What we will learn?

Metabolism & Energy sources.

How body utilizes these sources.
Focus on INSULIN and its various roles
Type-2 Diabetes mellitus & pathogenesis
 What we will learn?

Diagnosis of Type-2 Diabetes mellitus

Complications of Type-2 diabetes
Mechanism of complications
Management

Pharmacological therapies available

 Energy for human life

Carbohydrate Proteins

Fats
Most common energy sources
 Carbohydrates

 Fats
 Most common energy
sources

 Proteins
Gasoline for human being

 Two major fuels –

Glucose (Carbohydrate)
Fatty acids (Fats)
 What is a Carbohydrate?
Carbohydrates are compounds which have the
following basic composition:
I
(CH2O)n or H - C - OH
I
Classified as –
 Monosaccharides
 Disaccharides
 Oligosaccharides
 Polysaccharides
 Simple Sugars:Mono and
Disaccharides
 Monosaccharides – single sugar unit
Glucose
Found in fruits, vegetables, honey
used for energy

Fructose
“fruit
sugar”
Found in fruits, honey, corn syrup

Galactose
Found as part of lactose in milk
Disaccharides – two linked
sugar units
 Sucrose: glucose + fructose
“table sugar”
Made from sugar cane and sugar
beets
 Lactose: glucose + galactose
“milk sugar”
Found in milk and dairy products
 Maltose: glucose + glucose
Found in germinating cereal grains
Product of starch breakdown
 Complex
Carbohydrates

 Oligosaccharides
driedbeans, peas, lentils
Rafinose (gal-glu-fru)
Stachyose (gal-gal-gal-fru)
Metabolized by intestinal bacteria
Gaseous effects
 Complex
Carbohydrates
 Polysaccharides
contain 100’s or 1000’s of
monosaccharide units
starch-digestible
fiber-indigestible
Glycogen
 Glycogen
 Importance
 Stored form of glucose.
 Major sites – Muscles and Liver; 75% is stored in
muscles.
 Liver: major site for glycogen synthesis
 ~10% of wet weight of liver
 Muscles
 Glycogen < 1% weight
 Used as energy when body requires energy.
 Important for “instant” energy
 Glycogen Storage

 Skeletal muscle
 Function: serve as fuel reserve for synthesis
of ATP during muscle contraction
 Liver
 Function: maintain blood glucose
concentration in times of fasting

Total amount of stored carbohydrate is sufficient to

fulfill the energy requirements of a person for ~1/2
day!
Carbohydrate Digestion

Also known as
a-glucosidase
enzymes
 Metabolism of Carbohydrates

 Glucose is primary energy source for the

human body
 Brain is the most important glucose
consumer (50%)
 Metabolism results in:
1. Energy (ATP) production (conversion to CO2 + H2O)
2. Storage as glycogen in liver or triglyceride in
adipose tissue
3. Conversion to keto acids, amino acids, or protein
 Regulation of Blood Glucose
Concentration

Glycolysis Glycogenesis

Pathways of Glucose Metabolism

Gluconeogenesis Glycogenolysis
 Glycolysis (glucose  pyruvate)

 Derived from the Greek stem glyk-,

"sweet," and the word lysis,
"dissolution."
 Glycolysis: sequence of reactions that
metabolizes one molecule of glucose to 2
molecules of pyruvate (triose sugar)
 Also produce 2 molecules of ATP
 Anaerobic
 Pyruvate to lactate
 Aerobic
 Pyruvate to acetyl-CoA
 Gluconeogenesis

 Synthesis of glucose from noncarbohydrate

sources (pyruvate, amino acids, lactic acid)
 Converts lactate or amino acids to glucose in
starvation or stress
 Opposite of glycolysis
 Glycogenesis (glucose  glycogen)
i.e. genesis = creation

 In times of glucose excess (after eating),

any glucose that is not used immediately
is taken up by the liver and muscle where
it can be converted into glycogen
 Glycogen is synthesized depending on the
demand for glucose and ATP (energy)
 If both are present in relatively high
amounts, then the excess of insulin
promotes the glucose conversion into
glycogen for storage in liver and muscle
cells
 Glycogenolysis (glycogen  glucose)
i.e. lysis = break down

 When blood glucose concentration

drops, there is a breakdown of
glycogen to make glucose
 Mobilizes stored glycogen in liver &
skeletal muscle
 Regulation of Blood Glucose

 Glucose metabolism is under the

control of various hormones.

Most common are -

Insulin
Glucagon
Epinephrine
Somatostatin
 Regulation of Blood Glucose

 Pancreas: Islet of
Langerhans (α , β , δ )

 Controls blood glucose

levels by secreting
hormones into the blood
1. α -cells (20-30% of islet
cells)
- Glucagon
1. β -cells (60-70% of islet
cells)
- Insulin
1. δ -cells (2-8% of islet
cells)
- Somatostatin
 Insulin
 First hormone
identified
(1920’s) by
Banting and
Best
 Released when
glucose is
abundant
(elevated
plasma glucose)
and stimulates:
 How insulin is
synthesized?
Preproinsulin
NH2

S S

S S

HOOC
S S
 How insulin is
synthesized?
Proinsulin
NH2

S S

S S

HOOC
S S
 How insulin is
synthesized?
Insulin
HOOC NH2 β -
chain
S S

S S

HOOC NH2 α -
S S chain

C - peptide ESR11-08
 Role of C-Peptide
 Insulin is difficult to measure
 Half-life is only 5 mins
 Rapidly inactivated by various enzymes.
 C-Peptide has 30 mins half life
 Synthesized in equimolar conc to that of
insulin
 Determines amount of insulin secreted
from b-cell
 How insulin is secreted?
 Insulin is secreted in 2 phases –
1. First phase
 Sharp peak
 Within 3-5 mins of glucose intake
 Completed within 10 mins
 Release of mature granules.

• Promotes peripheral utilization of the prandial

nutrient
load.
• Suppresses hepatic glucose output.
• Limits post prandial glucose elevation
How insulin is secreted?

2. Second phase
 Release of secretory
granules that are
mobilized within the
beta cell for release.
 Granules contain newly
synthesized insulin.
 Second Phase helps to
attain normoglycemia.
 Insulin – the “hormone of plenty”

 Increases glucose uptake by muscle and adipose

cells
 Helps in increasing cells to breakdown glucose,
releasing its energy in the form of ATP
 The liver and muscle to store glucose as glycogen
(short-term energy reserve)
 Adipose tissue to store glucose as fat (long-term
energy reserve)
 Glycogen synthesis and protein synthesis

Insulin is the ONLY hormone that lowers

circulating glucose level!
Insulin: Summary
 Where insulin affects?
Insulin

Muscles Liver

Glucose Glycogenolysis
Uptake
Gluconeogenesis
Adipose cells
Glycolysis
Glycogenesis Lipogenesis

Brings plasma glucose level back to normal

 Glucagon Action on Cells:
Dominates in Fasting State Metabolism
 Secreted from a-cells of pancrease
 Major target organ: liver
 Stimulates production of glucose by glycogenolysis and
gluconeogenesis
 Glucagon prevents hypoglycemia by ↑ cell production of
glucose
 Principal hormone for producing a rapid increase in
plasma glucose concentration
 Secretion is suppressed in hyperglycemia
Glucagon Action on Cells

Endocrine response to hypoglycemia

 Epinephrine – “fight or flight”

 Catecholamine secreted by the adrenal

medulla
 Serves as a backup for glucagon
 Stimulates glucagon secretion and inhibits
insulin secretion by pancreas
 Stimulates
glycogen breakdown
(glycogenolysis) and decreases glucose use
 Physical/emotional stress epinephrine
production, releasing glucose for energy
 Somatostatin

 Secreted by g-cells of pancreas

 Primary act is to inhibit secretion of

insulin and glucagon

 Secreted by range of tissues (pancreas,

intestines, CNS)
Main Human Glucose Transporters

Transporter Tissue Insulin

dependent?
GLUT1 RBCs, brain, kidney No

GLUT2 β -cells of pancreas, No

small intestine, kidney

GLUT3 Neurons, placenta No

GLUT4 Skeletal & cardiac YES
muscle, adipose
tissue
GLUT5 Small intestine, No
kidney, brain, adipose
tissue
GLUT7 Some liver cells No
 Insulin Secretion
Ca++

K+ Depolarization
Voltage
ATP
dependent Ca+
sensitive K+ +
channels
channels
Binds and open
closes

Ca++
Glucose ATP

Secretary
granules
GLUT-2

Insulin
High
Glucose
 Insulin

Insulin
Receptor

Seri
es o
f e nz
reac
tion

GLUT 4
Mode of action of Insulin

Glucose
Insulin enters

Insulin GLUT-4
Receptor
Translocation
of GLUT-4
Series of
reaction
Glucose

Glycogen Glycolysis
Mode of action of insulin
Sources of blood glucose in the various nutritional states

fed postabsorptive gluconeogenic prolonged

40 Exogenous
(glucose
Glucose 30 from diet)
glucose from
Used gluconeogenesis
g/hr glucose from (lactate + amino acids) glucose from
20 liver glycogen gluconeogenesis
(mostly lactate)

10

0
4 8 12 16 2 7 42
HOURS DAYS
 Hyperglycemia & Hypoglycemia

 Hyperglycemia – too
little insulin

 Hypoglycemia – too little

intake or too much insulin
What’s “normal”?
Action of Insulin on LIPID metabolism
Triglycerides

Insulin
Non esterified Fatty acid (NEFA or FFA)

Acetyl CoA Ketone bodies

Hence insulin -
•Decreases lipolysis
•Increases lipogenesis
•Decreases ketoacidosis
Insulin on Protein metabolism

Amino acid

Insulin

Protein

Insulin –
•Increases protein synthesis
•Decreases proteolysis
Summary of insulin action
Increases –
 Glucose uptake
 Glycolysis
 Glycogenesis
 Lipogenesis
 Protein synthesis

Decreases –
•Gluconeogenesis
•Glycogenolysis
•Lipolysis
•Ketogenesis
•Proteolysis
Diabetes Mellitus

Disease, Pathogenesis
& Management
 Definition
A group of metabolic disorders
comprising of abnormal carbohydrate,
fat and protein metabolism and
characterized by chronic or persistence
hyperglycemia
 Due to lack of insulin hormone
OR
 Improper insulin secretion
 Risk Factors for Diabetes
 Family history of diabetes
 Obesity (> 20% over desired body weight or BMI > 27 kg/m2
 Age > 45 years
 Sedentary life style
 Some ethnic groups ( Indians, African-Americans and native
Americans, asian americans)
 Gestational diabetes or delivering a baby weighing more than 9
pounds (4kg or more)
 High blood pressure ( > 140/90mmHg)
 High blood levels of triglycerides (> 250mg/dl)
 low HDL cholesterol level (<35mg/dl)
 Symptoms of diabetes
 Frequent urination - Polyuria
 Excessive thirst - Polydypsia
 Excessive hunger - Polyphagia
 Fatigue
 Weight loss
 Blurred vision.

Symptoms more prominent in Type-1

DM
 Types of Diabetes Mellitus

Most common types are –

 Type-1 Diabetes mellitus

 Type-2 Diabetes mellitus

 Gestational diabetes.
 Type-1 Diabetes mellitus

 Due to total destruction of b-cells of the pancreas.

 Autoimmune destruction of islets
 Most prominent during childhood
 Therapy involves Insulin injection
 Type-2 Diabetes mellitus

 Most common type of diabetes (>90%)

 Related to genetic defect and life style
and food habits.
 Consists of 2 common defects –
1. Insulin resistance
2. B-cell impairment or Impaired insulin
secretion.
Genes & / or Life style and
diet

Abnormal
Insulin β -cell
resistance function

Type 2 diabetes
 Insulin resistance

 Decreased ability of normal insulin to

act effectively on peripheral tissues
(muscle & adipose tissues) and liver.
 b-cell
has to secrete more insulin to
maintain normal glucose level.
 Cause of Insulin resistance

FFA has been found to be one of the

major culprit
 Central or visceral obesity is the major cause
 Adipocytes secretes high conc of FFA.
 FFA enters muscle cells and interferes with insulin
signaling system
 Thereby less GLUT 4 translocation
 Less glucose uptake
 Cause of Insulin resistance

 Adipocytesalso secretes various

biochemicals like resistin, leptin, THF-α &
adiponectin

 Low adiponectin level or high conc of

resistin, leptin, THF-α has been associated
with insulin resistance
 Hyperinsulinemia

 Persons with IR, requires higher insulin level to

bring glucose back to normal.

 B-cells secretes additional insulin to compensate.

 Puts additional stress on b-cells

 Person may be normal or diabetic

 Risk factor for various cardiovascular disease

 Hyperinsulinemia
800
Insulin resistance
700
Insulin secretion (pmol/min)

Healthy
600

500

400

300

200

100

6 a.m. 10 a.m. 2 p.m. 6 p.m. 10 p.m. 2 a.m. 6 a.m.

Time
 B-cell impairment
 Condition where the beta cells are unable to produce
sufficient insulin as per rise in blood glucose level due to
both reduced β-cell mass and functional abnormalities of
the β-cell.
 Reduced β-cells works hard to compensate for the
synthesis of adequate insulin.
 Leads to β-cell fatigue.
 Development of progressive rise in glucose level
 Leading to development of frank diabetes type-2
 Natural History of Type 2
Diabetes
Obesity IGT* Diabetes Uncontrolled
Hyperglycemia
Postmeal
Plasma glucose
glucose
Fasting glucose
120 (mg/dL)

Relative β -cell Insulin resistance

function Progressive reduction in beta cell mass
100 (%)
Insulin level

-20 -10 0 10 20 30
Years of diabetes

Adapted from International Diabetes Center, Minneapolis, Minnesota.

 Result of IR & b-cell
impairment

1. Decrease glucose uptake in storage cells

2. Increased glucose production from liver

Hyperglycemia
 Types of Diabetes Type-2

 Obese
Very high degree of insulin resistance
compared to b-cell impairment
 Non-obese
Very high degree of b-cell impairment
compared to insulin resistance
 Diagnosis of Type-2
Diabetes
FPG (Fasting plasma glucose test)

Category FBS (mg/dl)

Normal < 100
Impaired (IFG) 100 - 125
Diabetes ≥ 126
IFG = Impaired fasting glucose tolerance
 Diagnosis of Type-2
Diabetes
OGTT (Oral glucose tolerance test)

Category PPG (mg/dl)

Normal < 140
(IGT) OR Prediabetic 140 - 199
Diabetes ≥ 200
IGT = Impaired glucose tolerance
 Glycosylated Hemoglobin
test (HbA1c)
 Glucose forms irreversible
complex with proteins

 Normal value 4 - 6%

 Used to monitor during

treatment

 Gives a good indication of

blood glucose during the
previous 3 - 4 months.

 Target level of less than

7.0 % indicates good
control
Complications of
Type-2 Diabetes
mellitus
 Complications

 Acute complications
Diabetes Ketoacidosis (DKA)
Non-ketotic hyperosmolar state (NKHS)

 Chronic complications
Vascular

Non-vascular
 Diabetic Ketoacidosis
(DKA)
Life threatening complication in Type-1 DM or
patients with lack of insulin
Inadequate insulin

Excess lipolysis leading to increased FFA

Increases ketone bodies leading to ketoacidosis

Coma or death
 Diabetic Ketoacidosis
(DKA)
Symptoms are –
 Nausea and vomiting.
 Thirst / polyuria.
 Abdominal pain.
 Altered mental function.
 Shortness of breath.

Treatment – Insulin
injection
 Non-Ketotic Hyperosmolar
State (NKHS)
 reported in all age groups, but it most frequently
affects older patients with type 2 diabetes
 initiating event in hyperosmolar hyperglycemic state is
glucosuric diuresis
 Decreased intravascular volume or underlying renal
disease decreases the glomerular filtration rate,
causing the glucose level to increase.
 The loss of more water than sodium leads to
hyperosmolarity
 Non-Ketotic Hyperosmolar
State (NKHS)

Symptoms are –
• Polyuria.
• Orthostatic hypotension.
• Neurological symptoms like - altered mental status,
lethargy, seizure and possibly coma.

Treatment
1. Vigorous intravenous rehydration,
2. Electrolyte replacement
3. Administration of intravenous insulin,
 Chronic Complications

Vascular
Microvascular
 Retinopathy
 Neuropathy
 Nephropathy

Marcovascular
 Cardiovascular disease
 Cerebrovascular disease
 Peripheral vascular disease
Layers of blood vessels
Hyperglycemia damages only a particular subset of
cell types:
capillary endothelial cells in the retina,
mesangial cells in the renal glomerulus,
and neurons and Schwann cells in peripheral
nerves.

What is distinct about these cells that makes them

so vulnerable to hyperglycemia?
So why does damage occur only in the few cell
types involved in diabetic complications? The
answer is that
• Most cells are able to reduce the
transport of glucose inside the cell
when they are exposed to
hyperglycemia, so that their internal
glucose concentration stays constant.

• In contrast, the cells damaged by

hyperglycemia are those that cannot
do this efficiently.
• Thus, diabetes selectively damages cells, like
endothelial cells and mesangial cells, whose
glucose transport rate does not decline
rapidly as a result of hyperglycemia, leading
to high glucose inside the cell.

• This is important, because it tells us that the

explanation for what causes complications
must involve mechanisms going on inside
these cells, rather than outside.
Important 4 pathways which cause complications
are:

 Increased Flux Through the Polyol Pathway

 AGE pathway

 PKC pathway

 Hexosamine pathway
PAI-1
 Microvascular
Complications
Retinopathy
 Leading cause of
blindness
 Starts with a small areas
of balloon-like swelling Hemorrhages in non-proliferative diabetic
in the retina's tiny blood retinopathy

vessels.
 As the disease
progresses, blood
vessels that nourish the
retina are blocked.

New blood vessel growth around optic nerve in

proliferative diabetic retinopathy
 Microvascular
Complications
Retinopathy
 At this advanced stage,
the signals sent by the
retina for nourishment
trigger the growth of new
blood vessels.
 These new blood vessels
are abnormal and fragile.
 If they leak blood, severe
vision loss and even
blindness can result.

Hemorrhage from new blood vessel growth in proliferative

diabetic retinopathy
 Microvascular
Complications
Neuropathy
 Damage to the nerves that helps to feel sensations such as
pain
 Two types

1. Peripheral Neuropathy
• Nerve damage in the feet can result in a loss of foot
sensation, increasing risk of foot problems. Symptoms
include –
• Tingling
• Numbness (severe or long-term numbness can become
permanent)
• Burning
 Microvascular
Complications
Neuropathy
2. Autonomic Neuropathy
 Autonomic neuropathy most often affects the digestive system,
especially the stomach, blood vessels, urinary system, and sex
organs. Symptoms can be –

 Bloating, Diarrhea, Constipation, Heartburn, Nausea, Vomiting,

Feeling full after small meals 
 Blacking out when you stand up quickly , Increased heart rate,
Dizziness, Low blood pressure
 Sexual dysfunction (males & females)
 Unable to completely empty bladder, Bloating, Incontinence
(leaking urine), Increased urination at night
 Microvascular
Complications
Diabetic Nephropathy
 Most common cause of
kidney failure.
 Five stages in the progression to
kidney failure in people with
diabetes

• Stage 1 (very early diabetes) Increased demand upon

the kidneys is indicated by an above-normal glomerular
filtration

• Stage 2 (developing diabetes) The GFR remains

elevated or has returned to normal; development of
microalbuminuria
 Microvascular
Complications
Diabetic Nephropathy

• Stage 3 (overt, or dipstick-

positive diabetes or
macroalbuminuria);
Hypertension may develop

• Stage 4 (late-stage diabetes).

"advanced clinical nephropathy."
GFR < 75 milliliters per minute.
Almost all patients have
• Stage 5 (end-stage renal disease, ESRD) - GFR <10
hypertension at stage 4.
mL/min) and renal
replacement therapy (i.e., hemodialysis, peritoneal dialysis,
kidney transplantation)
is needed
 Macrovascular
Complications
Cardiovascular
complications
• More than 60% of DM patients dies due to
CAD
• Most common CVD includes –
• Hypertension
• CAD
• Heart Failure
 Macrovascular
Complications
Cardiovascular
complications
Hypertension
Category SBP DBP
Normal < 120
and < 80
Pre hypertension 120- 139 and / or
80-89
Hypertension
Stage 1 140 - 159 and / or
90-99
Sustained increase in “Systolic “ Blood Pressure > 140 mmHg and /
Stage 2 >160 and / or
or “Diastolic” Blood Pressure > 90
>100
 Macrovascular
Complications
Cardiovascular
complications
Hypertension

● Closely associated with Hyperinsulinemia

● High insulin may cause Na+ & H2O retention

●Diabetes patients has higher risk of developing

hypertension than normal persons.
 Macrovascular
Complications
Cardiovascular
complications
Manageme
nt
● Therapeutic lifestyle management
● Pharmacological therapy
● Most preferred choices are ACEI and ARBs
● Others – Diuretics, Calcium channel
blockers, b-blockers etc
 Macrovascular
Complications
Cardiovascular
complications
CAD (Coronary Artery
Disease
When there is an Imbalance between

Demand of Blood Supply of Blood

(Oxygen) (Oxygen)
 Macrovascular
Complications
Cardiovascular
complications
 Causes of Obstruction
Atheroma (Atherosclerosis)
Thrombosis
Embolism
Spasm
Macrovascular Complications
Cardiovascular
complications
Symptoms
Angina Pectoris
 Stable

 Unstable

 Variant or Prinzmetal’s

Acute Myocardial Infarction

 Macrovascular
Complications
Cardiovascular
complications

Heart attack
 Death of muscle tissue
due to lack of oxygen
 Macrovascular
Complications
Cardiovascular
complications
Manageme
nt
Life Style Modifications

Drug Therapy

Surgery -Bypass and Angiolasty

 Macrovascular
Complications
Cardiovascular
complications
 Therapy
 O2 supply O2 demand

 Drugs
 Nitrates
 Beta blockers
 Calcium channel blockers
 Potassium channel openers
 Metabolic modifier
 Macrovascular
Complications
Cardiovascular
complications

Surgical Procedures
• Bypass surgery
• Balloon angioplasty
 Macrovascular
Complications
Cardiovascular
complications
Heart Failure
Inability of the heart to pump sufficient blood to meet the
body’s metabolic requirement

Major cause - CAD

 Class I : Heart disease with no limitations in physical activity

 Class II : Heart disease with slight limitations in physical activity. Comfortable
at rest
 Class III : Heart disease with marked limitations in physical activity. May
present at rest
 Class IV : Heart disease with discomfort at any activity
 Macrovascular
Complications
Cerebrovascular
complications
Stroke
Blood supply is interrupted,
resulting in tissue death and loss of
brain function

Transient Ischemic
Attack (TIA)
A brain disorder caused by
temporary
disturbance of blood supply to an
area of the brain, resulting in a
sudden, brief decrease in brain
 Macrovascular
Complications
Peripheral vascular disease

• Blocking of an artery in
the peripheral region of the
body
• Major cause -
atherosclerosis
 Non Vascular
Complications

•Galucoma, Cataract
•Diabetic foot ulcer
•Gastroparesis
•Sexual dysfunction
•Skin changes
Biochemical mechanism
of the development of
diabetic complications
 Hypothesis 1

Activation of protein kinase Cβ

Increase glucose level

Increase formation of diacylglycerol

Activates enzyme Protein Kinase Cβ

Increases cell proliferation and permeabilty

Damage to cells
 Hypothesis 2

Glycation
Increased glucose level

Forms complexes with cellular proteins called

AGE (Advanced glycated end products)

Causes cellular dysfunction

 Hypothesis 3

Oxidative stress
High glucose

Increases formation of reactive intermediates of

oxygen reduction - O2-, H2O2 and OH-

May cause oxidative damage to proteins, lipids

and nucleotides leading to cell damage.
 Hypothesis 4

Polyol Pathway

Hyperglycemia

Conversion of Glucose to Sorbitol by “aldolase

reductase”

Causes osmotic changes in cells

Cellular damage
Management of
Diabetes Type-2
 Goals

Immediate Goals:
Goals to stabilize the blood
sugar
Long-term goals:
 To prolong life,
 Relieve symptoms, and
 Prevent long-term complications
 Treatment Modalities

Life style modifications

Diet and Exercise

Pharmacological therapy.
 Importance of achieving
tight glycemic control
 Variouslandmark studies have confirmed that by
decreasing glucose level there is a significant
reduction in risk of microvascular and
macrovascular complications.

 UKPDS (United Kingdom Prospective Diabetes

Study)
 DCCT (Diabetes Control and Complication Trial)
 The Kumamoto Study
 DPP
 UKPDS

 Objective: improved glucose control of Type

2 diabetes will prevent clinical complications

 Design: Prospective observational study in 23

hospital based clinics in England, Scotland, and
Northern Ireland. 3642 patients were included in
analyses of relative risk. Total duration was
approximately 10 years.
 UKPDS

Results: Each 1% reduction in mean HbA1c was

associated with reductions in risk of -
 21% for any end point related to diabetes,
 21% for deaths related to diabetes,
 14% for myocardial infarction, and
 37% for microvascular complications

Conclusions: Any reduction in HbA1c is likely to

reduce the risk of complications, with the lowest
risk being in those with HbA1c values in the normal
range ( < 6.0%).
 DCCT
 Clinical study conducted from 1983 to 1993 by
the National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK)

 Involved 1,441 volunteers with type 1 diabetes

and 29 medical centers in the United States and
Canada. Volunteers had diabetes for at least 1
year but no longer than 15 years.

 They also were required to have no, or only early

signs of, diabetic eye disease.
 DCCT
 The study compared the effects of two treatment
regimens—standard therapy and intensive
control—on the complications of diabetes.

Result : Lowering blood glucose reduces risk

 Eye disease (Retinopathy) - 76% reduced risk

 Kidney disease (Nephropathy) - 50% reduced risk

 Nerve disease (Neuropathy) - 60% reduced risk

 Cardiovascular disease - 35%

 Kumamoto Study

 OBJECTIVE — To examine whether intensive glycemic

control could decrease the frequency or severity of diabetic
microvascular complications.

 DESIGN - 110 patients with type 2 diabetes (55 with no

retinopathy and 55 with simple retinopathy were randomly
assigned to multiple insulin injection therapy (MIT) groups
and administered three or more daily insulin injections or
assigned to conventional insulin injection therapy (CIT)
groups and administered one or two daily intermediate-
acting insulin injections. Incidence of nephropathy
(normoalbuminuria, microalbuminuria, and albuminuria)
were also monitored.
 Kumamoto Study

 RESULTS — the cumulative percentages of

worsening in retinopathy and nephropathy were
significantly lower in the MIT group than in the CIT
group.

 CONCLUSIONS — Intensive glycemic control can

delay the onset and progression of the early stages of
diabetic microvascular complications in Japanese
patients with type 2 diabetes.
United States Diabetes Prevention
Program: Results

Intensive Lifestyle
Placebo Intervention Metformin
(n = 1082) (n = 1079) (n = 1073)

Wt loss: 0.1 kg Wt loss: 5.6 kg Wt loss: 2.1 kg

Diabetes: 29% Diabetes: 14% Diabetes: 22%

 United States Diabetes Prevention
Program: Results
Intensive Lifestyle
Placebo Intervention Metformin
(n = 1082) (n = 1079) (n = 1073)

Wt loss: 0.1 kg Wt loss: 5.6 kg Wt loss: 2.1 kg

Diabetes: 29% Diabetes: 14% Diabetes: 22%

Risk reduction:Risk reduction:
58% 31%
 Anti - Diabetic Drugs
Type-2 Diabetes Mellitus
 Oral Hypoglycemic agents.
 Sulfonylureas – e.g., Glibenclamide, Gliclazide,
Glipizide and Glimepiride.
 Non-sulfonylureas (Magletinides) – e.g.,
Repaglinide and Nateglinide.
 Anti-hyperglycemic agents.
 Insulin sensitizers –
Biguanides – e.g., Metformin.
Thiazolidinediones – e.g., Rosiglitazone and Pioglitazone.
 α -Glucosidase inhibitors – e.g., Acarbose,
Miglitol.
 Anti - Diabetic Drugs
 Insulin analogoues – e.g., Bovine, porcine and
human.
 Newer agents –
 Aldolase reductase inhibitors – e.g., Aminoguanidine.
 Insulin mimetic agents – e.g., Vanadium salts.

 Glucagon antagonists – e.g., β 3-adrenergic agonists.

 Potentiatorsof insulin secretion – e.g., Glucagon like

peptide amide.
 Combination therapy

Commonly used combinations are:

 Sulfonylurea and metformin
A glitazone and a Sulfonylurea or insulin
 Non- SU and metformin
 Sulfonylurea and insulin
 Any other drug mentioned above and insulin
 Triple Therapy

The use of a glitazone in combination with

metformin and a sulfonylurea in patients
who have not responded to monotherapy
or with combination of two oral agents
have also been approved by FDA.
 Treatment Failure

Primary failure
No response with a drug given for the first
time
Secondary failure
Gradual lose of action of a drug when
used for a prolonged period. E.g.,
Sulfonylureas.