nerve between hypertensive and normotensive
disorders with progressive loss of nerve patients while controlling for confounders. The
function in 15% of diabetes mellitus (DM) means HbA1c for all diabetic, hypertensive
subjects. Vibration Perception Threshold and normotensive patients were 7.70, 7.55 and
(VPT) is one of the modalities of testing loss 8.01, respectively. The normotensive group
of protective sensation. Law of mobility for had a significant higher HbA1c (p = 0.004).

Current R&D Highlights, Jan.-Mar. 2009 97

R & D Technology
Significantly higher HbA1c was associated vildagliptin 10 and 50 mg bid, and placebo,
with lower age (CI of [beta]: -0.024 to -0.001, respectively) and none of them were severe or
p = 0.039), female gender (CI of [beta]: 0.039- dose related. Vildagliptin 50 mg bid was
0.552, p = 0.024) and medication use (CI of considered to be the most effective and well-
[beta]: 0.577-1.250, p < 0.001). The tolerated dose, and therefore can be considered
proportions with good glycemic control for the the recommended clinical dose for Japanese
all diabetic, hypertensive, normotensive patients with T2DM.
subjects were 0.235, 0.249 and 0.207,
Cost of medical care among type 2
respectively. No significant difference was diabetic patients with a co-morbid
shown for the two groups'proportions condition--Hypertension in India.
(p=0.283). Lower proportions of good control Tharkar, Shabana et al.
were shown in females (CI of OR: 0.398- Diabetes Research and Clinical Practice,
0.905, p=0.015) and those on medication (CI
83(2), 263 (Feb., 2009)
of OR: 0.211-0.543, p<0.001) by stepwise The aim was to estimate the cost of
logistic regression. The hypertensive diabetic medical care among hospitalized diabetic
patients had better glycemic control than the patients and to assess the influence of an
normotensives. additional co-morbid condition--hypertension.
Vildagliptin dose-dependently improves A pre tested and validated questionnaire was
glycemic control in Japanese patients with interviewer administered among 443
type 2 diabetes mellitus. (male:female, 235:208) hospitalized diabetic
Kikuchi, Masatoshi et al. patients. The JNC VII criteria for hypertension
Diabetes Research and Clinical Practice, was considered to divide the study population
83(2), 233 (Feb., 2009) into two groups; group I - diabetic patients
To assess the efficacy and tolerability of without hypertension (n = 269) and group II -
vildagliptin (10, 25 or 50 mg bid) in Japanese diabetic patients with hypertension (n = 174).
patients with type 2 diabetes mellitus (T2DM), Details of cost of inpatient and out-patient care
this 12-week, multicenter, randomized, and expenditure on hospitalization for the
double-blind, placebo-controlled, parallel- previous 2 years were obtained. The
group study was performed in 291 patients. prevalence of hypertension among the study
The primary assessment was change from subjects was 39.3% (174 subjects). Presence of
baseline to endpoint in HbA1c. Baseline hypertension made a significant impact on the
HbA1c averaged 7.4%, and the between- expenditure pattern. On an average a diabetic
treatment difference (vildagliptin-placebo) in patient with hypertension spent 1.4 times more
the HbA1c adjusted mean change was -0.8%, - than a diabetic subject without hypertension.
1.0% and -1.2% with vildagliptin 10, 25 and Median cost per hospitalization, length of stay
50 mg bid, respectively (p < 0.001). Relative during admission, and cost of 2 years for
to baseline, body weight did not change inpatient admission were all significantly
significantly in vildagliptin groups. There was higher for diabetic patients with a co-morbid
no increase in incidence of adverse events in condition. There is a need to develop a
the vildagliptin groups (62.0%, 62.5% and protocol on cost effective strategy for diabetes
61.8%, 10, 25 and 50 mg bid, respectively) care. Strict control of hypertension should be
compared to placebo (73.6%). No deaths or targeted to avoid excess treatment cost on
drug-related serious adverse events were diabetes care.
reported. Seven hypoglycemic events were Prevalence of diabetic retinopathy in
observed (four events (n = 3), two events India: Sankara Nethralaya diabetic
(n = 2), and one event (n = 1) in the retinopathy epidemiology and molecular

98 Current R&D Highlights, Jan.-Mar. 2009

R & D Technology
genetics study report 2. confidence interval [CI], 27.0-29.3), and the
Raman, Rajiv et al. prevalence of diabetic retinopathy in general
Ophthalmology, 116(2), 311 (Feb., 2009) population was 3.5% (95% CI, 3.49-3.54). The
The aim of the study was to estimate the prevalence of diabetic retinopathy in the
prevalence of diabetic retinopathy in an urban population with diabetes mellitus was 18.0%
Indian population older than 40 years. A (95% CI, 16.0-20.1). History-based variables
population-based cross-sectional study. Five that were significantly associated with
thousand nine hundred ninety-nine subjects increased risk of diabetic retinopathy included
residing in Chennai, India, were enumerated. gender (men at greater risk; odds ratio [OR],
A multistage random sampling, based on 1.41; 95% CI, 1.04-1.91); use of insulin (OR,
socioeconomic criteria, was followed. 3.52; 95% CI, 2.05-6.02); longer duration of
Identified subjects with diabetes mellitus diabetes (>15 years; OR, 6.43; 95% CI, 3.18-
(based on the World Health Organization 12.90); and subjects with known diabetes
criteria) underwent detailed examination at the mellitus (OR, 2.98; 95% CI, 1.72-5.17).
base hospital. The fundi of all patients were Differences in the socioeconomic status did
photographed using 45, 4-field stereoscopic not influence the occurrence of diabetic
digital photography. The diagnosis of diabetic retinopathy. The prevalence of diabetic
retinopathy was based on Klein's classification retinopathy was 18% in an urban population
of the Early Treatment Diabetic Retinopathy with diabetes mellitus in India. The duration of
Study scale. These included age- and gender- diabetes is the strongest predictor for diabetic
adjusted prevalence of diabetes and diabetic retinopathy. The author(s) have no proprietary
retinopathy, and correlation of prevalence with or commercial interest in any materials
history-based risk factors. The age- and discussed in this article.
gender-adjusted prevalence rate of diabetes in
an urban Chennai population was 28.2% (95%


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Current R&D Highlights, Jan.-Mar. 2009 99

New Leads
Drugs of the Future, 33(1): 7-12 (2008)
Alogliptin (SYR-322), a potent, highly
selective inhibitor of the serine protease
dipeptidyl-peptidase IV (DPP IV), is a new
Antidiabetic effect through islet cell investigational drug developed for the
protection in streptozotocin diabetes: A treatment of type 2 diabetes. Orally
preliminary assessment of two thiazolidin-4- administered alogliptin demonstrated antidia-
ones in Swiss albino mice. betic effects in preclinical studies in mice, rats,
Kishore, Anoop et al. dogs and monkeys, as well as a good safety
Chemico-Biological Interactions, 177(3), profile. Early clinical studies demonstrated that
242 (Feb., 12, 2009) alogliptin can be safely co-administered with
This study was undertaken on the basis of antidiabetic drugs such as pioglitazone,
several reports in the literature that pancreatic glyburide, metformin and warfarin without the
beta cells are capable of replication/ need for dose adjustment. Alogliptin also
regeneration and also being afforded demonstrated efficacy in reducing glucose and
protection against damage induced by increasing insulin levels and proved to be well
streptozotocin. Nicotinamide was reported to tolerated in healthy subjects and patients with
give protection against streptozotocin-induced type 2 diabetes. Global phase III clinical trials
damage in rats. In the present study, two of alogliptin as monotherapy and in
thiazolidine-4-ones with nicotinamide combination with other antidiabetic drugs for
substitution were administered to Swiss albino the treatment of type 2 diabetes are currently
mice with streptozotocin diabetes for 15 days. ongoing, and an NDA was recently submitted
Concurrently, one group received nicotinic to the FDA.
acid. Both the test compounds reversed the Liraglutide [N-[ (N-hexadecanoyl)--L
hyperglycaemia diabetic mice. Damage to -Glu]-L -Lys26 ,L -Arg34]-GLP-1 (7-37)]
pancreatic islets was also reduced in these GLP-1 receptor agonist treatment of type 2
groups compared to diabetic control and diabetes treatment of obesity.
nicotinic acid treated groups. Since these Gallwiz B et al.
compounds have been earlier found have Drugs of the Future. 33(1): 13-20(2008)
antioxidant activity, one of the possible Liraglutide (NN-2211), a novel glucagon-like
mechanisms of action could be by reducing peptide-1 (GLP-1) analogue for once-daily s.c.
oxidative stress in pancreas. Further, possibly injection, is in advanced clinical phase III
by releasing nicotinamide in vivo, the development for type 2 diabetes therapy. It is a
molecules could have contributed to the NAD GLP-1 derivative with two amino acid chains
pool in pancreas and afforded protection. It is and a fatty acid side-chain. The effects of
concluded that the test compounds have liraglutide are mediated exclusively by
potential to be developed for multiple activation of the GLP-1 receptor. It reduces
beneficial action in conditions like metabolic hemoglobin A1c (HbA1c), fasting and
syndrome. postprandial glucose by glucose-dependent
Alogliptin benzoate [2-[6-[3(R)-amino- stimulation of insulin secretion and inhibition
piperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4- of glucagon secretion, both as monotherapy
tetrahydropirimidin-1-ylmethyl] benzo- and in combination with oral antidiabetic
nitrile benzoate- dipeptidyl-peptidase IV drugs. Weight loss has also been observed in
(DPP IV) inhibitor treatment of type 2 obese patients and indirect measures show a
diabetes. possible improvement in -cell function.
Wang Y et al. Liraglutide does not cause hypoglycemia. The

100 Current R&D Highlights, Jan.-Mar. 2009

New Leads
main adverse events are nausea and diarrhea at dipeptidyl peptidase IV inhibitor
the beginning of treatment, which are mild to antidiabetic agent.
moderate and transient. The formation of anti- Cole P et al.
liraglutide antibodies has not been observed. Drugs of the Future, 33(7), 577 (2008)
Dapagliflozin [1-[4-Chloro-3-(4ethoxy- Targeting glucagon-like peptide 1 (GLP-
benzyl) phenyl]-1-deoxy- -D-glucopyranose 1) is an attractive strategy for the treatment of
(1S)-1 ,5-anhydro-1-C-[4-chloro-3-(4- type 2 diabetes, as this incretin hormone
enhances postprandial insulin secretion in a
ethoxybenzyl) phenyl]- D -glucitol (2S, 3R,
4R, 5S, 6R)-2 -[ 4-chloro-3-(4-ethoxybenzyl) manner dependent on glycemia. Evidence also
phenyl]-6-(hyd roxymethyl)tetrahydro-2H- indicates that GLP-1 reduces glucagon
pyran-3,4,5-triol-] SGL T2 inhibitor secretion, induces satiety, delays gastric
antidiabetic agent. emptying and enhances -cell functio'n
through stimulation of neogenesis and
Cole P et al.
Drugs of the Future, 33(9): 745-751 inhibition of apoptosis. One means of utilizing
(2008) this target is by inhibiting its degradation,
One potential means of treating diabetes is which is mediated by dipeptidyl peptidase IV
via modulation of glucose uptake. A novel (DPP IV). Saxagliptin is a DPP IV inhibitor
that has displayed promising preclinical
strategy for achieving this is through inhibition
of sodium-dependent glucose transporters characteristics, such as dosedependent
(SGL Ts), which mediate the process by which clearance of glucose in animal models of
plasma glucose filtered in the kidney diabetes. Data from clinical trials show
glomerulus is reabsorbed. The great majority significantly improved glycosylated
of this process of reabsorption is mediated by hemoglobin (HbA1c) and fasting serum
SGL T2 and SGL T2 inhibitors have therefore glucose in diabetes patients with saxagliptin
been sought and identified in order to prevent alone and in combination with metformin, and
renal glucose reabsorption and increase the agent was well tolerated. Results from
glucose excretion in urine. The compound that phase III studies are expected to soon provide
has advanced the furthest is dapagliflozin, a comprehensive view of saxagliptin's role in
which demonstrated superior metabolic the expanding effort to improve the lives of
stability compared to early agents. diabetic patients.
Dapagliflozin also exhibited potent inhibition B1-1356 [ 8-[3(R)-aminopiperidin-1-yl]-
of SGL T2 and selectivity over SGL T1 in 7-(2-butynyl)-3-methyl-1-(4-
vitro, and was associated with reduced plasma methylquinazolin-2-ylmethyl)xanthine,]
glucose levels in animal models of diabetes dipeptidyl-peptidase IV inhibitor
after acute and chronic dosing. Dapagliflozin antidiabetic agent.
has proven safe and well tolerated in humans, Wang Y et al.
with pharmacokinetic and pharmacodynamic Drugs of the Future, 33(6): 473-477
variables indicating that daily dosing is (2008)
appropriate. Double-blind trials in patients BI-1356 is a dipeptidyl-peptidase IV (DPP
with type 2 diabetes revealed reductions in IV, or CD26) inhibitor developed at for the
fasting and postprandial glucose, as well as treatment of type 2 diabetes. BI-1356
significant reductions in HbA 1 c. demonstrated long-lasting DPP IV inhibition
Dapagliflozin has entered phase III evaluation. both in vitro and in vivo. In vitro, BI-1356 was
Saxagliptin [(1 S,3S,5S)-2-[2( S)-amino- at least 10,000-fold more selective for DPP IV
2-(3-hydroxyadamantan-1-yl)acetyl]-2- than for DPP-8 and DPP-9. High potency and
azabicyclo [3.1.0] hexane-3-carbonitrile] long-lasting inhibitory effects were also

Current R&D Highlights, Jan.-Mar. 2009 101

New Leads
observed in vivo in' mice and rats, the glycemic control, reduced body weight and
inhibition induced by BI-1356 being longer improved-cell function. Taspoglutide is
lasting than that induced by any other DPP IV generally well tolerated, with mild
inhibitor tested. BI-1356 exhibited nonlinear gastrointestinal symptoms being the most com-
pharmacokinetics in healthy volunteers and monly reported adverse events. Several phase
patients with type 2 diabetes. Oral BI-1356 III clinical trials of this novel GLP-1 analogue
administered once daily proved to be well are under way.
tolerated in healthy volunteers and patients
Antihyperglycemic effects of ginseng
with type 2 diabetes. Treatment with BI-1356 and possible mechanisms.
increased concentrations of GLP-1 and D.C. Peng1 et al.
reduced concentrations of glucose in patients Drugs of the Future,33(6): 507-514
with type 2 diabetes, and it also significantly (2008)
reduced Hb1Ac in diabetic patients. Phase III
Ginseng is a medicinal plant valued
clinical trials are under way. throughout the world and is considered the
Taspoglutide--[L-Histidyl-2- king of herbs in traditional Chinese/Oriental
methylalanyl-L-glutamyl-glycyl-L-threonyl- medicine. Ginseng has gained popularity as a
L-phenylalanyl-L-threonyl-L-seryl-L- dietary supplement in the United States and
aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl- Canada in recent decades. The multiple
L-Ieucyl-L-glutamyl-glycyl-L-glutaminyl-L constituents of ginseng possess equally
alanyl-L- alanyl-L-lysyl-L-glutamyl-L- multifaceted pharmacological functions, as
phenyl-alanyl-Lisoleucyl- L-alanyl-L- demonstrated by numerous studies. According
tryptophyl-L-leucyl-L-valyl-L-lysyl-2- to previous reports, ginseng root and its
methylalanyl- L-argininamide ] GLP-1 constituents influence the central nervous
analogue for the treatment of diabetes. system (CNS), endocrine, cardiovascular,
Arjona A et al. gastrointestinal, sexual, renal and immune
Drugs of the Future, 33(11): 938-943 systems, etc. One important function of the
(2008) ginseng plant is its antihyperglycemic effect.
Incretin agonists and analogues are Ginseng extracts have been commonly used in
receiving increasing attention as potential Chinese/Oriental medicine to treat diabetes-
antidiabetic agents due to their ability to like conditions. Our recent data suggest that all
stimulate insulin secretion only during the main parts of the ginseng plant (including
hyperglycemic states. Exploitation of the berry, root, leaf and stem) exhibit potent
incretin effect reduces the risk of rebound antihyperglycemic effects and may provide an
hypoglycemia that accompanies many opportunity to develop a novel class of
antidiabetic treatments. Taspoglutide (R-1583, antidiabetic agents. In the current article,
BIM-51077, ITM-077) is a long-acting authors have discussed on the anti
glucagon-like peptide 1 (GLP-1) analogue that hyperglycemic effects of ginseng root, berry
shows promise for the treatment of type 2 and leaf extracts, as well as on the possible
diabetes. In addition to having enhanced mechanisms of the anti hyperglycemic action.
resistance to enzymatic degradation by the Drugs for the treatment of diabetes
protease dipeptidyl peptidase 4 (DPP4), complications. zycose: a new player in the
clinical studies have shown that taspoglutide field?
increases insulin levels and lowers glycemia. Alin Stirban et al.
Phase II trials have also demonstrated that Drugs of Today, 2008,44 (10): 783-796
weekly administration of a slowrelease Zycose is a newly released (2006)
formulation was associated with enhanced combined medication containing folic acid (1

102 Current R&D Highlights, Jan.-Mar. 2009

New Leads
mg) benfotiamine (150 mg) and benzamine Gly-Ala-Pro-Pro-Ser-Lys- Lys- Lys- Lys-
(850 mg), a proprietary blend of para- Lys- Lys-NH2. ] --- GLP-1 receptor agonist
aminobenzoic acid (PABA), vitamin E and a.- for the treatment of diabetes.
lipoic acid (ALA). Zycose protects vascular, Campas C et al.
retinal and kidney function by improving Drugs of the Future, 33(10): 838-840
cellular health and promoting peripheral nerve (2008)
health in people with diabetes. Zycose's Type 2 diabetes is associated with
therapeutic benefit is believed to be due to the progressive decreases in pancreatic -cell
additive effects of its compounds on lowering function. Most patients require increasingly
homocysteine levels (folic acid), reducing the intensive treatment, including oral
production of advanced glycation end products combination therapies followed by insulin.
(benfotiamine), improving endothelial function Fear of hypoglycemia is a potential barrier to
(folic acid, benfotiamine, ALA), reducing treatment adherence and glycemic control,
oxidative stress (ALA, vitamin E) and while weight gain can exacerbate
reducing carbonyl stress (benzamine). The hyperglycemia or insulin resistance.
complex composition of Zycose allows the Administration of insulin can roughly mimic
therapeutic intervention of several physiological insulin secretion but does not
hyperglycemiamediated disorders. The address the underlying pathophysiology.
compound consists mainly of vitamins, AVE-0010 (ZP-10) is a glucagon-like
therefore explaining, in part, the good safety peptide 1 (GLP-1) receptor agonist and an
profile and reduced adverse effects. insulin secretagogue. In preclinical studies,
People with type 2 diabetes have a 2- to 5- AVE-0010 improved glucose tolerance,
fold increased risk for cardiovascular mortality decreased water intake and produced a
when compared to the nondiabetic population. dosedependent decrease in glycosylated
The main causes are accelerated hemoglobin (HbA1c), without the risk of
atherosclerosis, microvascular disease causing hypoglycemia. AVE-0010 has shown glucose-
complications such as neuropathy, lowering activity similar to that of other GLP-
nephropathy and retinopathy, as well as a 1 agonists, while being devoid of nausea
prothrombotic status. Pathomechanisms of related side effects, and it has been shown to
diabetes are related to hyperglycemia, be safe and well tolerated in large clinical
hyperlipidemia, hyperinsulinemia, increased studies. AVE-0010 is currently in phase III
oxidative stress and accelerated aging. An clinical trials for the treatment of type 2
important role in triggering these changes is diabetes in patients treated with or without
attributed to the endothelium. Endothelial cells metformin, either alone or in combination with
are mainly responsible for the production of sulfonylureas, insulin or pioglitazone. A phase
nitric oxide (NO), a key mediator contributing II clinical trial comparing AVE-0010 with the
to vascular health. NO promotes vasodilatation already marketed GLP-1 analogue exenatide is
and has antiatherosclerotic, anti oxidative and also under way.
antithrombotic properties. Endothelial NO Emerging drug candidates of dipeptidyl
results from the transformation of L-arginine peptidase IV (DPP IV) inhibitor class for
into citrullin and NO by the enzyme NO the treatment of Type 2 Diabetes.
synthase (NOS). Gupta Rajesh et al.
AVE-0010[H-His-GIy-Glu-Gly- Thr- Current Drug Targets (2009), 10(1), 71-
Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-G 87.
lu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu- Dipeptidyl peptidase IV (DPP IV) is a key
Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser- regulator of insulin-stimulating hormones,

Current R&D Highlights, Jan.-Mar. 2009 103

New Leads
glucagon-like peptide (GLP-1) and glucose- complications and possibly macrovascular
dependent insulinotropic polypeptide (GIP), disease. In addition, results from the UKPDS
thus it is a promising target for the treatment of and other studies like the Heart Protection
Type 2 Diabetes mellitus (T2DM). Inhibition Study (HPS) have also shown that treatment of
of plasma DPP IV enzyme leads to enhanced concomitant risk factors like lipids and blood
endogenous GLP-1 and GIP activity, which pressure and the use of aspirin have favourable
ultimately results in the potentiation of insulin effects on cardiovascular complications and
secretion by pancreatic beta-cells and mortality in patients with type 2 diabetes. In
subsequent lowering of blood glucose levels, order to achieve glycaemic goals, we have
HbA[1(c)], glucagon secretion and liver several anti-hyperglycaemic agents in our
glucose production. Various classes of therapeutic armamentarium today. However,
structurally different DPP IV inhibitors are despite their availability, we have not been
currently being explored and few of them such able to achieve glycaemic goals in our patients
as Sitagliptin and Vildagliptin were with diabetes due to a variety of reasons.
successfully launched. These drugs have been However, there appears to be hope for the
approved as a once-daily oral monotherapy or future. The progress of research in all fields of
as a combination therapy with current anti- diabetes therapeutics from diabetes treatment
diabetic agents like pioglitazone, to continuous glucose monitoring systems to
glibenclamide, metformin etc. for the novel insulin delivery systems has been
treatment of T2DM. Several other novel DPP spectacular. These advances have resulted in
IV inhibitors are in pipeline. The present newer pharmacologic agents, implantable
review summarizes the latest preclinical and glucose sensors and inhaled insulin. There is
clinical trial data of different DPP IV also hope that large scale implementation of
inhibitors with a special emphasis on their intensive lifestyle programmes and education
DPP8/9 fold selectivity and therapeutic efforts may help to prevent diabetes in high
advantages over GLP-1 based approach. risk individuals. Indeed, the repertoire of
New frontiers in the management of options and strategies currently available (and
type 2 diabetes. in the pipeline) to treat and prevent/delay
Mudaliar Sunder diabetes and its complications is impressive. In
The Indian Journal of Medical Research this review, we will discuss the evolving
(2007), 125(3), 275-96 cardiovascular benefits of the
. Type 2 diabetes is a chronic, debilitating thiazolidinediones (TZDs); describe in detail
disease characterized by insulin resistance, the newer glucose lowering gut hormones with
impaired insulin secretion, and novel mechanisms of action; delineate the
hyperglycaemia, and afflicting at least 171 recent advances in non invasive insulin
million people worldwide (31.7 million in delivery systems (including inhaled insulin);
India). This chronic disease is not benign and review the ongoing developments in
patients with diabetes suffer from numerous continuous glucose measuring devices and
microvascular and macrovascular finally present an update on the prevention of
complications which cause a lot of morbidity diabetes.
and mortality. Results from the UKPDS Diabetes: assessing the pipeline.
(United Kingdom Prospective Diabetes Study) Lebovitz Harold
clearly demonstrate that tight glucose and Atherosclerosis. Supplements (2006), 7(1),
blood pressure control in patients with type 2 43-9.
diabetes prevents the development of and Type 2 diabetes is recognised as a major
delays the progression of microvascular cardiovascular risk factor, and future therapies

104 Current R&D Highlights, Jan.-Mar. 2009

New Leads
must therefore address more than just blood Modulation of the endogenous
glucose levels. Novel approaches to the endocannabinoid system by rimonabant, which
treatment of type 2 diabetes are now at various is under regulatory review, has been shown to
stages of development or regulatory approval. improve body weight, atherogenic lipid
Exenatide and pramlintide, analogues of gut- profiles and glycaemic control. In addition,
derived hormones glucagon-like peptide-1 enhanced understanding of the
(GLP-1) and amylin, respectively, have pathophysiology underlying the microvascular
demonstrated improvements in glycaemic complications of type 2 diabetes has led to the
control and bodyweight in clinical studies and development of targeted therapies for
have been recently approved for treatment of conditions such as diabetic retinopathy,
type 2 diabetes. Initial studies have indicated including the protein kinase C (PKC)-
that agents that activate both peroxisome antagonist ruboxistaurin, now in phase III
proliferator-activated receptor (PPAR)alpha trials. Such therapies should enable physicians
and gamma improve glycaemic control and to achieve more for their patients with type 2
have beneficial effects on lipid profiles. Two diabetes.
dual PPARalpha/gamma agonists, muraglitazar
and tesaglitazar, are under regulatory review
and in phase III trials, respectively.

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Current R&D Highlights, Jan.-Mar. 2009 105

Natural Products

Withania coagulans: Role in Diabetes

Akankshaa, Jayendraa, Arvind K. Srivastavab, Rakesh Mauryaa,*
Divisions of Medicinal and Process Chemistry and bBiochemistry
Central Drug Research Institute, Lucknow- 226001, India
Withania coagulans, is well known in the hyperglycaemia as well as its secondary
Ayurvedic system of medicine for the complications. The natural active principles of
treatment of various diseases. Withanolides are W. coagulans contributing to antihyper-
the major constituents of the plant. Its glycemic activity were not determined. It was
hepatoprotective, anti-inflammatory, therefore, necessary to determine the active
antihyperglycemic, hypolipidemic, free radical antihyperglycemic agent. We have reported the
scavenging and antimicrobial activities have withanolides responsible for its
been reported. Aqueous decoction of the fruit antihyperglycemic activity [2].
is used by traditional medical practitioner to In India two species of genus Withania,
treat diabetes. However, the active principle Withania somnifera and Withania coagulans
responsible for this activity had not been are found [3]. Withania somnifera is famous by
identified yet. We have reported the compound the name Ashwagandha in Hindi and Indian
responsible for its antidiabetic activity. Our Ginseng, Winter cherry in English. The
results show that it should be studied more morphologies of both the species are near
extensively to develop it as a antidiabetic drug.
about same.
Introduction Chemical Costituents
Since ancient time plants are being used
for their medicinal properties. Natural products Withania coagulans is rich in steroidal
have been the basis of treatment of human lactones, which are known as withanolides (1-
diseases. Many of todays drugs are of plant 37). Withanolides are naturally occurring
origin, e.g., penicillin, morphine and paclitaxel polyhydroxy C28 steroidal lactones. In the
(taxol), artemisinin etc. Plant derived drugs basic structure of all withanolides six- or five-
have safer side over synthetic drugs as they membered lactone ring is attached to an intact
show lesser or no side effects. Withania or rearranged ergostane skeleton.
coagulans Dunal (family Solanaceae), is Chemical constituents from the whole
reported in Ayurveda for its biological plant of Withania coagulans
potentials. It is commonly known as Paneer
ke phool in Hindi and Indian cheese maker Previous phytochemical examination of
or Vegetable rennet in English, distributed in this plant indicated the presence of
drier parts of India [1]. The effective treatment withanolides. The ethanolic extracts of the
of diabetes is dependent on active constituents whole plant have resulted in the isolation of
of medicinal plants capable of controlling one withanolide named coagulin (17,27-

106 Current R&D Highlights, Jan.-Mar. 2009

Natural Products
3,5,24-trienolide (1) [4]. Two withanolides,
14,15-epoxywithanolide I [(20S,22R)
witha-3,5,24-trienolide] (2) and 17-
hydroxywithanolide K [(20S,22R) 14,7,20-
trihydroxy-1-oxo-witha-2,5,24-trienolide] (3) [5,6].
Four withanolides, coagulin B (4), coagulin C (5),
coagulin D (6), coagulin E (7) [7], two withanolides
(steroidal lactones) named coagulin F (27-hydroxy-
(8) and coagulin G (17,27-dihydroxy-14,20-
epoxy-1-oxo-(22R)-witha-2,5, 24-trienolide) (9) [8],
five withanolides, namely coagulin H
hexahydroxy-1-oxowitha-2,24-dienolide (10),
coagulin I (14R,17S,20S,22R)-5,6,17-
(11), coagulin J (14R,17R,20R,22R)-3,27-
(12), coagulin K (14R,17R,20R,22R)-14,20-epoxy-
dienolide (13), coagulin L (14R,17S,20S,22R)-
1-oxowitha-5,24-dienolide (14) . Three
withanolides, coagulin M (14R,17R,20,22R)-
5,6,27-trihydroxy-14,20-epoxy-1-oxo-with a-
24-enolide) (15), coagulin N (14R,17S,20,22R)-
Fig 1: Compounds isolated from the whole plant of
glucopyranosyl)-1-oxo-witha-5,24-dienolide) (16),
Withania coagulans.
coagulin O (14R,20,22R)-14,20-dihydroxy-3-
(O--D-glucopyranosyl)-1-oxo-witha-5,24- Chemical constituents from the fruits of
dienolide) (17) [10]. Three withanolides, coagulin P Withania coagulans
The aqueous extract of fruits of Withania
oxo-(20S,22R)-witha-5,14,24-trienolide) (18),
coagulans have resulted in the isolation of
coagulin Q (1,20-dihydroxy-3- (O--D-
withanolides, 3,14,17,20F-tetrahydroxy-1-
oxo-20S,22R-witha-5,24-dienolide (26) and
(19), coagulin R (3,17-dihydroxy-14,20-epoxy [14]
ergosta-5,25-diene-3,24-diol (27) .
1-oxo-(22R)-witha-5,24-dienolide) (20) [11]. Three
withanolides, 20-hydroxy-1-oxo-(22R)-witha-
witha-5,24-dienolide (or 3-hydroxy-2,3-
2,5,24-trienolide (21), withacoagulin (22), and
dihydrowithanolide H) (28), sitosterol--D-
17-hydroxy-14, 20-epoxy-1-oxo-(22R)-witha- [15]
glucoside (29) , coagulanolide
3,5,24-trienolide (23) [12]. A withanolide, coagulin
S (24) and dimeric lignan, bispicropodophyllin
1-oxowitha-2,5,24-trienolide) (30) and
glucoside (25) have been isolated from the
withanolide F (31) [2].
ethanolic extract of whole plant of Withania
coagulans [13].

Current R&D Highlights, Jan.-Mar. 2009 107

Natural Products

H 3C H
CH 3 H O O
O CH 3 H
OH 12: Coagulin J
11 : Coagulin I

CH 3 CH 3

H 3C CH 3 H 3 C OH CH 3
H3C H H 3C H O
13: Coagulin K 14: Coagulin L

CH3 CH 3
H3 C CH 2OH H 3C CH3
H3 C H H 3C HO
CH 3 H CH 3 H

15: Coagulin M 16 : Coagulin N

H 3C H H3 C
CH 3 H H

17: Coagulin O 18: Coagulin P

108 Current R&D Highlights, Jan.-Mar. 2009

Natural Products

19: Coagulin Q 20: Coagulin R

H3C H3 C


21 22: Withacoagulin




23 24:Coagulin S



25: Bispicropodophyllin glucoside

Current R&D Highlights, Jan.-Mar. 2009 109

Natural Products
CH 3
Chemical constituents from the root of
H 3C OH CH 3
24 Withania coagulans
H3C 26
Chemical investigation of methanolic

HO extract of roots of Withania coagulans have
resulted in the isolation of withanolides,
26:3Hydroxy-2,3-dihydro-withanolide F 27:Ergosta-5,25-diene-3,24-diol

CH 3
witha-2,24-dienolide (32) and withaferin A
(33) [16, 17, 18]. 5,27-Dihydroxy-6,7-epoxy-1-
CH3 H [19]
oxo-(5)-witha-2,24-dienolide (34) .
Defatted methanolic extract of roots of
28: 3-hydroxy-2,3-dihydrowithanolide H 29: Sitosterol--D-glucoside
Withania coagulans have afforded withacoagin
H3 C OH CH 3 H 3C OH CH 3 2,6,24-trienolide (35), (20R,22R)-6,7-
CH 3 H O CH 3 H O
O epoxy-5-20-hydroxy-1-oxowitha-2,24-
OH H OH dienolide (36) and (20S,22R)-6,7-epoxy-
30: coagulanolide 31:Withanolide F 5-dihydroxy-1-oxowitha-2,24-dienolide (37)
Fig 2: Compounds isolated from the fruits of Withania coagulans Dunal possess interesting
Withania coagulans biological activities. The fruits of the plant are
CH 3 CH 3
sweet and are reported to be sedative, emetic,
CH 3
CH 3
alterative and diuretic. They are useful in the
chronic complaints of liver. In some places

they are used as blood purifier. It is also used
in dyspepsia, flatulent colic and other intestinal
32 33: Withaferin A
infections. These are used for the treatment of
CH3 CH 3 asthma, biliousness and stranguary [21]. In the
H 3C H

CH 3
CH3 Unani system of medicine, they are used for
CH 3 H
CH 3 H
H O the treatment of wounds and ulcers. In the
H H H H fruits of Withania coagulans high degree of
OH O OH proteolytic activity has been reported. Acetone
34 35: Withacoagin
and alcohol precipitated fractions of the plant
CH 3 CH 3 showed 50.0 and 33.0 units of activity per

CH 3 H 3C H CH3 gram respectively, which is about half of that
HO O found for papain [22]. This plant is reported to
H H H H possess hepatoprotective, anti-inflammatory,
antihyperglycemic, hypolipidemic, free radical
scavenging, antimicrobial, cardiovascular,
central nervous system depressant,
Fig 3: Compounds isolated from the root of immunomodulating, antitumor and cytotoxic
Withania coagulans. activities.
Pharmacology Antihyperglycemic activity
It has a prominent place in Ayurvedic, Administration of an aqueous extract of
Unani, and ancient Indian systems of fruits of W. coagulans (1 g/kg; p.o.)
medicine. The berries of the plant are used for significantly lowered the blood sugar, serum
milk coagulation [3]. A number of reports cholesterol, serum LPO and hepatic LPO
reveal that the withanolides isolated from

110 Current R&D Highlights, Jan.-Mar. 2009

Natural Products
levels in streptozotocin induced diabetic rats The db/db mice supplemented with compound
after 7 days of treatment (p<0.001). Such lipid 5 at a dose of 50 mg/kg body weight for 10
lowering activity in streptozotocin induced consecutive days, significantly lowered the
diabetic rats may also help in preventing postprandial blood glucose level by 22.7% (p <
associated atherogenesis and other secondary 0.01), whereas metformin declined the
complications of diabetes mellitus. Its serum postprandial blood glucose by 18.6% (p <
LPO and liver LPO reducing activity suggests 0.05), when compared to vehicle-treated
that it may prevent lipid peroxidation and may control group. After 10 days of treatment, the
protect tissues from free radicals. It also glucose tolerance significantly improved in the
significantly (p<0.01) decreased blood glucose compound 14 treated group, compared to the
level in normal rats (at the dose 1 g/kg; po) [23]. vehicle-treated group. It was observed that
We have demonstrated significant significant (p < 0.05) inhibition in rise of
antihyperglycemic activity in the aqueous postprandial blood glucose level at time
extract of W. coagulans fruits in interval 90 min and 120 min in compound 14
normoglycemic as well as in STZ-induced as well as metformin treated group. For the
diabetic rat models at 250 mg/kg po dose level. compound 14 db/db mice group, the area under
We have isolated five withanolides identified the curve (AUC) of blood glucose decreased
as coagulin C (5), 17-hydroxywithanolide K by approximately 40.5% compared to vehicle
(3), withanolide F (31), coagulanolide treated group. In the other experiment,
[(17S,20S,22R)-14,15,17,20- compound 5 at a dose of 50 mg/kg body
tetrahydroxy-1-oxowitha- 2,5,24-trienolide] weight, showed significant improvement in
(30), which is a new compound and coagulin L plasma lipid profiles of dyslipidemic db/db
(14) from the aqueous extract of its fruits. The mice after 10 days of consecutive treatment.
compounds were evaluated for their The effect of increasing oral doses of
antihyperglycemic activity in normoglycemic compound 14 declined the postprandial
rat model (SLM) and in streptozotocin induced glucose level, was dose-dependent with a
diabetic rat model (STZ) as well as in a well calculated ED50 of around 25 mg/kg of body
characterized model of type 2 diabetes, that is, weight following oral administration [2].
C57BL/KsJ-db/db mice. Compound 14 was Discussion
most active, it was found to improve glucose
tolerance up to the tune of 29.8% in SLM and Withania coagulans Dunal has variety of
23.3% in STZ-induced diabetic rats at a dose pharmacological acivities. Extracts, fractions
of 100 mg/kg body weight. Compounds 5, 3, and isolated withanolides from Withania
31 and 30 exhibited significant coagulans Dunal have been reported for their
antihyperglycemic activity, 22.8%, 20.4%, various biological potentials. More extensive
24.9% and 28.1% in SLM and 16.9%, 15.8%, research on the chemistry and pharmacology
18.2% and 19.3% in STZ, models, of the withanolides should be carried out.
respectively. Compound 14 was further Isolation at large scale, chemical
evaluated in db/db mice. The C57BL/KsJ- transformations and synthesis of the active
db/db mice at 12 weeks of age exhibited most compounds will definitely enhance its
of the human characteristics of type 2 diabetes pharmacological value. Clinical trials should be
including hyperglycemia in the fasting and fed carried out on the active principles.
states, hyperinsulinemia and insulin resistance.

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References [12] Rahman, Atta-Ur., Shabbir, M., Yousaf, M.,
[1] Kirtikar, K.R., Basu, B.D.; 1995; Indian Medicinal Qureshi, S., Shahwar, Dur-E., Naz, A., Rahman, Atta-
Plants; International Book Distributors, Dehradune, Ur., Shahwar, Dur-E., Naz, A., Choudhary, M.I., 2003;
India. Phytochemistry; 63; 387390.

[2] Maurya, R., Akanksha, Jayendra, Singh, A.B., [13] Alam, Nur-e., Yousaf, M., Qureshi, S., Baig, I.,
Srivastava, A.K., 2008; Bioorganic & Medicinal Nasim, S., Rahman, Atta-Ur., Choudhary, M.I., 2003;
Chemistry Letters; 18; 65346537. Helvetica Chimica Acta; 86; 607-614.

[3] Chadha, Y.R., 1976; The Wealth of India, Raw [14] Velde, V.V., Lavie, D., Budhiraja, R.D., Sudhir, S.,
Materials; CSIR, New Delhi; 10; 580-581. Garg, K.N.; 1983; Phytochemistry; 22(10); 2253-2257.

[4] Rahman, Atta-Ur., Abbas, S., Shahwar, Dur-E., [15] Ramaiah, P.A., David, L., Budhiraja, R.D., Sharan,
Jamal, S.A., Choudhary, M.I., 1993; Journal of Natural S., Garg K.N., 1984; Phytochemistry; 23; 143-149.
Product; 56; 1000-1006.
[16] Subramanian, S.S., Sethi, P.D., 1969; Current
[5] Choudhary, M.I., Shahwar, Dur-E., Zeba, P., Jabbar, Science; 38; 267-68.
A., Ali, I., Rahman, Atta-Ur., 1995; Phytochemistry; 40;
[17] Kupchan, S.M., Anderson, W.K., Bollinger, P.,
Doskotch, R.W., Smith, R.M., Renauld, J.A.S., Schnoes,
[6] Rahman, Atta-Ur., Choudhary, M.I.; 1998; Pure & H.K., Burlingame, A.L., Smith, D.H.; 1969; Journal of
Applied Chemistry; 70; 385-389. Organic Chemistry; 34; 3858-3866.
[7] Rahman, Atta-Ur., Shabbir, M., Shahwar, Dur-e., [18] Subramanian S.S., Sethi, P.D., Glotter, E., Kirson,
Choudhary. M. I., Voelter, W., Hohnholz, D., 1998a; I., Lavie, D., 1971; Phytochemistry; 10; 685-688.
Heterocycles; 47; 1005-1011.
[19] Sethi, P.D., Subramanian, S.S., 1976; 38; 22-23.
[8] Rahman, Atta-Ur., Choudhary, M.I., Qureshi, S.,
[20] Neogi, P., Kawai, M., Butsugan, Y., Mori, Y.,
Gul, W., Yousaf, M., 1998b; Journal of Natural
Suzuki, M., 1988; Bulletin of the Chemical Society of
Product; 61; 812-814.
Japan; 61; 4479-4481.
[9] Rahman, Atta-Ur., Yousaf, M., Gul, W., Qureshi, S.,
[21] Kirtikar, K.R., Basu, B.D., 1933; Indian Medicinal
Choudhary, M.I., Voelter, W., Hoff, A., Jens, F., Naz,
Plants; vol. 3; Ed. By Basu, L. M., Allahabad; 1777-
A., 1998c; Heterocycles; 48; 1801-1811.
[10] Rahman, Att-Ur., Choudhary, M.I., Yousaf, M.,
[22] Atal, C.K., Sethi, P.D., 1961; Indian Journal of
Gul, W., Qureshi, S., 1998d; Chemical &
Pharmacy; 23; 7-9.
Pharmaceutical Bulletin; 46; 1853-1856.
[23] Hemalatha, S., Wahi, A.K., Singh, P.N.,
[11] Choudhary, M.I., 1999; Phytochemistry; 52; 1361-
Chansouria, J.P.N., 2004; Journal of
Ethnopharmacology; 93; 261-264.

112 Current R&D Highlights, Jan.-Mar. 2009

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Marine Biota and Diabetics

The Ocean, which is called the mother of a variety of molecules with unique structural
origin of life, is also the source of structurally features to survive in the adverse physical and
unique natural products that are mainly chemical conditions in the marine
metabolised/accumulated in living organisms. environment. Thus marine environment is an
Among 34 fundamental phyla of life, 17 occur exceptional reservoir of bioactive natural
on land whereas 32 occur in the sea (with products, many of which exhibit
some overlap). From the fundamental point of structural/chemical features not found in
view of biodiversity, the ocean is far more terrestrial natural products. Marine organisms
diverse and really would have been the better have evolved biochemical and physiological
place to start to develop a natural Pharmacy. mechanisms that include the production of
To date, researchers have isolated bioactive compounds for such purposes as
approximately 7000 marine natural products, reproduction, communication, and protection
25 percent of which are from algae, 33 percent against predation, infection and competition.
from sponges, 18 percent from coelenterates Beyond the chemical diversity, the sea also
(sea whips, sea fans and soft corals), and 24 provides amazing biological diversity. This
percent from representatives of other diversity has been the source of unique
invertebrate phyla such as ascidians (also chemical compounds with the potential for
called tunicates), opisthobranch molluscs industrial development as pharmaceuticals,
(nudibranchs, sea hares etc), echinoderms cosmetics, nutritional supplements, molecular
(starfish, sea cucumbers etc) and bryozoans probes, fine chemicals and agrochemicals.
(moss animals). Thus lifesaving drugs are In recent years, a significant number of
mainly found abundantly in microorganisms, novel metabolites with potent pharmacological
algae and invertebrates, while they are scarce properties havebeen discovered from the
in vertebrates. A simplistic analysis of these marine organisms. Although there are only a
data reveals that as the search for Drugs from few marine-derived products currently on the
the Sea progresses at the rate of a 10 percent
market, several robust new compounds derived
increase in new compounds per year, from marine natural products are now in the
researchers are concentrating their efforts on clinical pipeline, with more clinical
slow-moving or sessile invertebrate phyla that development. While the marine world offers
have soft bodies, and lack of spines or a shell, an extremely rich resource for novel
i.e. animals that require a chemical defence
compounds, it also represents a great challenge
mechanism. that requires inputs from various scientific
Studies on marine natural products has led areas to bring the marine chemical diversity up
to the discovery of many potently active to its therapeutic potential.
agents/chemical compounds. The marine There is a need for consorted efforts
environment, due to its hostilities towards towards the antidiabetic agents of marine
almost every class of marine organism, origin. If required we must modify SOPs for
induces the inhabitants to produce/metabolise

Current R&D Highlights, Jan.-Mar. 2009 113

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sample collection, preservation, extract significant role in pinpointing the bioactive
preparation and newer test models. In future, biota for particular medicinal properties.
Bioinformatics is going to play a very

Selected Bibliography (Patents)

Bryhn, M., Holmeide, A. K., & Kopecky, J.
New DHA derivatives and their use as medicaments Liquid dosage compositions of stable nanoparticulate
for the treatment of diabetes type 2. drugs.
ed. (Pronova Biocare A/S, N. 2006-IB1155 ed. (Elan Pharma International, L. I. 2003-US22187
[2006117664], 97pp-20061109. WO. 5-4-2006. [2004006959], 68-20040122. WO. 7-16-2003.
Bulawa, C.
Compounds and methods for modulating protein Gaitanaris, G. A.
Nuclear receptors as diagnostic and risk markers for
ed. (Foldrx Pharmaceuticals, I. U. 2007-US84257
[2008058269], 97pp-20080515. WO. 11-9-2007. disease and as targets for therapy.
ed. (Nura, I. U. 2003-US36229[2004045369], 508-
Fan, X., Ma, C., Han, L., Shi, D., & Liu, Q. 20040603. WO. 11-12-2003.
Extraction of bromophenol compounds from red
algae and their uses in the treatment of diabetes and Holmeide, A. K. & Rosman, J.
obesity. Fatty acid alcohols as prodrugs for the treatment of
ed. (Institute of Oceanology, C. A. o. S. P. R. C. 2005- elevated triglyceride levels.
10046293[1853618], 10pp-20061101. CN. 4-20-2005. ed. (Pronova Biopharma Norge AS, N. 2007-IB4590
[2008139261], 59pp-20081120. WO. 11-2-2007.
Foong, F. W. & Kuwabara, M.
Sea slug-derived immunopotentiating, nerve Hovey, D., Pruitt, J., & Ryde, T.
repairing, antiulcerative, antidiabetic and Nanoparticulate megestrol formulations containing
neurogenic pain preventing agent. surface stabilizer.
ed. (Imex Japan Co.Ltd., J. 2006-JP317254 ed. (Elan Pharma International Ltd., U. 2004-878623
[2007026836], 45pp-20070308. WO. 8-31-2006. [2005008707], 38-20050113. US. 6-29-2004.

Hwang, C. G. Marshall, W. S.
System and method for modifying a fluid for oral IgG Fc-domain peptide conjugates as glucagon
administration. antagonists.
ed. (Remote Clinical Solutions, I. U. 2005-US30146 ed. (Amgen Inc., U. 2001-US14321[2001083527], 54-
[2006023985], 41-20060302. WO. 8-23-2005. 20011108. WO. 5-3-2001.

Bosch, H. W. Mayer, A. M. S. & Hamann, M. T.

Novel nanoparticulate nimesulide compositions. Marine pharmacology in 2001-2002: Marine
ed. (Elan Pharma International Ltd., I. 2003- compounds with anthelmintic, antibacterial,
US32731[2005051356], 87-20050609. WO. 10-31- anticoagulant, antidiabetic, antifungal, anti-
2003. inflammatory, antimalarial, antiplatelet,
Bosch, W. H. antiprotozoal, antituberculosis, and antiviral

114 Current R&D Highlights, Jan.-Mar. 2009

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activities; affecting the cardiovascular, immune and The curcuminoids- and anthocyanins-responsive
nervous systems and other miscellaneous genes in human adipocytes and their use in
mechanisms of action. screenings of anti-obesity and anti-diabetes drugs.
Comp.Biochem.Physiol., Part C: Toxicol.Pharmacol. ed. (Biomarker Science Co., L. J. 2004-
140C[3-4], 265-286. 2005. 53258[2005198640], 85-20050728. JP. 2-27-2004.

Urakami, T. et al.
Negreanu-Pirjol, T., Sirbu, R., & Guran, C. Process for producing oxazopyrroloquinolines, novel
New transitional metal complexes of biguanide oxazopyrroloquinolines, and use of oxazopyrro-
derivatives - biological activity on marine organisms. loquinolines.
J.Environ.Prot.Ecol. 6[4], 827-837. 2005. ed. (Mitsubishi Gas Chemical Co., I. J. 90-403176
[429333], 59-19910529. EP. 11-8-1990.
Sato, N.
Health food compositions for prevention and Van Kaer, L.
treatment of obesity. Drugs from the sea: A marine sponge-derived
eds. (Someya, H. J. & Tangolwood K.K.). 2004- compound prevents type 1 diabetes.
203833[2006020606], 12-20060126. JP. 7-9-2004. The Scientific World 1, 630-632. 2001
(Compiled byDr. RK Sharma,Botany Division, Central Drug
Research Institute, Lucknow)
Ueno, Y., Tsuda, T., Takanori, H., Yoshikawa, T., &
Osawa, T.
glutathione-S-transferase (GST), superoxide
Antidiabetic effect of Punica granatum dismutase (SOD) and catalase (CAT) were the
flowers: Effect on hyperlipidemia, salient features observed in diabetic rats. On
pancreatic cells lipid peroxidation and the other hand, oral administration of PgAq at
antioxidant enzymes in experimental doses of 250 mg/kg and 500 mg/kg for 21 days
diabetes. resulted in a significant reduction in fasting
Bagri, Priyanka et al. blood glucose, TC, TG, LDL-C, VLDL-C and
Food and Chemical Toxicology, 47(1), 50 tissue LPO levels coupled with elevation of
(Jan., 2009) HDL-C, GSH content and antioxidant enzymes
The study investigated the effects of in comparison with diabetic control group. The
Punica granatum aqueous extract (PgAq) on results suggest that PG could be used, as a
streptozotocin (STZ) induced diabetic rats by dietary supplement, in the treatment of chronic
diseases characterized by atherogenous
measuring fasting blood glucose, lipid profiles
(atherogenic index), lipid peroxidation (LPO) lipoprotein profile, aggravated antioxidant
and activities of both non-enzymatic and status and impaired glucose metabolism and
enzymatic antioxidants. Diabetes was induced also in their prevention.
by single intraperitoneal injection of STZ Effect of bitter gourd and spent
(60 mg/kg) to albino Wistar rats. The increase turmeric on glycoconjugate metabolism in
in blood glucose level, total cholesterol (TC), streptozotocin-induced diabetic rats.
triglycerides (TG), low-density lipoprotein Vijayalakshmi, B. et al.
cholesterol (LDL-C), very low density Journal of Diabetes and its
lipoprotein (VLDL), LPO level with decrease Complications, 23(1), 71 (2009)
in high density lipoprotein cholesterol (HDL- Changes in glycoconjugate metabolism
C), reduced glutathione (GSH) content and during the development of diabetic
antioxidant enzymes namely, glutathione complications and their modulation by feeding
peroxidase (GPx), glutathione reductase (GR), bitter gourd and spent turmeric as fiber-rich
Current R&D Highlights, Jan.-Mar. 2009 115
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source. This was studied by measuring the model). We observed that STZ administration
contents of total sugar, uronic acid, amino (at a dose of 65 mg/kg body weight, injected in
sugar, and sulfate in the streptozotocin-induced the tail vain) caused increased production of
diabetic rats. Total sugar content decreased in both ROS and RNS in the pancreas tissue of
liver, spleen, and brain, while an increase was experimental animals. Formation of these
observed in heart and lungs. Uronic acid reactive intermediates decreased the
content in liver, spleen, and brain decreased, intracellular antioxidant defense, increased the
and marginal increase was observed in testis. levels of lipid peroxidation, protein
Amino sugar content decreased in liver, carbonylation, serum glucose and TNF-
spleen, lungs and heart during diabetes, and [alpha]. Investigating the signaling pathways,
augmentation was observed to different we found that STZ administration caused the
extents. Decrease in sulfation of activation of phospho-ERK1/2, phospho-p38,
glycoconjugates was observed in liver, spleen, NF-[kappa]B and destruction of mitochondrial
lungs and heart during diabetes and was transmembrane potential, release of
significantly ameliorated by bitter gourd and cytochrome c as well as activation of caspase 3
spent turmeric, except brain. Protein content in the pancreas tissue keeping the levels of
decreased in liver, while an increase was total ERK1/2 and p38 significantly unchanged.
observed in brain. The studies clearly showed Treatment of animals with AA (at a dose of
alteration in glycoconjugate metabolism during 20 mg/kg body weight, orally) both prior and
diabetes and amelioration to different extents post to the STZ administration effectively
by feeding bitter gourd and spent turmeric. reduced these adverse effects by inhibiting the
Improvement is due to slow release of glucose excessive ROS and RNS formation as well as
by fiber in the gastrointestinal track and short- by down-regulating the activation of phospho-
chain fatty acid production from fiber by colon ERK1/2, phospho-p38, NF-[kappa]B and
microbes. mitochondrial dependent signal transduction
Protective role of arjunolic acid in pathways leading to apoptotic cell death.
response to streptozotocin-induced type-I Combining all, these results suggest that AA
diabetes via the mitochondrial dependent plays some beneficial roles against STZ-
and independent pathways. induced diabetes.
Manna, Prasenjit et al. Modification of psyllium poly-
Toxicology (In Press) saccharides for use in oral insulin delivery.
Increasing evidences in both experimental Singh, Baljit et al.
and clinical studies suggest that oxidative Food Hydrocolloids, 23(3), 928 (May
stress is involved in the pathogenesis of 2009)
diabetic tissue damage. Pancreatic [beta]-cell There is no doubt that fibers, in particular
death is the cause of decreased insulin viscous dietary fibers, have positive effects on
production in diabetes. Streptozotocin (STZ) is human health, both in the prevention and in
widely used to induce experimental diabetes treatment of chronic diseases. Psyllium, a
due to its ability to selectively target and medicinally important serum glucose reducing
destroy insulin producing pancreatic [beta]- natural polysaccharide, if suitably tailored to
cells via the formation of both reactive oxygen prepare the hydrogels for controlled release of
species (ROS) and RNS (reactive nitrogen insulin; it can act as double potential candidate
species). This study investigated the for cure of diabetes mellitus. Keeping in view
prophylactic role of arjunolic acid (AA) the therapeutic importance of psyllium and its
against STZ-induced diabetes in the pancreas gel-forming nature we have prepared psyllium
tissue of the Swiss albino rats (as a working and methacrylamide based hydrogels by using

116 Current R&D Highlights, Jan.-Mar. 2009

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N,N'-methylenebisacrylamide as crosslinker. Glucose Tolerance Test was done to determine
The present paper discusses the effect of pH on the effective dose of Costus pictus extract.
swelling kinetics of the hydrogels and release Aqueous extract of Costus pictus leaves was
dynamics of insulin from drug-loaded given orally to the diabetic rats for 14 days.
hydrogels, for the evaluation of the swelling The insulin secretory action of the leaf extract
mechanism and drug release mechanism from was investigated using isolated pancreatic
the hydrogels. Non-Fickian diffusion islets from rat. Liver glucose uptake activity
mechanism has been observed for the release was measured using D-[14C] glucose. The oral
of insulin in pH 2.2 buffer and pH 7.4 buffer. administration of an aqueous extract of Costus
Inhibition of 11[beta]-hydroxysteroid pictus at a dose of 250 mg/kg body weight
dehydrogenase type 1 by plant extracts used significantly decreased the blood glucose with
as traditional antidiabetic medicines. significant increase in plasma insulin level in
diabetic rats at the end of 14 days treatment.
Gumy, Christel et al.
Fitoterapia The Costus pictus leaf extract significantly
Elevated glucocorticoids are a key risk increased glucose induced insulin secretion at
factor for metabolic diseases, and the both 4 mM and 20 mM glucose concentrations
glucocorticoid-activating enzyme 11[beta]- which represents normal physiological and
diabetic condition respectively. The decreased
hydroxysteroid dehydrogenase 1 (11[beta]-
HSD1) represents a promising therapeutic glucose uptake activity of the liver of diabetic
target. Authors have measured the potential of rats were reverted back to near normal levels
six traditional antidiabetic medicinal plants after the treatment with Costus pictus leaf
extracts to inhibit 11[beta]-HSD1 activity and extract. Our results suggest the glucose
glucocorticoid receptor (GR) activation in lowering effect of Costus pictus to be
transfected HEK-293 cells. Leave extracts of associated with potentiation of insulin release
Eriobotrya japonica preferentially inhibited from pancreatic islets and enhancement of
11[beta]-HSD1 over 11[beta]-HSD2. Extracts peripheral utilization of glucose. (ScienceDirect).
of roasted but not native coffee beans A novel compound from Casearia
preferentially inhibited 11[beta]-HSD1 over esculenta (Roxb.) root and its effect on
11[beta]-HSD2, emphasizing the importance carbohydrate metabolism in streptozotocin-
of sample preparation. Thus, natural diabetic rats.
compounds inhibiting 11[beta]-HSD1 may Chandramohan, Govindasamy et al.
contribute to the antidiabetic effect of the European Journal of Pharmacology,
investigated plant extracts. (ScienceDirect) 590(1-3), 437 (Aug., 20, 2008)
Antihyperglycemic and insulin Casearia esculenta root (Roxb.) is widely
secretory activity of Costus pictus leaf used in traditional system of medicine to treat
extract in streptozotocin induced diabetic diabetes in India. An active compound 3-
rats and in in vitro pancreatic islet culture. hydroxymethyl xylitol (3-HMX) has been
Gireesh, G. et al. isolated and its optimum dose has been
Journal of Ethnopharmacology determined in a short duration study and
The leaves of Costus pictus D Don were patented. In the present study, the long-term
used extensively for its anti hyperglycemic effect of 3-HMX in type 2 diabetic rats has
activity by the people in Kerala, India. In the been investigated. An optimum dose of 3-
present study, the antihyperglycemic and HMX (40mg/kg body weight) was orally
insulin secretory activity of an aqueous extract administered for 45days to streptozotocin-
of Costus pictus leaf extract was investigated diabetic rats for the assessment of glucose,
in streptozotocin induced diabetic rats. Oral insulin, hemoglobin (Hb), glycated

Current R&D Highlights, Jan.-Mar. 2009 117

Natural Products
hemoglobin (HbA1c), hepatic glycogen, and HMX at 40mg dose produced similar effects
activities of carbohydrate metabolizing on all biochemical parameters studied as that
enzymes, such as glucokinase, glucose 6- of glibenclamide, a standard drug. Histological
phosphatase, fructose 1,6-bisphosphatase and study of pancreas also confirmed the
glucose-6-phosphate dehydrogenase and biochemical findings. These results indicate
hepatic marker enzymes, such as aspartate that 3-hydroxymethyl xylitol, the compound
aminotransferase (AST), alanine amino- from C. esculenta, possesses antihyper-
transferase (ALT), alkaline phosphatase (ALP) glycemic effect on long-term treatment also.
and gammaglutamyl transferase (GGT) in
normal and streptozotocin-diabetic rats. 3-

Drugs & Pharmaceuticals

Current R&D Highlights
Form IV (See rule 8)

1. Place of Publication : Lucknow

2. Periodicity of its publication : Bi-Monthly
3. Printer's Name : Dr. Sheela Tandon
(Whether citizen of India?) : Yes
Address : CDRI, Chattar Manzil Palace,
Lucknow-226 001.
4. Publisher's Name : Dr. Sheela Tandon
(Whether citizen of India?) : Yes
Address : CDRI, Chattar Manzil Palace,
5. Editor's Name : Dr. Sheela Tandon
(Whether citizen of India?) : Yes
Address : CDRI, Chattar Manzil Palace,
6. Names and Addresses of individuals who own : Government publication
the newspaper and partners or shareholders
holding more than one per cent of the total capital.
I, Dr. Sheela Tandon, hereby declare, that the particulars given above are true to the best of my
knowledge and belief.

Dated: 31.03.2009 Signature of Publisher


118 Current R&D Highlights, Jan.-Mar. 2009


Latent Autoimmune Diabetes in Adults (LADA)

Introduction GAD/ICA positivity and/or high-titer anti-
Latent autoimmune diabetes in adults GAD was found to correlate with an early age
(LADA) is the term that was coined to of onset, reduced -cell function, the presence
describe a condition that, although of other autoimmune disorders, fewer markers
phenotypically identical to type 2 diabetes, of metabolic syndrome (high body mass index,
also features circulating pancreatic islet cell hypertension, dyslipidemia) and increased
antibodies (ICAs) and a slow progression to frequency of high-risk diabetes type 1-
autoimmune -cell failure. Thus, LADA associated HLA class II alleles (discussed
shares features with both type 1 and type 2 below).
diabetes. The acronynm LADA has generally Clinical Symptoms
been surrounded by controversy since it has As mentioned earlier, LADA shares
been difficult to define the disorder as a metabolic features with type 1 and type 2
distinct etiological entity and not a mere diabetes. Thus, type 2 diabetes and LADA
subtype of type 1 diabetes. The term latent has patients have been shown to present with a
also been questioned, as the disease is not similar degree of insulin resistance and
typically latent (i.e., existing but not yet elevated glucagon levels, but the latter exhibit
apparent) since autoimmune serology is severe and progressive defects in -cell
present and is required for diagnosis. function, hence resembling type 1 diabetes.
Therefore, other acronyms and names have However, unique clinical features may be
been proposed, such as ADA (autoimmune associated with this form of diabetes.
diabetes in adults) or autoimmune diabetes not Fourlanos et al. found that, compared to
requiring insulin at diagnosis, among others. patients with type 2 diabetes, most patients
Regardless of the term used, the diagnosis with LADA exhibited at least two of the
of LADA is based on three criteria: 1) diabetes following five clinical parameters: 1) age of
onset occurs at adult age (25-40 years); 2) the onset < 50 years; 2) acute symptoms; 3) body
presence of circulating ICAs; and 3) insulin mass index (BMI) < 25 kg/m2; 4) personal
therapy is not required for at least 6 months history of autoimmune disease; or 5) family
after diagnosis. The serology of LADA history of autoimmune disease. Moreover, the
patients at diagnosis typically shows presence of at least two of these features at
circulating islet cell antibodies of the IgG type diagnosis had a sensitivity and specificity for
and antibodies to glutamic acid decarboxylase LADA detection of 90% and 70%,
(GAD), the presence of which has been respectively. Alternatively, the presence of less
correlated with further insulin dependence. than two distinguishing clinical parameters
Moreover, the clinical picture of LADA resulted in a negative predictive value of 99%,
patients may be associated with titers of hence representing a highly reliable method for
diabetes-associated autoantibodies, as some excluding the disease. When compared to type
authors have proposed. Thus, combined anti- 1 diabetes patients, LADA subjects have been

Current R&D Highlights, Jan.-Mar. 2009 119

noted to show higher BMI, elevated Moreover, N-terminal binding by GAD65
triglycerides and HDL cholesterol, greater antibodies was inversely correlated with the
insulin resistance, as well as greater plasma C- time to insulin requirement. However,
peptide concentrations, an indicator of insulin reactivity against C-terminal and middle
production by -cells. epitopes of GAD65 has also been described in
The criterion of insulin independence in LADA patients, with no relationship found
LADA can be rather subjective and may between binding and time to treatment or
disease progression. This study confirmed the
depend on insulin-prescribing trends, among
other factors. A recent study showed that the long-term persistence of GAD antibodies (6
time to insulin treatment depended on whether years) after diagnosis, indicating that it is a
autoantibody testing was performed or not, valid criterion for the diagnosis of LADA
thus being shorter in those centers that several years after the onset of hyperglycemia.
routinely performed laboratory tests for Genetics
diabetes-associated autoantibodies. Similarly to what occurs in type 1
Pathophysiology of LADA diabetes, certain HLA class II genes appear to
The loss of tolerance to self-antigens be associated with higher LADA risk.
present in insulin-secreting -cells in Particularly, HLA DR3 and/or DR4 and DQ2
pancreatic islets appears to be the underlying and/or DQ8 are the highest-risk HLA alleles
pathogenic process in LADA, as well as in for type 1 diabetes, which have also been
type 1 diabetes. However, both LADA and found in LADA patients, hence suggesting a
type 1 diabetes present with specific similar genetic basis. For instance, LADA and
serological markers. The four islet antibody type 1 diabetes patients exhibited an increased
subtypes, namely ICAs, GAD antibodies, prevalence of the high-risk HLA-DQB1*0302,
insulinoma antigen 2 (IA-2) antibodies and -DR4, -D3 and -DR3/DR4 genotypes and the
insulin autoantibodies, are also present in type high-risk DR3/DR4-DQB1*0302 haplotype
1 diabetes, whereas IA-2 and insulin compared to a control population.
autoantibodies are rarely seen in LADA Interestingly, another study evaluating the
patients. Detection of ICAs and GAD genotypes of patients with LADA and
antibodies is thus key in the diagnosis of nondiabetic individuals found that DR4
LADA. The enzyme GAD has two isoforms, antigen specificity subtypes may confer a
GAD65 and GAD67, which catalyze the differential risk for LADA, with DRB1*0401
formation of -aminobutyric acid (GABA) in and DRB1*0403(06/07) being predisposing
neurons and pancreatic Langerhans islets. The and protective, respectively. Besides HLA
GAD65 isoform appears to be particularly genes, LADA has also been associated with
important in the detection of type 1 diabetes, other genetic factors. Thus, variations in the
since it is found in up to 80% of patients and is variable number of tandem repeats (VNTR)
considered a predictive marker. GAD65 anti- minisatellite upstream of the insulin gene
region 100M2, which accounts for about 10%
bodies appear to bind specific epitopes
comprised in the N-terminal region of the of familial risk for type 1 diabetes, have also
GAD enzyme (the membrane anchoring site), been significantly associated with
according to a study in patients with "slowly susceptibility to LADA. However, these
progressive type 1 diabetes". In contrast, genetic variations did not help to distinguish
between type 1 diabetes and LADA. Also,
GAD65 antibodies from the sera of type 1
diabetes patients did not react with this outside the HLA region, the tyrosine-protein
specific N-terminal site. phosphatase non-receptor type 22 gene
(PTPN22) encoding a lymphoid-specific

120 Current R&D Highlights, Jan.-Mar. 2009

phosphatase known as LyP, which is a yet clear which are the best treatments for this
powerful inhibitor of T-cell activation, has condition.Lifestyle intervention (diet and
been identified with type 1 diabetes in young exercise) together with insulin therapy is
subjects. A recent study has demonstrated an usually the strategy of choice. Although
association between the PTPN22 C1858T gene efficacy for early insulin treatment (at
polymorphism and patients with adult-onset diagnosis) in preventing -cell failure has been
diabetes and high GAD antibody titers, reported , some evidence suggests that it may
compared to those with low antibody titers, not be superior to diet or oral hypoglycemic
type 2 diabetes and a control population. Other control. A randomized, open study is currently
authors have encountered a higher frequency examining the clinical efficacy of early insulin
of the C1858T gene polymorphism in LADA treatment in patients with LADA compared to
patients compared to type 1 diabetes and oral hypoglycemic agents (metformin,
nondiabetic subjects. The PTPN22 C1858T sulfonylureas, rosiglitazone).
gene variant has also been linked to other The efficacy of thiazolidinedione
autoantibody-producing autoimmune diseases. treatment in LADA has not been thoroughly
A recent study confirmed these findings studied. Nevertheless, a pilot study evaluating
and showed that LADA shared genetic features 23 LADA patients randomized to receive
with type 1 diabetes, namely associations with premixed human insulin twice daily alone or
HLA-DQB1, insulin gene (INS) VNTR and rosiglitazone (4 mg/day) plus insulin found
PTPN22, but LADA patients also presented that this latter approach may be more effective
with a variant of the transcription factor 7 -like in preserving -cell function than insulin
2 (TCF7L2) gene, which is strongly associated alone. Combined insulin and rosiglitazone
with type 2 diabetes. The authors concluded treatment stabilized C-peptide levels after
that these results support the hypothesis that glucose load (PCP) and glucagon-stimulated
LADA is a combination of type 1 and type 2 11 C-peptide (I1CP) at 12 and 18 months after
diabetes, rather than just a form of type 1 treatment onset, while both parameters
diabetes. Another study investigated the declined with insulin monotherapy at those
potential relationship of LADA with cytokine time points (Table I).
genes involved in the pathogenesis of other Current investigations are focusing on two
autoimmune disorders and found an increased vaccine candidates, which attempt to provide
frequency in the interleukin 1L10-1082A1G better prevention of islet -cell destruction
gene variant in LADA compared to type 2 (Table I). DiamydID is a recombinant human
diabetics. Other studies have shown
DNA vaccine consisting of the recombinant
associations of LADA with insulin resistance human GAD 65-kD isoform (rhGAD65) that is
genes (lRS1, IRS2) and vitamin D receptor currently in phase 11/111 clinical trials for the
(VOR) gene polymorphisms. subcutaneous (s.c.) treatment of type 2
Treatment diabetes at Diamyd Medical, and in phase III
trials for the treatment of children and
In general, the treatment of LADA, as
well as the major diabetes types, is aimed at adolescents with type 1 diabetes, also as an s.c.
providing optimal glycemic control and formulation.
preserving -cell function. However, it is not

Current R&D Highlights, Jan.-Mar. 2009 121

Table 1: Summary of Therapeutic Strategies in LADA

Drug Design Treatments N Conclusions / Objectives

Rosiglitazone Randomized Rosiglitazone, 4 23 In comparison with insulin monotherapy,

combined insulin plus rosiglitazone
mg/d + Insulin, treatment preserved l3-cell residual
b.Ld Insulin, b.Ld. function at 12 and 18 months of follow-up.
No severe hypoglycemic attacks or other
adverse events were reported during the
study period
Human Randomized 160 This phase II/III study will investigate the
Human recombinant
GAD65 Double-blind GAD65, 4, 20, 100 safety and efficacy of DiamycfID
or500 Ilg s.c. at wks (rhGAD65) for the treatment of LADA.
1 and 4 Placebo The primary outcome measure will assess
the change in glycosylated hemoglobin
(HbA1c) at 18 months (main study period)
after the prime injection of Diamyd@ 20
Ilg versus baseline in comparison with

Human recombinant 47 This randomized, double-blind, dose-
GAD65 , 20 Ilg s.c. escalation trial of Diamyd@ showed
at wks 1 and 4 increased C-peptide levels at 24 weeks at a
Placebo dose of 20 Ilg in LADA patients. No safety
issues were reported.

DiaPep277 100 This study will assess the safety,

Randomized DiaPep277, s.c. immunological and clinical efficacy of
Double-blind Placebo DiaPep277 versus placebo. DiaPep277 will
be administered at 0, 1 and 3 months, and
then every 3 months for a total of 8
administrations. The duration of the trial
will be 18 months of treatment plus 6
months of follow-up

(Based on the article written by E. Ferrer, C. Dulsat and published in Drugs of the Future 2008, 33(11): 963-967)

122 Current R&D Highlights, Jan.-Mar. 2009

treatment of diabetes and manufacturing
method thereof.
Mansilla; Audino et al.
US Patent 7,482,030 January 27, 2009
Therapeutic agent for diabetes mellitus. Appl. No.:11/809,747 June 1, 2007
Kamiya , et al. The invention refers to a new composition
Kyowa Hakko Kogyo Co., Ltd. ,Tokyo, comprising natural herbs for the treatment of
Japan diabetes, and to a method for preparing said
US Patent 7,485,662 February 3, 2009 composition. The composition contains the
Appl. No.: 10/549,155 March 19, 2004 herb Mulinum spinosum and Chamaemelum
An object of the invention is to provide a nobile mixed in a specific proportion using
therapeutic agent for diabetes mellitus and an mineral water as solvent.
insulin resistance improving agent. In order to Systems and methods for modulation of
achieve such an object, the agents comprised pancreatic endocrine secretion and
of hydroxyproline and derivatives were used. treatment of diabetes.
Peptides acting as both GLP-1 receptor Whitehurst ,TK et al
agonists and glucagon receptor antagonists Boston Scientific Neuromodulation,
and their pharmacological methods of use. Valencia, California, US
Pan; Clark , et al. US Patent 7,477,944 January 13, 2009;
Bayer Pharmaceuticals Corporation, West 19.12.2004
Haven, Connecticut, US Systems and methods for introducing one
US Patent 7,488,714 February 10, 2009 or more stimulating drugs and/or applying
Appl. No.:11/212,439 August 26, 2005 electrical stimulation to the pancreas and/or
nerve fibers innervating the pancreas to treat or
The invention provides polypeptides that prevent diabetes and/or to modulate pancreatic
act both as an agonist of the GLP-1 receptor endocrine secretions uses at least one system
and an antagonist of the glucagon receptor. control unit (SCU) producing electrical pulses
Such polypeptides are useful for treating delivered via electrodes and/or producing drug
individuals with type-2 diabetes or other infusion pulses, wherein the stimulating
metabolic disorders. drug(s) are delivered via one or more pumps
Cannabinoid receptor antagonists/ and infusion outlets.
inverse agonists useful for treating Glycinamide derivatives as raf-kinase
metabolic disorders, including obesity and inhibitors.
diabetes. Buchstaller , HP et al
McElroy , et al Merck Patent GmbH, Darmstadt,
Jenrin Discovery, Inc., West Chester, Germany
Pennsylvania, US US Patent 7,476,683 January 13, 2009
US Patent 7,482,470 January 27, 2009 Appl. The invention relates to glycinamide
No.: 11/745,162 May 7, 2007 derivatives of formula (I), the use of the
The invention provides novel pyrazoles compounds of formula (I) as inhibitors of raf-
that are useful as cannabinoid receptor kinase, the use of the compounds of formula
antagonists and pharmaceutical compositions (I) for the manufacture of a pharmaceutical
thereof and methods of using the same for composition and a method of treatment,
treating obesity, diabetes, and/or comprising administering said pharmaceutical
cardiometabolic disorders. composition to a patient.
Natural herb composition for the

Current R&D Highlights, Jan.-Mar. 2009 123

Bicyclic pyrazolo protein kinase Denmark
modulators US Patent 7,470,542 December 30, 2008
Bounaud , et al. The invention relates to the use of
SGX Pharmaceuticals, Inc. San Diego, naturally occurring compounds and derivatives
California, US thereof as markers for predisposition of
US Patent 7,473,783 January 6, 2009 diabetes related diseases. The invention also
Appl. No. 11/016,126 December 17, 2004 relates to a pharmaceutical composition for
treatment of the diabetes related diseases.
The invention provides novel bicyclic
pyrazolo kinase modulators and methods of Use of gp130 activators in diabetic
using the novel bicyclic pyrazolo kinase neuropathy.
modulators to treat diseases mediated by Dreano; Michel, et al.
kinase activity. Laboratoires Serono SA ,Vaud,
Pyrazole compounds useful as protein Switzerland
kinase inhibitors. US Patent 7,465,441 December 16, 2008
Davies; Robert , et al. Appl. No.: 10/492,087 October 10, 2002
Vertex Pharmaceuticals Incorporated The invention relates to the use a
Cambridge, Massachussetts, US substance signaling through gp130 for the
US Patent 7,473,691 January 6, 2009 manufacture of a medicament for the treatment
Appl. No.: 09/952,875 September 14, 2001 and/or prevention of diabetic neuropathy. The
This invention describes novel protein use of IL-6 is preferred.
kinase inhibitors of formula are useful for System and method for evaluating
treating diseases such as cancer, diabetes and impaired glucose tolerance and diabetes
Alzheimer's disease. mellitus within a patient using an
Metastable benzoxepne derivatives implantable medical device.
which can be used in the treatment of Bharmi; Rupinder et al.
dyslipidaemia atherosclerosis and diabetes, Pacesetter, Inc., Sylmar, California, US
pharmaceutical compositions comprising US Patent 7,462,150 December 9, 2008
them and processes for the preparation Appl. No.: 11/450,937 June 9, 2006
thereof.. Techniques are described for use by a
Bosc; Nathali et al. pacemaker or implantable cardioverter/
Merck Patent GmbH ,Darmstadt, defibrillator (ICD) or other implantable
Germany medical device. The techniques are provided
US Patent 7,470,719 December 30, 2008 for evaluating the likelihood that the patient, in
Appl. No.: 10/530,571 September 1, 2003 which the device is implanted, has impaired
The present invention relates to novel glucose tolerance (IGT) or diabetes mellitus.
metastable derivatives of benzoxepines of the Briefly, a value representative of sleep quality
formula (I) in which n represents 0, 1 or 2; and of the patient is detected and then the
likelihood that the patient has IGT or diabetes
the radicals R, which may be identical or
different, are alkyl or alkoxy groups, or mellitus is determined based on the sleep
halogen atoms, which can be used in the quality value. In this regard, it has been found
treatment of dyslipidaemia, atherosclerosis and that a decrease in overall sleep quality is
diabetes. associated with an increased likelihood of IGT
or diabetes mellitus, which is in turn
Proteins in type 2 diabetes. associated with an increased risk of mortality.
Hojlund; Kurt et al. Hence, sleep quality may be used as a proxy
Pride Proteomics A/S ,Odense M, for evaluating the likelihood that the patient

124 Current R&D Highlights, Jan.-Mar. 2009

has IGT or diabetes mellitus and for assessing diseases in which the dipeptidyl peptidase-IV
associated mortality risk. enzyme is involved, such as diabetes and
Treatment of diabetes with copper particularly type 2 diabetes. The invention is
binding compounds also directed to pharmaceutical compositions
Baker; John Richard et al. comprising these compounds and the use of
US Patent 7,459,446 December 2, 2008 these compounds and compositions in the
Appl. No 11/023,827 December 28, 2004 prevention or treatment of such diseases in
which the dipeptidyl peptidase-IV enzyme is
Novel methods of treating a patient for
diseases, disorders, and conditions including involved.
diabetes mellitus, comprising administering, Treatment of gestational diabetes
for example, copper binding compounds. Hiles; Richard A. et al
Substituted carboxylic acid derivatives Amylin Pharmaceuticals, Inc., San Diego,
for the treatment of diabetes and lipid California,US
disorders, their preparation and use US Patent 7,452,858 November 18, 2008
Choi; Yong Moon et al Methods for treating gestational diabetes
SK Holding Co., Ltd., Seoul, Korea which comprise administration of an effective
US Patent 7,456,293 November 25, 2008 amount of an exendin or an exendin agonist,
Appl. No 11/391,031 March 28, 2006 alone or in conjunction with other compounds
The invention is concerned with racemic or compositions that lower blood glucose
or enantiomerically enriched substituted levels.
carboxylic acids and derivatives or Chroman carboxylic acid derivatives
pharmaceutically acceptable salts thereof. The for the treatment of diabetes and lipid
present invention also includes pharmaceutical disorders.
compositions comprising an effective amount Choi; Yong Moon et al.
of a compound of Formula 1 in admixture with SK Holdings Co, Ltd., Seoul, Korea
a pharmaceutically acceptable carrier or US Patent 7,446,127 November 4, 2008
excipient. The compositions may include Appl. No.: 10/926,615 August 26, 2004
additional therapeutic agents for combination There are disclosed derivatives of 3-
therapy. The present invention provides a new chromancarboxylic acid and their
class of pharmaceutically active compounds, pharmaceutically acceptable salts thereof and
which are useful in the treatment and control prodrugs thereof which are useful for treatment
of diabetes and its related metabolic diseases. and control of non-insulin dependent diabetes
Cyclohexylglycine derivatives as mellitus (type II diabetes) and its related
dipeptidyl peptidase inhibitors for the vascular disease as well as obesity and lipid
treatment or prevention of diabetes. disorders.
Edmondson; Scott D. et al Herbal compositions for the treatment
Merck & Co., Inc.,Rahway, New Jersy, of diabetes and/or conditions associated
US therewith.
US Patent 7,456,204 November 25, 2008 Fogel, Dov; et al.
Appl. No 10/560,771 June 10, 2004 Ascarit Ltd; Illinois,US
The present invention is directed to novel WO/2009/001362 Application No.:
cyclohexylglycine derivatives which are PCT/Il2008/000880 Publication Date:
inhibitors of the dipeptidyl peptidase-IV 31.12.2008, Filing Date:26.06.2008
enzyme ("DP-IV inhibitors") and which are The present invention discloses herbal
useful in the treatment or prevention of compositions comprising at least one Urtica

Current R&D Highlights, Jan.-Mar. 2009 125

species or an extract thereof, at least one levels in a patient with diabetes and the use
Artemisia species or an extract thereof, and an thereof for treating diabetes the formulations
extract of at least one Morus species, wherein according to the present invention are
this extract is prepared of morus leaves and particularly useful for treating patients with
comprises morus latex further are disclosed diabetes type 2. for this, the present invention
methods for the preparation of these provides a herbal formulation comprising
compositions, uses thereof in treating and /or cinnamon and gymnema sylvestre extract.
preventing diabetes, related conditions and
Non-invasive in vivo imaging and
hypertriglyceridemia, as well as methods of methods for treating type I diabetes.
treating subjects suffering from these
conditions. Biocrine AB, Stockholm Sweden.
Biomarkers for pre-diabetes, WO/2009/027106 Application No.: PCT/
cardiovascular diseases, and other EP2008/007130 Publication Date:05.03.2009
metabolic-syndrome related disorders and filing date:01.09.2008
methods using the same. The invention provides novel drug
Hu, Yun, Fu; discovery platforms and methods for treating
Metabolon, Inc.; Capitola, Durham, North type I diabetes.
Carolina, US Molecules and methods for treatment
WO/2009/014639 Application No.PCT/ and detection of diabetes.
US2008/008756 Publication Date:29.01.2009 University of Washington Seattle,
Filing Date:17.07.2008 Washington, US
Biomarkers relating to insulin resistance, WO/2009/033121 Application No.:PCT/
pre-diabetes, type-2 diabetes, metabolic
US2008/075524 Publication Date:12.03.2009
syndrome, atherosclerosis, and Filing Date:06.09.2008
cardiomyopathy are provided, as well as Described are antibodies that specifically
methods for using such biomarkers as recognize and bind the epitope of glutamate
biomarkers for insulin resistance, pre-diabetes, decarboxylase (gad65) that is bound by
type-2 diabetes, metabolic syndrome,
antibody b96 11, and anti-idiotypic antibodies
atherosclerosis, and cardiomyopathy. in that are capable of competing with gad65 for
addition, methods for modulating the binding with b96.11 and competitively inhibit
respective disorders or conditions of a subject such binding these antibodies can be provided
are also provided also provided are suites of in the form of a pharmaceutical composition
small molecule entities as biomarkers for
and can be used in methods for delaying the
insulin resistance, pre-diabetes, type-2 onset of type 1 diabetes and for inhibiting
diabetes, metabolic syndrome, atherosclerosis, insulitis and other diabetic symptoms also
and cardiomyopathy. provided are methods for detecting a
Herbal formulations for controlling susceptibility to type 1 diabetes in a subject
blood glucose levels in patients with and for detecting the presence of anti-idiotypic
diabetes. antibodies to gad65 the method comprises
ATP Marketing & Promotion AG Nied- contacting a specimen with an antibody of the
erumen, Switzerland invention the method further comprises
WO/2009/024175 Application No.: PCT/ detecting binding of the molecule to the
EP2007/007426 Publication Date:26.02.2009 specimen the absence (or relative absence) of
Filing Date:21.08.2007 binding is indicative of susceptibility to type 1
The present invention relates to herbal diabetes and of the absence of anti-idiotypic
formulations for controlling blood glucose antibodies.

126 Current R&D Highlights, Jan.-Mar. 2009

A method for treating diabetes. US2008/069145 Publication Date:08.01.2009
Mclane, Michael et al. Filing Date:03.07.2008
Genaera Corporation, Campus Drive, Methods of identifying subjects having, or
Plymouth Meeting, Pennsylvania, US at risk of developing, diabetes, obesity, and/or
WO/2009/032321 Application No.:PCT/ hypertension are disclosed, as well as methods
US2008/010455 Publication Date:12.03.2009 of identifying biomarkers for diabetes, obesity,
Filing Date:08.09.2008 and/or hypertension, and biomarkers identified
This application is directed to the use of by such methods.
steroid compounds for the selective inhibition Novel AS160-like protein, test systems,
of the enzyme ptp1b in a mammal for the methods and uses involving it for the
treatment of diabetes. identification of diabetes type 2 thera-
Therapeutic agent for type-2 diabetes. peutics.
Ishii, Shinichi et al. Tennagels, Norbert; (DE).
Mitsubishi Tanabe Pharma Corporation Sanofi-Aventis [FR/FR]; 174, Avenue De
Osaka, Japan. France, F-75013 Paris (FR) (All Except US).
WO/2009/011420 Application No.: PCT/ WO/2009/015808 Application No.:PCT/
JP2008/063008 Publication Date:22.01.2009 EP2008/006024 Publication Date:05.02.2009
Filing Date:18.07.2008 Filing Date:23.07.2008
Disclosed is a medicinal agent comprising The present invention relates to novel
ursodeoxycholic acid or a pharmacologically AKT substrate 160kDa-like protein (AS160-
acceptable salt thereof as an active ingredient, like protein), to a method of identifying a
which can be act as a therapeutic agent for substance altering glucose uptake and/or
type-2 diabetes accompanied by fatty liver or GLUT4 translocation to the plasma membrane
liver dysfunction. cell comprising contacting a test system
The use of compounds such as comprising AKT substrate 160kDa-like protein
pyridoxal derivatives for the treatment of (AS160-like protein) with a test substance, and
diabetes or diseases associated with the identifying a test substance as a substance
altering glucose uptake of a cell by detecting a
metabolic syndrome.
Erlinge, David et al. signal indicative for altered glucose uptake of
Strom and Gulliksson AB, Malmo, a cell; a test system comprising a gene coding
Sweden for the AKT substrate 160 kDa-like protein
WO/2009/005469 Application No.: PCT/ (AS160-like protein) and an inducible
promoter providing for controllable expression
SE2008/050831 Publication Date:08.01.2009
Filing date:03.07.2008 of the gene; the use of the test system for the
The invention relates to compounds identification of a substance improving
having the general formula (i), (ii) or (iii), and glucose uptake and/or GLUT4 translocation to
which are useful for the treatment or the plasma membrane of a cell; and the use of
prevention of diabetes or diseases associated AS160-like protein in a model for type 2
with the metabolic syndrome. diabetes.

Biomarkers for diabetes, obesity, Method, system and computer

and/or hypertension. simulation environment for testing of
Hancock, William, S et al. monitoring and control strategies in
Northeastern University, Boston,
Massachusetts, US Kovatchev, Boris, P et al.
WO/2009/006568 Application No.:PCT/ University of Virginia, Virginia, US
WO/2008/157781 Application No.: PCT/

Current R&D Highlights, Jan.-Mar. 2009 127

US2008/067725 Publication Date:24.12.2008 the blood or in the hypodermic medium by
Filing Date:20.06.2008 means of an optical and/or electrochemical
A simulation environment for in silico method, and consists in periodically injecting
testing of monitoring methods, open-loop and test doses of (ultra) short insulin into a
closed-loop treatment strategies in type 1 measuring point, thereby generating a short-
diabetes some exemplary principal term local deterioration of a glucose level and
components of the simulation environment obtaining a difference in measurement results
comprise, but not limited thereto, the for determining a current glucose level during
following: 1) a 'population' of in silico a given measuring interval the inventive
'subjects' with type 1 diabetes in three age method makes it possible to increase the
groups; 2) a simulator of cgm sensor errors; 3) accuracy of measurement of a current
a simulator of insulin pumps and discrete glycemia level, also when using a non-invasive
insulin delivery; 4) an interface allowing the method of measurement, since the result
input of user-specified treatment scenarios; depends only on two parameters, i.e. the
and 5) a set of standardized outcome measures insulin test dose and the current glucose level
and graphs evaluating the quality of the tested in the organism.
treatment strategies these components can be N-azacyclic substituted pyrrole,
used separately or in combination for the
pyrazole, imidazole, triazole and tetrazole
preclinical evaluation of open-loop or closed- derivatives as agonists of the RUP3 or
loop control treatments of diabetes. GPR119 receptor for the treatment of
Method for monitoring diabetes insulin diabetes and metabolic disorders.
therapy. Metabolex, Inc., Hayward, California, US
Chuvashov, Vladimir Dmitryevitch et al. WO/2009/014910 Application No.: PCT/
Petersburg, Russia US2008/069714 Publication Date:29.01.2009
WO/2009/031943 Application No.:PCT/ Filing Date:10.07.2008
RU2008/000577 Publication Date:12.03.2009 Compounds and methods are provided for
Filing Date:25.08.2008 the treatment of, inter alia, type ii diabetes and
The invention relates to medicine, in other diseases associated with poor glycemic
particular to endocrinology, more specifically control.
to the monitoring of insulin therapy of patients
suffering from diabetes. the method for
monitoring diabetes insulin therapy is based on
the measurement of a glucose concentration in

128 Current R&D Highlights, Jan.-Mar. 2009

CDRI Publications

Papers Published on Diabetes by

Central Drug Research Institute, Lucknow
During the period from 1952 to 2008.

1. Ahamad R, Srivastava SP, Maurya R, Rajendran SM, Arya KR and Srivastava A - Mild
antihyperglycaemic activity in Eclipta alba, Berberis aristata, Betula utilis, Cedrus deodara, Myristica
fragrans, Terminalia chebula (2008) - Ind. J. Sci. & Technology 1,1-6
2. Maurya, R., Akanksha, Jayendra, Singh, A.B., Srivastava, A.K., 2008; Bioorganic & Medicinal
Chemistry Letters; 18; 65346537.
3. Dixit A and Saxena AK - QSAR analysis of PPAR-? agonists as anti-diabetic agents (2008) - Eur. J.
Med. Chem. 43, 73-80
4. Khan MM, Saxena R, Puri Anju, Chander R, Khanna AK, Saxena AK and Saxena JK - Regulation of
glycogen metabolism by antidyslipidemic action of gemfibrozil and cholestyramine in dyslipidemic
diabetic hamster model (2008) - Med Chem Research 17, 245-257
5. Singh AB, Chaturvedi JP, Narender T and Srivastava AK - Preliminary studies on the hypoglycemic
effect of Peganum harmala seeds ethanol extract on normal and streptozotocin induced diabetic rats
(2008) - Indian Journal of Clinical Biochemistry 23, 391-393
6. Tamrakar AK, Tiwari P, Ahmad R, Kumar R, Lakshmi V, Srivastava MN and Srivastava AK -
Antihyperglycaemic activity of Sinularia firma and Sinularia erecta in streptozotocin induced diabetic
rats (2008) - Med Chem Research 17, 62-73
7. Tiwari P, Tamarkar AK, Ahmad R, Kumar R, Lakshmi V. and Srivastava AK - Antihyperglycemic
activity of ceriops tagal in normoglycemic and streptozotocin-induced diabetic rats (2008) - Med
Chem Research 17, 74-84
8. Suryawanshi, Satyendra; Mehrotra, Nitin; Asthana, R K; Gupta, Ram C - Liquid
chromatography/tandem mass spectrometric study and analysis of xanthone and secoiridoid glycoside
composition of Swertia chirata, a potent antidiabetic (2006) - Rapid Communications In Mass
Spectrometry: RCM, 20, 3761-3768
9. Gupta, Asheesh ; Raghubir, Ram, - Energy metabolism in the granulation tissue of diabetic rats during
cutaneous wound healing, (2005) - Molecular And Cellular Biochemistry, Volume 270, Issue 1-2,

Current R&D Highlights, Jan.-Mar. 2009 129

CDRI Publications
10. Prathipati, P , Pandey, G , Saxena, A.K. - CoMFA and docking studies on glycogen phosphorylase a
inhibitors as antidiabetic agents. (2005) - J Chem Inf Model. 2005 Jan-Feb;45(1):136-45.
11. Gupta, A. & Raghubir, R. - Energy metabolism in granulation tissues of normal and diabetic rats
during cutaneous wound healing. (2004) - Mol. Cell. Biochem., 260, 1-7.
12. Verma, S.S., Mishra, C., Tamrakar, A.K., Tripathi, B.K., Srivastava, A.K. & Tripathi, R.P. - Reductive
amination of glycosyl aldoses: Synthesis of N-glycosylated beta-glycosyl amino alcohols and their
antidiabetic potential. (2004) - J. Carbohydrate Chem., 23, 493-511.
13. Rizvi, F., Puri, A., Bhatia, G., Khanna, A.K., Wulff, E.M., Rastogi, A.K. & Chander, R. -
Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model. (2003) - Biochem.
Biophys. Res. Commn., 305, 215-22.
14. Saxena, A.M., Murthy, P.S.R. & Mukherjee, S.K. - Mode of action of three structurally different
hypoglycaemic agents: A comparative study. (1996) - Indian J. Expt. Biol., 34, 351-55.
15. Singh, S., Gupta, J. & Agarwal, C.G. - Conjugated dienes in lipids of apolipoprotein containing
lipoproteins of normal and type-2 (non-insulin dependent) diabetic patients. (1992) - Indian J.
Biochem., Biophys., 29, 282-86.
16. Ahmad, Faiyaz, Khan, M.M., Rastogi, A.K. & Kidwai, J.R. - Insulin and glucagon releasing activity in
coleonol, its effect on blood glucose level in normal and aloxan diabetic rats. (1991) - Acta Diabetol,
Lat., 28, 71-7.
17. Bajpai, Madhubala, Asthana, R.K., Sharma, N.K., Chatterjee, S.K. & Mukherjee, S.K. -
Hypoglycaemic effect of swerchirin form the hexane fraction of Swertia chirayita. (1991) - Planta
Med., 57, 99-202.
18. Sethi, P.P.S., Mitra, M.K., Sircar, A.R., Shanker, Kripa, Gaur, S.P.S. & Rastogi, A.K. - The effect of
antiplatelet drug on micorproteineuria in different stages of diabetic nephropathy. (1991) - Indian J.
Neph., 1, 144.
19. Agarwal, V.R., Rastogi, A.K. & Sagar, P. - In vitro insulin action on erythrocyte glucose metabolism
in normal and diabetic rats. (1988) - Diabetologia, 31, 51-53.
20. Agarwal, V., Rastogi, A.K., Sahib, M.K. & P. Sagar. - Insulin binding parameters in erythrocytes of
alloxan induced diabetic rat. (1987) - Indian J. Expt. Biol., 25, 43-44.
21. Kumari, K., Bansal, V., Jagmohan, Agarwal, C.G., Rastogi, A.K. & Sahib, M.K. - Retrospective
glycemic status of diabetic patients: Glycosylation of blood proteins in diabetes and chronic renal
failure. (1987) - Acta Diabet. Latina, 24, 91.
22. Mukjherjee, B., Bhatia, G.S., Chatterjee, A.K. & Mukherjee, S.K. - Impairment of insulin mechanism
of islets of Langerhans in rats made diabetic by alloxan and streptozotocin. (1986) - Indian J. Physiol.
Allied., Sci., 39, 108.

130 Current R&D Highlights, Jan.-Mar. 2009

CDRI Publications
23. Agarwal, V.R., Rastogi, A.K., Sahib, M.K. & Sagar, P. - In vitro effect on acetylcholinesterase of
erythrocyte membranes of normal and diabetic rats. (1985) - Acta diabet. Latina, 22, 359.
24. Agarwal, V.R., Rastogi, A.K., Sahib, M.K. & Sagar, P. - In vitro insulin action on different AT Pases
of erythrocyte membranes in normal and diabetic rats. (1985) - Acta diabet. Latina, 22, 111.
25. Gitika, S.B. & Mukherjee, S.K. - Changes in blood lactic and pyruvic acid level in phenyl ethyl-
biguanides treated diabetic rhesus monkeys and albino rats. (1981) - Ind. J. Physiol. And Allied Sci.,
35, 102-103.
26. Mathur, K.B. & Kishore, V. - Synthesis and hypoglycaemic activity of arginine peptides. (1980) -
Indian J. Biochem. Biophys., 17, 303-05.
27. Mukerjee, S.S., Sethi, N., Roy, A.K., Srivastava, G.N. & Mukherjee, S. K. - Chronic toxicity studies of
a hypoglycaemic compound, Centpiperalone, in rats and rhesus monkeys. (1979) - Indian J. Exp.
Biol., 17, 1346-49.
28. Mukerjee, S.S. & Mukherjee, S.K. - Activators of serum lipoprotein lipase in alloxan diabetic rats.
(1978) - Experientia, 34, 1429-30.
29. Asthana, T.C. & Jain, P.C. - b-Phenoxy-b-phenylpropionic acid,a-benzyloxy-, a-thiobenzyloxy-&a-
anilino-a-phenylacetic acids & their derivatives as potential hypoglycaemic agents. (1977) - Indian J.
Chem., 15B, 383-85.
30. Mukherjee, S.K. - A novel hypoglycaemic compound. (1973) - Biochem. Pharmacol., 22, 1529.
31. Gupta, C.M., Bhaduri, A.P., Khanna, N.M. & Mukherjee, S.K. - A novel class of hypoglycaemic
agents : Syntheses & SAR in 2-substituted-4 (3H)-quinazolones, 2-substituted-4-
hydroxypolymethylene [5,6] pyrimidines & 3-substituted-4-oxo-pyrido[1,2-a] pyrimidines. (1971) -
Indian J. Chem., 9, 201-06.
32. Asthana, T.C., Gupta, S.K., Khosla, M.C. & Anand, N. - a-Phenoxy and thiophenoxyphenylacetic acid
derivatives as hypoglycaemic agents. (1970) - Indian J. Chem., 8, 1086-95.
33. Asthana, T.C., Gupta, S.K., Khosla, M.C. & Anand, N. - a-Phenoxy & thiophenoxyphenylacetic acid
derivatives as hypoglycaemic agents. (1969) - Indian J. Chem., 8, 1086-95.
34. Shoeb, A., Popli, S.P., Mukherjee, S.K. & Dhar, M.L. - Studies in possible oral hypoglycaemic agents
: Part V - Synthesis of carbamoylindoles, carbamoylisoindolines, 3-indolylethyl urea (or thiourea) & 2-
isoindolinylpropyl urea (or thiourea) derivatives & their biological activity. (1967) - Indian J. Chem.,
5, 142-44.
35. Shoeb, A., Popli, S.P., Mukherjee, S.K. & Dhar, M.L. - Studies in possible oral hypoglycaemic agents
: Part VI - Synthesis of some 2- & 4-pyridylethyl ureas & thioureas & some barbiturates & their
biological activity. (1967) - Indian J. Chem., 5, 145-46.

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36. Shoeb, A., Mukerjee, S.K., Anand, N. & Dhar, M.L. - Oral hypoglycaemic agents. Part IV - Synthesis
of 1-aryl sulphonyl 3-substituted-2-imidazolidinones & 1,1,3-trisubstituted ureas. (1965) - Indian J.
Chem., 3, 507-509.
37. Acharya, B.P., De, U.N. & Mukherjee, S.K. - Effect of synthetic antidiabetic compounds & insulin on
the alcohol induced gastric acidity in rabbits. (1961) - Indian J. Med. Res., 49, 62-67.
38. Dhar, D.N., Popli, S.P. & Dhar, M.L. - Studies in possible oral hypoglycaemic agents: Part II-
Synthesis of hydantoins & hydantoic esters by alternate methods. (1961) - J. Sci. Industr. Res., 20C,
39. Mukherjee, S.K., De, U.N. & Mukerji, B. - Comparative study of the hypoglycaemic action of
sulphonylureas & their nature of action. (1960) - J. Sci. Industr. Res., 19C, 268-274.
40. Roy, A.K., Zaidi, S.H. & Popli, S.P. - Hypoglycaemic activity of some hydantoins, hydantoic ester &
related compounds in rats. (1960) - J. Sci. Industr. Res., 19C, 75-77.
41. Mukherjee, S.K. & De, U.N. - Studies on D 860-Another new oral hypoglycaemic sulfonamide. (1958)
- Indian J. Med. Res., 46, 223-233.
42. Mukherjee, S.K., De, U.N. & Mukerji, B. - Clinical experience with a new oral hypoglycaemic drug.
(1957) - J. Indian Med. Ass., 28, 466-468.
43. Mukherjee, S.K., De, U.N. & Mukerji, B. - Studies in experimental diabetes: Part IV - Tissue
phosphatase activity in protected & in alloxan diabetic rats. (1956) - Indian J. Med. Res., 44, 415-
44. Raja Rama Rao, M.R. & De, N.N. - An antidiabetic principle from Rivea cuneata (Wight). (1952) -
Curr. Sci., 21, 69.

(Based on the information available in Annual reports of C.D.R.I.

Occurance of any error or omission may kindly be ignored.
Compiled by: Wamiq F. Rahman)

132 Current R&D Highlights, Jan.-Mar. 2009