PHYTOTHERAPY RESEARCH

Phytother. Res. 30: 357–366 (2016)

Published online 7 January 2016 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/ptr.5559

REVIEW
The Significance of Tinospora crispa in Treatment
of Diabetes Mellitus

Alex Thomas,1 E. K. Rajesh2 and D. Suresh Kumar1*

1
CARe Keralam Ltd, KINFRA Small Industries Park, KINFRA Park P.O., Koratty 680 309 Kerala, India
2
My Holdings Consultancy Pvt Ltd, First Floor, Supriya Tower, Chalakudy 680307 Thrissur District, Kerala, India

Tinospora crispa is a medicinal plant belonging to the botanical family Menispermiaceae. The plant is widely
distributed in Southeast Asia and the northeastern region of India. A related species Tinospora cordifolia is used
in Ayurveda for treating a large spectrum of diseases. Traditional healers of Thailand, Malaysia, Guyana,
Bangladesh and the southern Indian province of Kerala use this plant in the treatment of diabetes. Many diterpenes,
triterpenes, phytosteroids, alkaloids and their glycosides have been isolated from T. crispa. Cell culture and animal
studies suggest that the herb stimulates secretion of insulin from β-cells. It also causes dose-dependent and
time-dependent enhancement of glucose uptake in muscles. However, in view of the reported hepatotoxicity, this
herb may be used with caution. This article reviews the animal studies and human clinical trials carried out using this
herb. Areas of future research are also identified. Copyright © 2016 John Wiley & Sons, Ltd.
Keywords: Tinospora crispa; diabetes mellitus; traditional medicine; Thai medicine; hyperglycaemia.

Indonesia, makhamukay in the Philippines and boraphet

INTRODUCTION
The incidence of diabetes mellitus is on the rise because
of population growth, ageing, urbanization, increasing
prevalence of obesity and decreasing physical activity.
Diabetes is broadly divided into type 1 and type 2. Type
1 is caused by the lack of insulin, and type 2 is character-
ized by low insulin sensitivity (Anonymous, 2013a). The
International Diabetes Federation has forecast that by
2025, there will be 334 million people with diabetes
globally. A coordinated global initiative is therefore
required to address the diabetes epidemic (Wild et al.,
2004). Ever since the adoption of Alma Ata Declaration
in 1978 by the WHO, there is a growing global interest
in the use of plants for treating diseases. This trend is en-
couraged by the belief that herbal medicines are devoid
of adverse side effects (Kumar, 2015). Medicinal plants
are increasingly being used in the treatment of diabetes,
and nearly 800 plants are now reported to possess anti-
diabetic activity (Patel et al., 2012). Medicinal herbs or
products derived from them are extensively used in
developing countries. Interest in herbal and other forms
of traditional medicine is growing all over the world
(Hong et al., 2015).
Tinospora crispa Hook.f. & Thomson is a member of
the family Menispermiaceae. It is a vine growing 4 to
20 m high with numerous characteristic protuberances
on the stem (Fig. 1). Flowers are pale green and fruits
are orange berries (Tan, 1980). The plant is widely dis-
tributed in Southeast Asia. However, in India, it grows
only in the northeastern Himalayas of Assam (Ahmed
et al., 2006). It is known as bratawali and andawali in
* Correspondence to: D. Suresh Kumar, Research & Development, CARe
Keralam Ltd, KINFRA Small Industries Park, KINFRA Park P.O., Koratty
680 309, Kerala, India.
E-mail: dvenu21@yahoo.com
Copyright © 2016 John Wiley & Sons, Ltd.
in Thailand. It has various synonyms like Tinospora
rumphii, Tinospora gibbericaulis, Tinospora mastersii,
Tinospora thorelii, Tinospora tuberculata, Cocculus
crispus, Cocculus coriaceus, Menispermum verrucosum,
Menispermum crispum and Menispermum tuberculatum
(Anonymous, 2013b). A related species Tinospora
cordifolia is used in Ayurveda for treating a large
spectrum of diseases (Panchabhai et al., 2008). Many
diterpenes, triterpenes, phytosteroids, alkaloids and their
glycosides have been isolated from T. crispa (Pathak et al.,
1995; Koay and Amir, 2013) (see Table 1). Literature for
this review was collected by searching databases like
Pubmed, ScienceDirect and Google Scholar using key
words such as Tinospora crispa, Thai medicine, Philippine
medicine and the synonyms mentioned earlier.
T. CRISPA IN TREATMENT OF DIABETES
Known as Akar patawali and Akar seruntum in Malay
language, T. crispa is used in traditional Malaysian med-
icine for treating several diseases including diabetes
(Gimlette et al., 1930; Aminah et al., 2015). The Murut
tribe in Borneo, Indonesia traditionally uses the plant
to treat the same ailment (Hirschhorn, 1983). In tradi-
tional Thai medicine also, T. crispa is used in the treat-
ment of diabetes (Dweck and Cavin, 2006). The
indigenous people of Guyana use it in a different way.
Stems of T. crispa are macerated in rum, cognac or ab-
sinthe and mixed with the bark of Quassia amara into
a bitter beverage to control diabetes and albuminuria
(Grenand et al., 1987). T. crispa is being widely used in
the southern Indian province of Kerala for treating dia-
betes. A video on this subject has already been viewed
380,000 times (Anonymous, 2015). Kavirajas or folk
Received 29 April 2015
Revised 22 October 2015
Accepted 04 December 2015
358
Figure 1. A twig of T. crispa with wart-like protuberances.
healers of Bangladesh consider this as an important
plant in the treatment of many diseases including diabe-
tes mellitus (Jahan et al., 2010).
PRECLINICAL STUDIES
In vitro experiments
The insulinotropic action of T. crispa was investigated
using isolated rat islets of Langerhans or HIT-T15 B
cells. HIT-T15 is a cell line derived from Syrian hamster
pancreatic β-cells that were transformed with simian
virus 40. These cells secrete insulin in response to a
variety of compounds, including glucose (Santerre
et al., 1981; Ashcroft et al., 1986; Skelin et al., 2010).
When incubated with rat islets and HIT-T15 B cells,
T. crispa extract caused a dose-related stimulation of
basal and glucose-stimulated insulin secretion, respec-
tively. The insulinotropic effect was also demonstrated
in perifused human islets, rat islets and HIT-T15 B cells.
This is a simple procedure that can be used for quantita-
tive studies on the rates of insulin secretion per islet,
excluding the exocrine pancreas. It provides an opportu-
nity to correlate biochemical changes in the islets at
precise intervals during the first and second phases of
insulin secretion (Lacy et al., 1972; Shorten and Wall,
2001). In all the three models, insulin secretion rates
returned to basal levels after removal of the extract. In
rat islets, a second challenge with T. crispa extract
caused an additional stimulated response. All these
Copyright © 2016 John Wiley & Sons, Ltd.
A. THOMAS ET AL.
observations indicate physiological release of insulin
by β-cells (Noor et al., 1989).
The insulinotropic property of T. crispa was evaluated
using BRIN-BD11 cell line, which is a novel insulin-
secreting cell line established after electrofusion of
RINm5F cells with New England Deaconess Hospital
rat pancreatic islet cells (McClenaghan et al., 1996;
Hamid et al., 2008). Secretory characteristics of this cell
line have been described extensively, and BRIN-BD11
cell line is widely used as a model for insulin secretory
studies (Beauwens et al., 2006). In a 30-min acute static
incubation test, T. crispa showed high insulinotropic
activity. It showed an insulin-secretory response with
more than threefold insulin release at 2.0 mg/mL
(Hamid et al., 2008).
The mechanism of T. crispa-induced insulin release was
characterized by culturing HIT-T15 cells and studying the
effect of T. crispa extract and insulin-secretory antagonists
like adrenaline, somatostatin, verapamil and nifedipine
on glucose-stimulated insulin release. High glucose alone
(10 mM) induced a 4.5-fold stimulation of basal line
insulin release, and T. crispa potentiated this effect signif-
icantly by nearly 40%. Glucose-stimulated insulin release
was inhibited around 60% when the HIT-T15 cells were
incubated for 1 h with the insulin secretory antagonists.
These results suggest that the antihyperglycaemic effect
is due to stimulation of insulin release through modula-
tion of β-cell Ca2+ concentration (Noor and Ashcroft,
1998a).
Pancreatic islets from Wistar and Goto–Kakizaki rats
were isolated and perifused in the presence of glucose
and borapetol B isolated from stems of T. crispa.
Borapetol B dose-dependently increased insulin secre-
tion from Wistar and Goto–Kakizaki rat islets at 3.3
and 16.7 mM glucose. As insulin secretion gradually
returned to basal level on removal of borapetol B from
the perifusion medium, it can be inferred that the com-
pound did not cause nonspecific insulin leakage by
damaging β-cells in the islets. It is evident from this
study that borapetol B stimulates the secretion of insulin
from islets of Langerhans (Lokman et al., 2013).
Pancreatic islets from Wistar and Goto–Kakizaki rats
were cultured overnight and then exposed to modula-
tors and inhibitors of insulin secretion. Borapetol B
seems to have an effect partly on K-ATP channels, as
diazoxide partly suppressed borapetol B-induced stimu-
lation at 16.7 mM glucose. The stimulatory effect of
borapetol B on insulin secretion was also dependent
on L-type Ca2+ channels, as nifedipine suppressed the
insulin response to borapetol B at 16.7 mM glucose. This
effect also seems to be partly dependent on pertussis
toxin-sensitive Ge protein. As H89 and calphostin C
did not affect the insulin response to borapetol B, it
can be inferred that there was no modulation by protein
kinase A and protein kinase C inhibitors. The major
stimulatory effect of borapetol B may be on exocytosis
(Lokman et al., 2014).
Skeletal muscle is a major consumer of blood glucose
after meals and during exercise. The transport of glu-
cose in skeletal muscle is regulated by both insulin-
dependent and insulin-independent pathways (Klip
and Marette, 1992; Sakamoto and Goodyear, 2002). In
insulin-dependent pathway, the GLUT4 gene is
activated via p13 kinase and p38 map-kinase (Okada
et al., 1994). As it is still not clear whether T. crispa has
a peripheral effect, Noipha et al. (2008) studied the
Phytother. Res. 30: 357–366 (2016)
 TINOSPORA CRISPA AND DIABETES MELLITUS 359

Table 1. Phytochemicals reported from T. crispa

Sl. no. Name of compound References

Alkaloids
1 N-acetylnornuciferine Pachaly et al. (1992)
Bukhari et al. (2005)
2 Columbamine Hamid (2013)
Yusoff et al. (2014)
3 Cytidine Choudhary et al. (2010)
4 N-demethyl-N-formyldehydronornuciferine Choudhary et al. (2010)
5 Dihydrodiscretamine Hamid (2013)
Yusoff et al. (2014)
6 N,N-dimethylhexadecan-1-amine Hamid (2013)
7 4-13-dihydroxy-2,8,9-trimethoxydibenzo[a,g]quinolizinium Hamid (2013)
Yusoff et al. (2014)
8 N-cis-feruloyltyramine Fukuda et al. (1983)
9 N-trans-feruloyltyramine Choudhary et al. (2010)
Hamid (2013)
Yusoff et al. (2014)
10 N-formylannonaine Pachaly et al. (1992)
Choudhary et al. (2010)
Pachaly et al. (1992)
Hamid (2013)
Yusoff et al. (2014)
11 N-formyldehydroannonaine Choudhary et al. (2010)
12 N-formylnornuciferine Pachaly et al. (1992)
Choudhary et al. (2010)
Pachaly et al. (1992)
Bukhari et al. (2005)
Hamid (2013)
Yusoff et al. (2014)
13 Liriodenine Hamid (2013)
14 Lysicamine Bukhari et al. (2005)
Hamid (2013)
15 Magnoflorine Choudhary et al. (2010)
Hamid (2013)
Yusoff et al. (2014)
16 Paprazine Choudhary et al. (2010)
Glycosides
17 Borapetol A Fukuda et al. (1985)
18 Borapetol B Fukuda et al. (1986)
19 Borapetoside A Ruan et al. (2013)
20 Borapetoside B Fukuda et al. (1986)
Ruan et al. (2013)
21 Borapetoside C Martin et al. (1996)
Fukuda et al. (1993a)
Ruan et al. (2013)
22 Borapetoside D Fukuda et al. (1993a)
23 Borapetoside E Fukuda et al. (1993a)
24 Borapetside F Martin et al. (1996)
Fukuda et al. (1993a)
25 Borapetoside G Fukuda et al. (1993a)
26 Borapetoside H Fukuda et al. (1995)
27 Rumphioside I Martin et al. (1996)
28 Tinocrisposide Pachaly and Adnan (1992)
29 Tinotuberide Fukuda et al. (1983)
30 Cordioside Ahmed et al. (2006)
31 Diosmetin Umi Kalsom and Noor (1995)
32 N-formylasimilobine 2,O-β-D-glucopyranoside Choudhary et al. (2010)
33 N-formylasimilobine 2,O-β-D-glucopyranosyl-(1–2)-β-D-glucopyranoside Choudhary et al. (2010)
34 Genkwanin Umi Kalsom and Noor (1995)
35 Genkwanin 7-glucoside Umi Kalsom and Noor (1995)
36 Luteolin 4′-methylether 3-glucoside Umi Kalsom and Noor (1995)
37 Luteolin 4′-methylether 7-glucoside Umi Kalsom and Noor (1995)

(Continues)
Copyright © 2016 John Wiley & Sons, Ltd. Phytother. Res. 30: 357–366 (2016)
360 A. THOMAS ET AL.

Table 1. (Continued)
Sl. no. Name of compound References

38 Tinosporaside Ahmed et al. (2006)

39 2-O-lactoylborapetoside B Lam et al. (2012)
40 6′-O-lactoylborapetoside B Lam et al. (2012)
Diterpenes
41 Columbin Ahmed et al. (2006)
42 Crispene E Mantaj et al. (2015)
43 Tinocrispol A Lam et al. (2012)
44 Tinotufolin A Fukuda et al. (1993b)
45 Tinotufolin B Fukuda et al. (1993b)
46 Tinotufolin C Fukuda et al. (1994)
47 Tinotufolin D Fukuda et al. (1994)
Regasa et al. (2000)
48 Tinotufolin E Fukuda et al. (1994)
49 Tinotufolin F Fukuda et al. (1994)
50 Vitexilactone Regasa et al. (2000)
Triterpenes
51 Cycloeucalenol Kongathip et al. (2002)
52 Cycloeucalenone Kongathip et al. (2002)
Steroid
53 20-β-hydroxyecdysone Ahmed et al. (2006)
Flavonoids
54 Catechin Amom et al. (2009)
55 Luteolin Amom et al. (2009)
56 Morin Amom et al. (2009)
57 Rutin Amom et al. (2009)

glucose uptake activity of T. crispa in skeletal muscle
cells, using the skeletal muscle cell line L6 myoblasts.
The myoblasts grown to the stage of fused myotubes
were pre-incubated with and without lyophilized water
extract of T. crispa stems. Thereafter, a 2-[3H]-deoxy-
D-glucose uptake test was carried out. In another set
of experiments, prior to the glucose uptake study, the
T. crispa pre-incubated cells were either treated or
untreated with specific inhibitors of the p13-kinase
and p38 map-kinase pathways (wortmannin and SB
203580). It was observed that T. crispa extract at a
dose of 4 mg/mL significantly enhanced glucose
uptake of L6 myotubes in dose-dependent and time-
dependent manner. Wortmannin and SB203580 had
no effect on T. crispa-stimulated glucose uptake,
suggesting that the stimulatory effect of T. crispa
on glucose uptake is exerted through an insulin-
independent mechanism. The effect on glucose uptake
was completely abolished by 10 μM of cytochalasin B.
This indicates that T. crispa stimulates the uptake
of glucose through the hexose transport reaction(s)
(Mizel and Wilson, 1972). In a subsequent study, it
was demonstrated that glucose transport by T. crispa
in L6 myotubes is mediated by the upregulation of
GLUT1, AMPKα and PPARγ expression (Noipha
and Ninla-aesong, 2011).
C2C12 is an immortalized mouse myoblast cell line
that readily proliferates in high-serum conditions and
is a very useful tool to study aspects of myogenesis, me-
tabolism and muscle biology (Yaffe and Saxel, 1977).
Borapetoside A was found to increase the glycogen
content of C2C12 skeletal muscle cells and Hep3B cells
at very low concentrations. Borapetoside A also en-
hanced glycogen synthesis in C2C12 cells, which were
made to be insulin resistant by treatment with IL-6
(Ruan et al., 2013).
Copyright © 2016 John Wiley & Sons, Ltd.
Experiments indicate that the antihyperglycaemic ef-
fect of T. crispa is not due to glucose absorption from
circulation. The methyl-glucose transport into rat adipo-
cytes was assessed in the presence or absence of insulin
or 1 mg/mL T. crispa water extract for 15 min at 37 °C.
There was a significant increase in glucose uptake after
a 15-min incubation with insulin. Nevertheless, T. crispa
extract produced no effect on glucose uptake either in
the presence or in the absence of insulin (Noor and
Ashcroft, 1998a).
While there is consensus agreement on the stimula-
tion of insulin secretion, the reports on glucose uptake
are conflicting. Noor and Ashcroft (1998a) reported that
the antihyperglycaemic effect of T. crispa is not due to
interference with intestinal glucose uptake or sugar up-
take into peripheral cells. But Noipha and Ninla-aesong
(2011) reported that enhancement of glucose uptake by
T. crispa in L6 myotubes is mediated by upregulation of
GLUT 1. Ruan et al. (2013) reported that borapetoside
A increases glucose utilization in peripheral cells and
that the hypoglycaemic effects are mediated through
insulin-dependent and insulin-independent pathways.
A summary of the reports on in vitro experiments is pro-
vided in Table 2.
ANIMAL STUDIES
Aqueous extract of T. crispa was administered to nor-
mal and alloxan-induced diabetic rats through drinking
water. Significant hypoglycaemic effect and improve-
ment in insulinaemia were observed in moderately dia-
betic rats. Two-week treatment with the extract
improved the glucose tolerance of these animals. Acute
intravenous administration of the extract (50 mg/kg)
Phytother. Res. 30: 357–366 (2016)
 TINOSPORA CRISPA AND DIABETES MELLITUS
Table 2. In vitro studies reported on T. crispa
Sl. Plant part Type of extract/
no. used phytochemical Cell line
1 Stem Freeze-dried water extract Isolated human islets, isolated
rat islets, HIT-T15 B cells
2 Stem bark Methanolic extract BRIN-BD11
3 Stem Freeze-dried water extract HIT-T15 cells
4 Stem Freeze-dried water extract Rat skeletal muscle L6 cell line
5 — Borapetol C Isolated pancreatic islets
from Wistar
and Goto–Kakizaki rats
6. — Borapetoside A C2C12 and Hep 3B cells
7. — Borapetol B Isolated pancreatic islets from
Wistar and Goto–Kakizaki rats
increased plasma insulin levels, suggesting that T. crispa
might be improving diabetic conditions by stimulating
β-cells of the endocrine pancreas (Noor and Ashcroft,
1989).
After 2 weeks of oral administration of T. crispa, the
mean body weight of diabetic animals increased signifi-
cantly, when compared with diabetic controls. This
observation rules out the possibility of weight loss ame-
liorating type 2 diabetes (Noor et al., 1989).
Similar results were reported by Anulukanapakorn
et al. (1999). Ninety-five per cent ethanolic extract of
T. crispa given orally at doses of 250 and 500 mg/kg
of body weight improved oral glucose tolerance in
normoglycaemic rats. A dose of 250 mg/kg of body weight
could reduce blood glucose levels of diabetic rats by
12.15% and 12.48% at 4 and 6 h, respectively. Ether frac-
tion of the extract did not produce any hypoglycaemic
effect in normal and alloxan-diabetic rats. However, buta-
nol and aqueous fractions of the 95% ethanolic extract
produced significant hypoglycaemic effect in alloxan-
diabetic rats.
Post-prandial hyperglycaemia can be prevented if the
rate of absorption of glucose from intestine into circula-
tion can be reduced (Martin and Montgomery, 1996).
The antihyperglycaemic properties of T. crispa were
characterized by studying its effect on intestinal glucose
absorption. The lumen of the upper and lower parts of
the jejunum of Wistar rats was perfused with Krebs-
Ringer phosphate buffer containing 1 M glucose with
or without 4 mg/mL T. crispa water extract. It was
observed that the addition of T. crispa extract into the
perfusion fluid did not alter significantly the rate of
glucose absorption into intestine (Noor and Ashcroft,
1998a).
Intraperitoneal injection of borapetosides A and C
(5 mg/kg) significantly stimulated insulin release and
lowered plasma glucose in a dose-dependent way in
non-diabetic and type 2 diabetic mice, which were made
diabetic by feeding with fat-rich chow and 20% fructose-
sweetened water for 4 weeks. The effects were not ob-
served in type 1 (streptozotocin-induced) diabetic mice.
The plasma insulin level significantly rose to plateau
level at 3 mg/kg of borapetoside C administration in
non-diabetic and type 2 diabetic mice. This effect was
comparable with glibenclamide (5 mg/kg). In the intra-
peritoneal glucose tolerance test, levels of plasma glu-
cose of non-diabetic and type 2 diabetic mice treated
with borapetoside C were lower than the levels
Copyright © 2016 John Wiley & Sons, Ltd.
361
Duration
Dose of incubation Reference
10–1000 μg 1h Noor et al. (1989)
2 mg/mL 30 min Hamid et al. (2008)
10 μg/mL 1h Noor and Ashcroft (1998a)
2 mg/mL 48 h Noipha et al. (2008)
10 μg/mL 1h Lokman et al. (2014)
8 7
10 –10 mol/L 30 min Ruan et al. (2013)
0.1, 1 and 10 μg/mL 1h Lokman et al. (2013)
observed in mice treated with the vehicle. Treatment
of mice with 5 mg/kg borapetoside C twice a day for
7 days caused a decrease in the level of hepatic phos-
phoenolpyruvate carboxykinase (PEPCK), comparable
with that of insulin-treated mice. PEPCK is an enzyme
that catalyses gluconeogenesis. These observations sug-
gest that borapetoside C improves glucose utilization in
peripheral tissues and reduces hepatic gluconeogenesis
(Lam et al., 2012).
Acute treatment with borapetoside C from T. crispa
(5 mg/kg, i.p.) lowered the level of plasma glucose ele-
vated by oral glucose feeding in normal and type 2
diabetic mice. Compared with insulin (0.5 IU/kg),
borapetoside C caused a significant increase in glycogen
content in skeletal muscle of type 2 diabetic mice. The
effect was less pronounced in type 1 diabetic mice. Con-
comitant treatment with borapetoside C (0.1 mg/kg, i.p.)
and insulin increased insulin-induced lowering of plasma
glucose and insulin-induced increase in muscle glycogen.
Continuous treatment with borapetoside C (5 mg/kg) for
7 days increased the phosphorylation of insulin receptor
(IR), protein kinase B (Akt) and expression of glucose
transporter 2 (GLUT2) in type 1 diabetic mice. Contin-
ued administration of a low dose of borapetoside C
(0.1 mg/kg, twice a day) and insulin for 7 days increased
insulin-induced IR Akt phosphorylation and GLUT2 ex-
pression in liver of type 1 diabetic mice. This study shows
that borapetoside C can stimulate glucose utilization,
delay the development of insulin resistance and enhance
insulin sensitivity (Ruan et al., 2012).
Borapetoside A was also shown to increase glucose
utilization in peripheral tissues, reduce hepatic gluco-
neogenesis and activate insulin-signalling pathway in
mice. Borapetoside attenuated the elevation of plasma
glucose induced by intraperitoneal glucose tolerance
test. Additionally, the increased expression of PEPCK
was reversed by borapetoside A treatment twice a day
for 7 days (Ruan et al., 2013). Comparison of the
structures of borapetosides A, B and C suggests that
the C-8 stereochemistry plays a key role in evoking
hypoglycaemic effect. The active borapetosides A
and C possess 8-R chirality, whereas the inactive
borapetoside B possesses 8-S chirality.
The glycoside is located at C-3 in borapetoside A, while
it is located at C-6 in the case of borapetoside C. A lactone
is formed in borapetoside A between C-4 and C-6 (Fig. 2).
These differences may be the cause of the difference in
potency between the two compounds.
Phytother. Res. 30: 357–366 (2016)
362
Figure 2. Borapetoside A, borapetoside B and borapetoside C.
Acute oral administration of borapetol B to
normoglycaemic Wistar rats and diabetic Goto–
Kakizaki rats improved blood glucose levels in treated
versus control groups with areas under curves
0–120 min being 72 ± 17 versus 344 ± 10 mmol/L, and
492 ± 63 versus 862 ± 55 mmol/L in Wistar and Goto–
Kakizaki rats, respectively. Plasma insulin levels were
increased twofold in treated Wistar and Goto–Kakizaki
rats (Lokman et al., 2013).
Consumption of high amounts of fat-rich and calorie-
rich diet leads to obesity. Through a series of steps, obe-
sity leads to insulin resistance (Kahn and Flier, 2000;
Qatanani and Lazar, 2007). The effects of T. crispa in
ameliorating insulin resistance induced in obese Wistar
rats were studied. After 8 weeks of oral administration
of T. crispa powder in distilled water, body weight,
adiposity index and serum levels of aspartate amino-
transferase, alanine aminotransferase, total cholesterol,
triglycerides, blood glucose, resistin and leptin were re-
duced significantly. These results favour the long-term
administration of T. crispa for treating obesity in pa-
tients with insulin resistance and diabetes mellitus
(Abu et al., 2015). A summary of the reports on animal
experiments is provided in Table 3.
HUMAN STUDIES
A randomized, double-blind, placebo-controlled clinical
trial was conducted to determine the blood sugar lower-
ing property of T. crispa. The subjects were 20 patients
Table 3. In vivo studies reported on T. crispa
Sl. Plant Type of extract/
no. part used phytochemical Animal model
1. Stem Water extract Alloxan-diabetic rat
2 Stem Water extract Alloxan-diabetic rat
3 Stem Freeze-dried water extract Alloxan-diabetic rat
4 Stem 95% ethanolic extract Alloxan-diabetic rat
Ether fraction of 95% Alloxan-diabetic rat
ethanolic extract
Butanol fraction of 95% Alloxan-diabetic rat
ethanolic extract
Aqueous fraction of 95% Alloxan-diabetic rat
ethanolic extract
5. — Borapetosides A and C Streptozotocin-diabetic mice
6. — Borapetoside C Streptozotocin-diabetic mice
7. — Borapetoside A Streptozotocin-diabetic mice
8. — Borapetol B Spontaneously type 2 diabetic
Goto–Kakizaki rats
9. Stem Water extract Obese Wistar rats
Copyright © 2016 John Wiley & Sons, Ltd.
A. THOMAS ET AL.
with type 2 diabetes who did not respond to oral
hypoglycaemic drugs and refused insulin injection. The
study population received additional T. crispa powder
at a dose of 1 g thrice daily for 6 months. Fasting blood
sugar, glycosylated haemoglobin and insulin levels of
patients in experimental and control groups were not
significantly different during the 6 months. At the con-
clusion of the study, patients in the T. crispa group had
higher glycosylated haemoglobin and cholesterol values.
Each patient had lost approximately 2 kg of body weight
(Sangsuwan et al., 2004).
A clinical trial on healthy Thai volunteers was con-
ducted to evaluate the effect of T. crispa on blood sugar
and the safety of the treatment. Firstly, the effect of
T. crispa on oral glucose tolerance was studied in nine
healthy subjects. A single dose of 6 g of the herb did
not improve glucose tolerance. In the second experi-
ment, the effects of T. crispa on blood glucose and insu-
lin levels were studied in six healthy subjects. It was
observed that blood glucose concentration decreased
significantly after each subject consumed 6 g of T. crispa
powder. But the concentration of insulin in serum was
not increased. Lastly, the effects of T. crispa on haema-
tological and biochemical parameters were studied.
Twelve subjects received T. crispa at the dose of 1 g
thrice a day before meals for 8 weeks, and 13 subjects
received the drug at a dose of 1.05 g thrice daily before
meals for 4 weeks. The treatments did not cause any
change in haematological parameters including serum
glucose. However, the liver enzyme aspartate amino-
transferase (AST) and alanine aminotransferase
(ALT) tended to increase after T. crispa administration,
suggesting hepatotoxicity (Rattanajarasroj et al., 2004).
A study to determine the effect on blood glucose and
insulin levels of ten healthy subjects and ten diabetic
participants was carried out. After overnight fasting,
serum from them was collected every 30–60 min during
3 h of continued fasting and during the 3 h after inges-
tion of 75 g of glucose with or without ingestion of
250 mg of T. crispa powder. Glucose and insulin levels
in healthy and diabetic subjects were not different be-
tween with or without T. crispa powder (Klangjareonchai
and Roongpisuthipong, 2012).
Duration of
Dose administration Reference
4 g/L of drinking water 2 weeks Noor and Ashcroft (1989)
50 mg/kg i.v. 2 weeks Noor and Ashcroft (1989)
4 g/L of drinking water 2 weeks Noor et al. (1989)
250 and 500 mg/kg 6h Anulukanapakorn et al.
25, 50 and 100 mg/kg 6h (1999)
50, 150 and 450 mg/kg 6h
125, 250 and 500 mg/kg 6h
5 mg/kg 7 days Lam et al. (2012)
5 mg/kg 7 days Ruan et al. (2012)
0.1–10 mg/kg 7 days Ruan et al. (2012)
10 μg/100 g 2h Lokman et al. (2013)
100 mg/kg 8 weeks Abu et al. (2015)
Phytother. Res. 30: 357–366 (2016)
 TINOSPORA CRISPA AND DIABETES MELLITUS 363

The only study reporting a positive effect of T. crispa
is the one by Sriyapai et al. (2009), who conducted a ran-
domized, double-blind, placebo-controlled, crossover
study in 36 patients with metabolic syndrome. They
received 250 mg of T. crispa dry powder, twice daily
for 2 months. Patients who received T. crispa powder
had significantly lower fasting blood sugar and triglycer-
ide levels. Curiously, an increase of more than three
times baseline levels of AST and ALT was observed in
16.7% of the subjects. A summary of the clinical studies
is given in Table 4.
CONCLUSION
Results of the several studies show that T. crispa is
a promising herb in the treatment of diabetes
mellitus. Cell culture and animal studies suggest that
the herb stimulates secretion of insulin from β-cells
(Noor et al., 1989; Noor and Ashcroft, 1989, 1998a;
1998b; Anulukanapakorn et al., 1999; Hamid et al.,
2008; Lam et al., 2012). It also causes dose-dependent
and time-dependent enhancement of glucose uptake in
muscles (Noipha et al., 2008). Borapetosides A and C
isolated from T. crispa improve glucose utilization in pe-
ripheral tissues and reduce hepatic gluconeogenesis
(Lam et al., 2012; Ruan et al., 2013). A schematic dia-
gram of mode of action of T. crispa is given in Fig. 3.
Results of clinical trials suggest that T. crispa induces
hepatotoxicity. Sangsuwan et al. (2004) reported that 2
of the 20 subjects who received T. crispa in the clinical
trials had elevated levels of the liver function marker en-
zymes SGOT and SGPT (>200 U/L), which returned to
normal values on discontinuing the herbal remedy. Sim-
ilar side effect was reported by Rattanajarasroj et al.
(2004) and Sriyapai et al. (2009).
A definite case of hepatotoxicity induced by T. crispa
was recently reported (Langrand et al., 2014). A
Vietnamese man with no medical history on his return
to France from Vietnam started to take daily ten pellets
of a herbal medicine made up of T. crispa. Four weeks
later, he developed dark urine, pale stools and right
hypochondrial pain. Two months after starting the treat-
ment, he was tested and was found to have high levels of
bilirubin and γ-glutamyltransferase, a liver function
marker enzyme. The herbal medicine was immediately
stopped on admission, and he recovered fully without

Table 4. Human studies

Sl. no. Test material Number of subjects Dose Duration of administration Reference

1 Stem powder in capsule 20 1 g t.i.d.1 6 months Sangsuwan et al. (2004)

2 Stem powder 9 4 or 6 g (single dose) 6h Rattanajarasroj et al. (2004)
6 6 g (single dose) 2h
12 1 g t.i.d.1 8 weeks
13 1.05 t.i.d.1 4 weeks
3 Stem powder in capsule 20 125 or 250 g (single dose) 3h Klangjareonchai and
Roongpisuthipong (2012)
4 Stem powder in capsule 36 250 mg b.i.d.2 2 months Sriyapai et al. (2009)
1
Three times a day.
2
Two times a day.

Figure 3. Schematic diagram of mode of action of T. crispa.

Copyright © 2016 John Wiley & Sons, Ltd. Phytother. Res. 30: 357–366 (2016)
364 A. THOMAS ET AL.
treatment, 2 months after developing the symptoms.
Presence of T. crispa in the herbal medicine was
detected by microscopic analysis of the crushed pellets
and comparison with a certified reference sample of
T. crispa provided by Hanoi University of Pharmacy.
Further evidence was available from reversed-phase
TLC and reversed-phase HPLC–UV analysis of dichlo-
romethane extract of the pellets.
T. crispa has a high content of furanoditerpenoids
like borapetosides (Fukuda et al., 1993a). These
furanoditerpnoids, similar to the ones in germander
(Teucrium chamaedrys) (Piozzi et al., 1987), form toxic
metabolites through the action of cytochrome P 450 3A.
Formation of these compounds is enhanced by induction
of cytochrome P 450 3A and by depletion of glutathione
(Loeper et al., 1994; Kouzi et al., 1994). The toxic
diterpenoids induce apoptosis of hepatocytes (Lekehal
et al., 1996; Fau et al., 1997; Stickel et al., 2005; Langrand
et al., 2014). Considering the hepatotoxic nature of
T. crispa, there is an urgent need to identify the other
hepatotoxic compounds in the herb so that methods for
their removal from the extracts can be discovered.
While cell culture and animal studies unequivocally
prove that T. crispa has insulinotropic activity, three of
the four human trials failed to confirm this clinically.
This calls for a re-examination of the subject. It is evi-
dent that the doses used in these studies are too low
(125 mg, 250 mg and 1 g of herb powder). On the
contrary, the doses used in the preclinical studies are
REFERENCES
Abu MN, Samat S, Kamarapani N, Hussein FN, Ismail WIW, Hassan
HF. 2015. Tinospora crispa ameliorates insulin resistance
induced by high fat diet in Wistar rats. Evidence Based Compl
Alt Med Article ID 985042.
Ahmed SM, Manhas LR, Verma V, Khajuria RK. 2006. Quantitative
determination of four constituents of Tinospora sps. by a
reversed-phase HPLC–UV–DAD method. Broad-based studies
revealing variation in content of four secondary metabolites
in the plant from different eco-geographical regions of India.
J Chromatogr Sci 44: 504–509.
Aminah H, Ahmad Fauzi MS, Tariq Mubarak H, Hamzah M. 2015.
Effect of hormone and cutting length on the rooting of
Tinospora crispa. Int J Sci Res Pub 5: 1–4.
Amom Z, Bahari H, Isemaail S, Ismail NA, Shah ZM, Arsyad MS.
2009. Nutritional composition, antioxidant activity and flavonoid
content of Tinospora crispa stem. Adv Nat Appl Sci 3: 88–94.
Anonymous. 2011. The Ayurvedic Formulary of India, Part III (1st ed.).
Controller of Publications: Delhi; 1–710.
Anonymous. 2013a. Diagnosis and classification of diabetes
mellitus. Diabetes Care 36: S67–S74.
Anonymous. 2013b. Shen jin teng (Tinospora crispa (L.) Miers.
hen jin t). http://www.wikiherb.info/2011/06/shen-jin-teng-
tinospora-crispa-l.html Accessed on 25.10.2013
Anonymous. 2015. Wonderful cure for diabetics. 600+ reduced
into 60 in just one week!!! https://www.youtube.com/
watch?v=Dx9dEG5z_TE Accessed on 18 December, 2015
Anulukanapakorn K, Pancharoen O, Bansiddhi J. 1999. Hypoglyce-
mic effect of Tinospora crispa (Linn.) Miers ex Hook. F. & Thoms
(Menispermiaceae) in rats. Bull Depart Med Sci 41: 231–243.
Ashcroft SJH, Hammonds P, Harrison DE. 1986. Insulin secretory
responses of a clonal cell line of simian virus 40-transformed
β-cells. Diabetologia 29: 727–733.
Beauwens R, Best L, Markadieu N, et al. 2006. Stimulus-secretion
coupling of hypotonicity-induced insulin release in BRIN-BD11
cells. Endocrine 30: 353–363.
Bukhari NA, Sadikun A, Choon TS, Ying TS, Asmawi MZ. 2005.
Aporphine alkaloids isolated from the cardiovascular active
fraction of Tinospora crispa. Malaysian J Sci 24: Issue 1.
Choudhary MI, Ismail M, Ali Z, Shaari K, Lajis NH, Rahman AU.
2010. Alkaloidal constituents of Tinospora crispa. NPC Nat
Prod Commun 5: 1747–1750.
Copyright © 2016 John Wiley & Sons, Ltd.
reasonable. For example, Anulukanapakorn et al.
(1999) administered orally 250 and 500 mg/kg of 95%
ethanolic extract, which was obtained at a yield of
5.50%. However, 250 mg of T. crispa powder at the
extraction rate yields only 13.75 mg of extract. This dose
is certainly too low for a phytomedicine in humans. It
may be recalled here that Chinese medicine recom-
mends high dose range for most of the herbs. For exam-
ple, Radix Astragali Membranacei (Huang Qi) is
commonly dosed at 18–60 g per day (Flaws and
Sionneau, 2005). Ayurveda considers 24–48 g as the
standard dose of a decoction per day. Medicinal pow-
ders are administered at the rate of 3–6 g twice or thrice
a day (Anonymous, 2011; Williamson, 2002). Therefore,
well-controlled clinical trials using therapeutically active
doses of crude T. crispa powder or the extract are
required, as animal studies show promising results.
Acknowledgements
We thank the anonymous reviewers for their valuable help in improving
the quality of the manuscript.
Conflict of Interest
The authors declare that there is no conflict of interest.
Dweck AC, Cavin JP. 2006. Andawali (Tinospora crispa)—a
review. Personal Care Mag 7: 1–3.
Fau D, Lekehal M, Farrell G, et al. 1997. Diterpenoids from
germander, an herbal medicine, induce apoptosis in isolated
rat hepatocytes. Gastroenterology 113: 1334–1346.
Flaws B, Sionneau P. 2005. The Treatment of Modern Western
Medical Diseases with Chinese Medicine (2nd ed.). Blue
Poppy Press: Colorado; 33–35.
Fukuda N, Yonemitsu M, Kimura T. 1983. Studies on the constituents
of the stems of Tinospora tuberculata Beumee. I. N-trans- and
N-cis-feruloyltyramine and a new phenolic glucoside, tinotuberide.
Chem Pharm Bull 31: 156–161.
Fukuda N, Yonemitsu M, Kimura T. 1985. Studies on the constitu-
ents of the stems of Tinospora tuberculata Beumee. II. New
diterpenoids borapetoside A and borapetol A. Chem Pharm
Bull 33: 4438–4444.
Fukuda N, Yonemitsu M, Kimura T. 1986. Studies on the constitu-
ents of the stems of Tinospora tuberculata Beumee. III. New
diterpenoids, borapetoside B and borapetol B. Chem Pharm
Bull 34: 2868–2872.
Fukuda N, Yonemitsu M, Kimura T. 1993a. Studies on the constit-
uents of the stems of Tinospora tuberculata, IV. Isolation and
structure elucidation of the five new furanoid diterpene
glycosides borapetoside C–G. Liebigs Annal Chem 1993:
491–495.
Fukuda N, Nakamura M, Yonemitsu M, Kimura T, Isobe R, Komori
T. 1993b. Studies on the constituents of the leaves of
Tinospora tuberculata, I. Isolation and structure elucidation
of two new furanoid diterpenes, tinotufolin A and B. Liebigs
Annal Chem 1993: 325–327.
Fukuda N, Yonemitsu M, Kimura T, Isobe R, Komori T. 1994.
Studies on the constituents of the leaves of Tinospora
tuberculata, II. Isolation and structure elucidation of four
new furanoid diterpenes, tinotufolin C–F. Liebigs Annal Chem
1994: 755–757.
Fukuda N, Yonemitsu M, Kimura T. 1995. Studies on the constitu-
ents of the stems of Tinospora tuberculata, V. Isolation and
structure elucidation of the new furanoid diterpene glucoside
borapetoside H. Liebigs Annal Chem 1995: 1689–1691.
Gimlette JD, Burkill LH, Munshi I. 1930. The medicinal book of
Malayan medicine. Gard Bull Straits Settlem 6: 323–474.
Phytother. Res. 30: 357–366 (2016)
 TINOSPORA CRISPA AND DIABETES MELLITUS
Grenand P, Moretti C, Jacquemin H. 1987. Pharmacopées
Traditionnelles en Guyane: Créoles, Palikur, Wayapi. Editions
de l’Orstom: Paris; 299–300.
Hamid HWB. 2013. Characterisation and biological activities of
Tinospora crispa (Menispermiaceae) extract with emphasis
on alkaloids. Thesis submitted to Faculty of Industrial Sci-
ences and Technology, Universiti Malaysia Pahang.
Hamid M, Bohari SPM, Bastami MS, Ali A, Mustapha NM, Shari K.
2008. Evaluation of the insulinotrophic activity of Malaysian
traditional plants extract. J Biol Sci 8: 201–204.
Hirschhorn HH. 1983. Botanical remedies of the former Dutch East
Indies (Indonesia). Part II: dicotyledons up to and including
Leguminosae. J Ethnopharmacol 8: 65–96.
Hong L, Guo Z, Huang K, et al. 2015. Ethnobotanical study on me-
dicinal plants used by Maonan people in China. J Ethnobiol
Ethnomed 11: 32.
Jahan R, Khatun MA, Nahar N, et al. 2010. Use of Menispermaceae
of Bangladesh. Adv Nat Appl Sci 4: 1–9.
Kahn BB, Flier JS. 2000. Obesity and insulin resistance. J Clin
Invest 106: 473–481.
Klangjareonchai T, Roongpisuthipong C. 2012. The effect of
Tinospora crispa on serum glucose and insulin levels in pa-
tients with type 2 diabetes mellitus. J Biomed Biotechnol
2012: . DOI:10.1155/2012/808762.
Klip A, Marette A. 1992. Acute and chronic signals controlling
glucose transport in skeletal muscle. J Cell Biochem 48:
51–60.
Koay YC, Amir F. 2013. A review of the secondary metabolites and
biological activities of Tinospora crispa (Menispermiaceae).
Trop J Pharm Res 12: 641–649.
Kongathip N, Dhumma-upakorn P, Kongathip B, Chawananoraset
K, Sangchomkaeo P, Hatthakitpanichakul S. 2002. Study on
cardiac contractility of cycloeucalenol and cycloeucalenone
isolated from Tinospora crispa. J Ethnopharmacol 83: 95–99.
Kouzi SA, McMurty RJ, Nelson SD. 1994. Hepatotoxicity of ger-
mander (Teucrium chamedrys L.) and one of its constituent
neoclerodane diterpenes, teucrin A in the mouse. Chem Res
Toxicol 7: 850–856.
Kumar DS. 2015. Herbal Bioactives and Food Fortification: Extrac-
tion and Formulation. CRC Press: Boca Raton; 1–28.
Lacy PE, Walker MM, Fink CJ. 1972. Perifusion of isolated rat
islets in vitro. Participation of the microtubular system in the
biphasic release of insulin. Diabetes 21: 987–998.
Lam SH, Ruan CT, Hsieh PH, Su MJ, Lee SS. 2012. Hypoglyce-
mic diterpenoids from Tinospora crispa. J Nat Prod 75:
153–159.
Langrand J, Regnault H, Cachet X, et al. 2014. Toxic hepatitis in-
duced by a herbal medicine: Tinospora crispa. Phytomedicine
21: 1120–1123.
Lekehal M, Pessayre D, Lereau JM, Moulis C, Fourasté I, Fau D.
1996. Hepatotoxicity of the herbal medicine, germander: meta-
bolic activation of its furano diterpenoids by cytochrome P450
3A depletes cytoskeleton-associated protein thiols and forms
plasma membrane blebs in rat hepatocytes. Hepatology 24:
212–218.
Loeper J, Descatoire V, Letteron P, et al. 1994. Hepatotoxicity of
germander in mice. Gastroenterology 106: 464–472.
Lokman FE, Gu HF, Mohamud WNW, Yusoff MM, Chia KL, Östenson
CG. 2013. Antidiabetic effect of oral borapetol B compound
isolated from the plant Tinospora crispa, by stimulating insulin
release. Evidence Based Compl Alt Med Article ID 727602
Lokman FE, Gu HF, Mohamud WNW, Yusoff MM, Chia KL,
Östenson CG. 2014. The possible mechanisms by which
borapetol B stimulates insulin release from rat islets. Int J
Med Med Sci 47: 1461–1468.
Mantaj J, Rahman SM, Bokshi B, et al. 2015. Crispene E, a cis-
clerodane diterpene inhibits STAT3 dimerization in breast can-
cer cells. Org Biomol Chem 13: 3882–3886.
Martin AE, Montgomery PA. 1996. Acarbose: an alpha-glucosidase
inhibitor. AmerJ Health Syst Pharm 53: 2277–2290.
Martin TS, Ohtani K, Kasai R, Yamasaki K. 1996. Furanoid diter-
pene glucosides from Tinospora rumphii. Phytochemistry 42:
153–158.
McClenaghan NH, Barnett CR, Ah-Sing E, et al. 1996. Characteri-
zation of a novel glucose-responsive insulin-secreting cell
line, BRIN-BD11, produced by electrofusion. Diabetes 45:
1132–1140.
Mizel SB, Wilson L. 1972. Inhibition of the transport of several
hexoses in mammalian cells by cytochalasin B. J Biol Chem
247: 4102–4105.
Copyright © 2016 John Wiley & Sons, Ltd.
365
Noipha K, Ninla-aesong P. 2011. The activation of GLUT1, AMPKα
and PPARγ by Tinospora crispa in L6 myotubes. Spatula DD 1:
245–249.
Noipha K, Purintrapiban J, Herunsalee A, Ratanachaiyavang S.
2008. In vitro glucose uptake activity of Tinospora crispa in
skeletal muscle cells. Asian Biomed 2: 415–420.
Noor H, Ashcroft SJH. 1989. Antidiabetic effects of Tinospora
crispa in rats. J Ethnopharmacol 27: 149–161.
Noor H, Ashcroft SJH. 1998a. Pharmacological characterization of
the antihyperglycaemic properties of Tinospora crispa. J
Ethnopharmacol 62: 7–13.
Noor H, Ashcroft SJH. 1998b. Insulinotropic activity of Tinospora
2+
crispa extract: effect on β-cell Ca handling. Phytother Res
12: 98–102.
Noor H, Hammonds P, Sutton R, Ashcroft SJH. 1989. The
hypoglycaemic and insulinotropic activity of Tinospora crispa:
studies with human and rat islets and HIT-T15 B cells.
Diabetologia 32: 354–359.
Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M. 1994. Essen-
tial role of phosphatidylinositol 3-kinase in insulin-induced
glucose transport and antilipolysis in rat adipocytes: studies
with a selective inhibitor wortmannin. J Biol Chem 269:
3568–3573.
Pachaly P, Adnan AZ. 1992. Tinocrisposid, ein neues
Furanditerpenklykosid aus Tinospora crispa Miers. Arch Pharm
325: 705–708.
Pachaly P, Adnan AZ, Will G. 1992. NMR assignment of N-acylaporphine
alkaloids from Tinospora crispa. Planta Med 58: 184–187.
Panchabhai TS, Kulkarni UP, Rege NN. 2008. Validation of thera-
peutic claims of Tinospora cordifolia: a review. Phytother Res
22: 425–441.
Patel DK, Kumar R, Laloo D, Hemalatha S. 2012. Diabetes mellitus:
an overview on its pharmacological aspects and reported me-
dicinal plants having antidiabetic activity. Asian Pac J Trop
Biomed 2: 411–420.
Pathak AK, Jain DC, Sharma RP. 1995. Chemistry and biological
activities of the genera Tinospora. Int J Pharmacogn 33:
277–287.
Piozzi F, Rodriguez B, Savona G. 1987. Advances in the chemistry
of the furanoditerpenoids from Teucrium species. Heterocy-
cles 25: 807–841.
Qatanani M, Lazar MA. 2007. Mechanisms of obesity-associated
insulin resistance: many choices on the menu. Genes Develop
21: 1443–1455.
Rattanajarasroj S, Pinthong T, Warachit P, Bansiddhi J, Bunjob M,
Techadamrongsin Y. 2004. Effect on blood sugar level and
safety of Tinospora crispa in healthy Thai volunteers. Bull
Depart Med Sci 46: 72–88.
Regasa CY, Cruz MC, Gula R, Rideout JA. 2000. Clerodane
diterpenes from Tinospora rumphii. J Nat Prod 63: 509–511.
Ruan CT, Lam SH, Chi TC, Lee SS, Su MJ. 2012. Borapetoside C
from Tinospora crispa improves insulin sensitivity in diabetic
mice. Phytomedicine 19: 719–724.
Ruan CT, Lam SH, Lee SS, Su MJ. 2013. Hypoglycemic action of
borapetoside A from the plant Tinospora crispa in mice.
Phytomedicine 20: 667–675.
Sakamoto K, Goodyear LJ. 2002. Invited review: intracellular
signaling in contracting skeletal muscle. J Appl Physiol 93:
369–383.
Sangsuwan C, Udompanthurak S, Vannasaeng S, Thamlikitkul V.
2004. Randomized controlled trial of Tinospora crispa for addi-
tional therapy in patients with type 2 diabetes mellitus. J Med
Assoc Thai 87: 543–546.
Santerre RF, Cook RA, Crisel RM, et al. 1981. Insulin synthesis in a
clonal cell line of simian virus 40-transformed hamster pancre-
atic beta cells. Proc Natl Acad Sci U S A 78: 4339–4343.
Shorten PR, Wall DJN. 2001. A model of dispersion in perifusion
systems. J Theor Med 3: 191–211.
Skelin M, Rupnik M, Cencič A. 2010. Pancreatic beta cell lines
and their applications in diabetes mellitus research. Altex 27:
105–113.
Sriyapai C, Dhumma-upakorn R, Sangwatanaroj S, Kongkathip N,
Krittiyanunt S. 2009. Hypoglycemic effect of Tinospora
crispa dry powder in outpatients with metabolic syndrome at
King Chulalongkorn memorial hospital. J Health Res 23:
125–133.
Stickel F, Patsenker E, Schuppan D. 2005. Herbal hepatotoxicity. J
Hepatol 43: 901–910.
Tan ML. 1980. Philippine Medicinal Plants in Common Use. AKAP
Research: Quezon City, Philippines; 53–54.
Phytother. Res. 30: 357–366 (2016)
366 A. THOMAS ET AL.

Umi Kalsom Y, Noor H. 1995. Flavone O-glycosides fromTinospora
crispa. Fitoterapia 66: 280.
Wild S, Roglic G, Green A, Sicree R, King H. 2004. Global preva-
lence of diabetes—estimates for the year 2000 and projec-
tions for 2030. Diabetes Care 27: 1047–1053.
Williamson EM. 2002. Major Herbs in Ayurveda. Elsevier Science
Ltd: London; 1–361.
Yaffe D, Saxel O. 1977. Serial passaging and differentiation of
myogenic cells isolated from dystrophic mouse muscle.
Nature 270: 725–727.
Yusoff M, Hamid H, Houghton P. 2014. Anticholinesterase inhibi-
tory activity of quaternary alkaloids from Tinospora crispa.
Molecules 19: 1201–1211.

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