Introduction
·
Diabetes 2
Features
·
Diabetes: CurebyNature 4
· Development of the Thiazolidinediones as PPAR γ Agonists for the Treatment
of Type 2 Diabetes 22
·
Exploring Role of 5-Hydroxytryptamine in
Diabetes Mellitus and Cardiovascular
Complications 31
·
SystemBiology
Enables Novel Strategies for the Management of Type 2 Diabetes 40
·
Overview of Diabetes Mellitus
Management 51
News & Views 64
R&D Highlights RDHABSTRACTS
Cellbased Treatments for Diabetes 72
R& D Technology Abstracts
· RiskFactors and Complications of
Diabetes 89
New Leads Abstracts 100
Natural Products
· Withania coagulans: Role in Diabetes 106
·
Marine Biota and
Diabetics 113
Biotechnology
·
Latent Autoimmune
Diabetes in Adults (LADA) 119
Patents 123
CDRI Publications 129
Diabetes
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 don’t produce enough insulin, or the insulin they do produce
does not work properly, or their cells don’t 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 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.
Editor

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

The effects of two dietary
doses of freeze-dried onion powder, i.e.,
onion low (ONL; 0.5%) and onion high (ONH; 2.0%) on streptozotocin
(STZ)-induced diabetes rat model was studied. After 4 weeks on the experimental
diets, fasting blood glucose levels for both onion-fed groups were found
elevated. Serum insulin concentrations and insulin resistance were
dose-dependently increased in the onion-fed groups. The ONH group had
significantly higher lipid concentrations, ONL group showed a similar
hyperlipidemic trend to a lesser extent31.
Allium sativum L. (Family: Alliaceae)
Commonly known as Lahasun in Hindi and Garlic in English. Ethanolic extract of garlic at the doses of 0.1, 0.25
and 0.5 g/kg body weight was orally given to normal and streptozotocin-induced
diabetic rats for 14 days. The level of serum glucose, total cholesterol,
triglycerides, urea, uric acid, creatinine, aspartate amino transferase (AST)
and alanine amino transferase (ALT) were found decreased. The antidiabetic
effect of the extract was found more active than that of glibenclamide18.
The antidiabetic effect of garlic is thought to be due to the formation
of a colloidal type suspension in the stomach and intestines when the
mucilaginous fiber of garlic is hydrated, therefore affecting gastro-intestinal
transit and slowing glucose absorption47. S-allyl cysteine
sulphoxide, a sulphur containing amino acid which is the precursor of allicin and
garlic oil, has been found to show significant antidiabetic effects in alloxan
diabetic rats at a dose of 200 mg/kg body weight. It increased significantly
liver and intestinal HMG CoA reductase activity and liver hexokinase activity (Sheela & Augusti, 1992). Allicin
(thio-2-propene-1-sulfinic acid S-allyl ester), isolated from garlic, produced
significant blood glucose lowering activity in experimental diabetic animals48.

Aloe vera (L.) Burm.f. (Family: Aloaceae)
Commonly known as Ghee Kunwar or Kumar panthu in Hindi. Aloes have long
been used all over the world for their various medicinal properties. Separate
experiments on 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 extract showed hypoglycaemic activity on IDDM
and NIDDM rats. Whereas, leaf gel extract showed hyperglycaemic activity on NIDDM
rats. This study directed that the pulps of A.
vera leaves devoid of the gel could be useful in the
treatment of non-insulin dependent diabetes mellitus54.
Andrographis paniculata Nees
(Family: Acanthaceae)
Commonly known as Kalmegh in Hindi and
King of bitters in English. Andrographolide,
a principle present in

Andrographis
paniculata is suggested to increase
glucose utilization in peripheral tissue via an insulin-dependent mechanism80.
Annona squamosa L. (Family: Annonaceae)
Commonly known as Sharifa or Sitafal in
Hindi and Sugar apple or Custard apple in English. Aqueous leaf extract has
shown hypoglycemic activity in streptozotocin-nicotinamide induced diabetic
rats. At the dose of 350 mg/kg ethanolic leaf extract has been found to possess
hypoglycemic as well as antihyperglycemic potential in normal, streptozotocin-
diabetic rats and alloxanized rabbits48
Areca catechu L. (Family: Arecaceae)
Commonly
known as Supari in Hindi and Betelnut in English. Subcutaneous

administration
of alkaloid fraction at the dose 0.05-0.5 mg/kg in alloxanized rabbits showed
significant hypoglycemic effect15. Arecoline, isolated from A.
catechu is reported to have hypoglycemic activity48.
Artemisia pallens Wall. ex DC. (Family: Compositae)
Commonly known as Davana in
Hindi. Oral administration of the methanol extract of the aerial parts of Artemisia pallens, led to significant
blood glucose lowering effect in glucose-fed hyperglycaemic and alloxan-induced
diabetic rats. This effect of the extract was dose dependent and significant at
100 mg/kg level in glucose-fed rats. In fasted normal rats, the extract caused
a moderate hypoglycaemic effect at 1000 mg/kg74.
Azadirachta indica A. Juss. (Family: Meliaceae)
Commonly
known as Neem. Studies showed that
petroleum ether extract of neem seed kernel (NSK) and husk (NSH) showed
significant protection against the oxidative damage induced by STZ in heart and
erythrocytes of rats. NSK and NSH may act as cardioprotective and free radical
scavenger agent. Serum creatine phosphokinase (CPK) increased in diabetic rats
was significantly decreased on insulin, NSK and NSH treatments. The decrease in
activities of superoxide dismutase (SOD) and catalase (CAT) and increase in
lipid peroxidation (LPO) of erythrocytes as observed in diabetes was regained
after insulin, NSH and NSK treatments. Results suggest that NSH and NSK prevent
oxidative stress caused by STZ in heart and erythrocytes25.
Pretreatment with A. indica leaf extract, blocked the
depressive effect of epinephrine in diabetic rabbits as well as in normal ones.
In in vitro trials, A. indica leaf extract, failed to alter the
hepatic glycogen, but it partially blocked epinephrine action on hepatic
glycogen both in normal and diabetic rabbits12. A. indica leaf extract blocks
significantly the inhibitory effect of serotonin on insulin secretion mediated
by glucose14.
Barleria lupulina Lindl. (Family: Acanthaceae)
Commonly known as Snake bush in English. The methanol extract
of aerial parts of Barleria
lupulina Lindl. showed a
pronounced blood-glucose-lowering potential in streptozotocin hyperglycemic
rats. The extract at dose of 200 mg/kg body
weight exhibited a maximum activity (p<0.001) at 12 h after administration.
The most significant activity (15.35% blood glucose reduction) was observed for
the group administered 300 mg/kg body
weight at 12 h after administration, while the standard drug glibenclamide (10
mg/kg body weight) showed an
18.80% reduction of blood glucose at the same time interval73.
Beta vulgaris L. (Family: Chenopodiaceae)
It
is known as Chukander in Hindi and Garden beet in English. Beta vulgarosides
II-IV, isolated have been shown to ameliorate glucose tolerance in OGTT conducted
in rats. Uncontrolled
induced diabetes caused significant increases in nonenzymatic glycosylation of
skin proteins, lipid peroxidation and blood glucose. Administration of B. vulgaris extract inhibited these
effects except the increase in lipid peroxidation. These findings indicated
that the use of B. vulgaris may
decrease the development of some diabetic complications23.
Biophytum sensitivum (L.) DC.
(Family: Oxalidaceae)
It
is commonly called as Lajjalu in Hindi and Life plant in English. Leaf extract
has been proved to show antihyperglycemic effect in alloxan diabetic male
rabbits. It was found ineffective in severe diabetes23.
Boerhavia diffusa L. (Family: Nyctaginaceae)
Commonly known as Punarnava in Hindi. Oral administration of B. diffusa leaf extract at 200 mg/kg of body weight for 4 weeks
resulted in significant reduction in serum and tissue cholesterol, free fatty
acids, phospholipids, and triglycerides. It was found to be more effective than
glibenclamide in the treatment of diabetic rats57.
Bombax ceiba L. (Family: Bombacaceae)
Common
name is Semul in Hindi and Red silk cotton tree in English. Shamimin, a flavonol glucoside known as Shamimin,
isolated from the leaves of the plant has been reported to possess significant
hypoglycemic activity at dose of 500 mg/kg in rats65.

Brassica juncea (L.) Czern. (Family: Brassicaceae)
Common
name is Rai in Hindi and Indian mustard in English. Study was made on the effects of daily oral
feeding of 10% powder of seeds of Brassica juncea for 60 days on serum
glucose concentrations and kidney functions in streptozotocin diabetic rats.
After 60 days of STZ administration, urine volume per day and UAE levels were
significantly higher (P<0.0005) in diabetic controls as compared to
normal controls24.
Caesalpinia bonducella (L.) Roxb.
(Family: Cesalpinaceae)
Commonly known as Kantkarej or Kantikaranja in Hindi and Fever
nut or Bonduc nut in English. In normal rats,
aqueous and 50% ethanolic extracts of C. bonducella seeds
exhibited hypoglycaemic activity at a dose of 100 mg/kg after 4 hour of
administration. The hypoglycaemia produced by the aqueous extract was of
prolonged duration as compared to ethanolic extract. In diabetic rats, both the
extracts produced significant (p<0.01) antihyperglycaemic effect from
day 5 onwards66.
Cajanus cajan (L.) Millsp. (Family: Fabaceae)
Common name is Tuvar in Hindi and Red gram in English. Oral administration of graded doses of aqueous extract of
C. cajan leaves in streptozotocin
induced type 2 diabetic rats showed significant increase in 14.3 % in fasting
blood glucose levels of normal rats. The dose of 1000 mg/kg showed the maximum
rise of 17.1, 71.2 and 50.7 % in blood glucose levels of normal, sub and mild
diabetic rats respectively in glucose tolerance test32.
Camellia sinensis Kuntze (Family: Theaceae)
Commonly known as Tea in
English. The hot water extract of C.
sinensis significantly reduced the blood
glucose level and was found to possess both preventive and curative effects on
experimentally produced diabetes in rats. The green tea as well as black tea
both possess antidiabetic activity20.
Capparis decidua (Forsk.) Edgew. (Family: Capparidaceae)
Commonly known as Keekar, Karir, Kirir, Karril, etc. in Hindi and Caper plant in English. Oral feeding of diet containing (30%) C. decidua
fruit powder for 3 weeks to alloxanized diabetic rats showed significant
hypoglycemia23.
Casearia esculenta Roxb. (Family: Flacourtiaceae)
Commonly known as Saptarangi in Hindi. The plant root extract
exhibited significant hypolipidaemic and antiperoxidative activity in red blood
cells of streptozotocin diabetic rats48.
Cassia auriculata L. (Family: Cesalpinaceae)
Common name is Tanner’s Cassia. Extract of flowers of C. auriculata suppressed the elevated blood glucose and
lipid levels in diabetic rats at doses of 0.15, 0.30 and 0.45 g/kg body weight
for 30 days. At the dose of 0.45 g/kg was found to be comparable to
glibenclamide. Extract significantly reduced the levels of serum and
tissue lipids56.
Catharanthus roseus (L.) G. Don.
/ Vinca rosea (Family: Apocynaceae)
Commonly called as Sadabahar in Hindi and Madagascar
periwinkle in English. Administration of aqueous
extracts of V. rosea flower and leaf
have been found to regulate the blood sugar level in alloxan diabetic male
albino rats19. Ethanol extract of V. rosea promotes
significant wound healing and closure in diabetic rats compared with mupirocin
At the dose of 100 mg/kg body weight, it significantly reduced (p<0.001)
wound size in streptozotocin induced diabetic rats53. Alkaloids
isolated catharanthine, vindoline and vindolinine lower blood sugar level48.

Citrullus colocynthis (L.) Schrad.
(Family: Cucurbitaceae)
Common name is Indryan in Hindi and Bitter apple in English. Oral administration of 300 mg/kg of aqueous extract
produced significant reduction in plasma glucose after 1 hour and highly
significant after 2,3 and 6 hour in normal rabbits. The glycosidic extract at a
oral dose of 50 mg/kg significantly lowered the fasting glucose levels after 2
and 3 hour and highly significant after 6 hour. The saponin extract at the same
oral dose significantly lowered the fasting glucose levels after 1 and 2 hour
and highly significant (p<0.001) after 3 and 6 hour1.
Coccinia indica Wight & Arn. (Family: Cucurbitaceae)
Common
name is kundru. It have been used in the
traditional treatment of diabetes mellitus. Toluene, chloroform, ethyl acetate
and n-butanol fractions of the dried alcoholic extract of the aerial part were
fed to alloxan treated diabetic rats orally, twice daily at a dose of 150
mg/kg. The toluene fraction prevented the elevation of lipid profile
significantly (p<0.001) in comparison to control diabetic rats16.
Ethanol extract of C. grandis showed
significant triglyceride (TG) and cholesterol-lowering effects in dyslipidemic
hamster model. Activity was proved to be concentrated in chloroform-soluble
fraction. Chloroform soluble fraction on repeated column chromatography,
furnished a polyprenol characterized as C60-polyprenol. It significantly
decreased serum TG by 42%, total cholesterol (TC) 25% and glycerol (Gly) 12%,
accompanied HDL-C/TC ratio 26% in highfat diet (HFD)-fed dyslipidemic hamsters
at the dose of 50 mg/kg body weight. Results are comparable to standard drug
fenofibrate at the dose of 108 mg/kg70.
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Curcuma longa (Family:
Zingiberaceae)
Commonly known as Haldi in Hindi and
Turmeric in English. Ethanol extract of
rhizome significantly suppressed an increase in blood glucose level in type 2
diabetic mice. The extract stimulated human adipocyte differentiation in a
dose-dependent manner and showed human peroxisome proliferator-activated
receptor (PPAR)-γ ligand-binding activity in a GAL4-PPAR-γ chimera
assay (Kuroda et al., 2005). Ferulic acid (4-hydroxy-3-methoxycinnamic
acid) is found in many plants, isolated from Curcuma too. It has shown
hypoglycemic activity in both type of diabetes48.

Cynodon dactylon (Family: Poaceae)
Commonly known as Doob in Hindi. At a dose of 500 mg/kg,
aqueous extract lowered blood glucose level around 31% after 4 hour of
administration in normal rats. During glucose tolerance test (GTT) of
mild diabetic rats, the same dose produced a fall of 23% in blood glucose level
within 1 hour. This dose has almost similar effect as that of standard drug
tolbutamide at the dose of 250 mg/kg body weight. A significant reduction of
59% was observed in fasting blood glucose level of severely diabetic
rats at same dose given for 14 days. It reduced urine sugar level. In
severely diabetic rats total cholesterol (TC), low density lipoprotein
(LDL) and triglyceride (TG) levels were decreased by 35, 77 and 29%,
respectively, whereas, cardioprotective, high density lipoprotein (HDL) was
increased by 18%. These results suggested
antidiabetic potential of aqueous extract along with significant
hypoglycemic and hypolipidemic effects70,71.
Enicostemma littorale Blume
(Family: Gentiaceae)
Commonly
known as Chhota chirata in Hindi and Whitehead in English. At the dose of
1.5 g/100g body weight/day of
aqueous extract of E. littorale increased HDL levels and
decreased serum cholesterol, triglyceride, LDL, VLDL, LDL/HDL ratio in rats fed
with hypercholesterolaemic diet. It showed a decrease in activities of
erythrocyte catalase, superoxide dismutase and lipid peroxidation levels, with
an increase in reduced glutathione levels. It also showed decrease in liver and
kidney cholesterol levels and triglyceride levels76.
Eucalyptus globulus Labill.
(Family: Myrtaceae)
Commonly known as Safeda in
Hindi. In diabetic rats, the repeated oral administration of E. globulus aqueous leaf extract significantly
increased the basal plasma insulin concentrations (p<0.05)27. An
aqueous extract of E. globulus at the
dose of 0.5 g/L enhanced 2-deoxy-glucose transport
by 50%, glucose oxidation by 60% and incorporation of glucose
into glycogen by 90% in mouse abdominal muscle. In acute,
20 min incubations, administration of 0.25-0.5 g showed stepwise 70-160%
enhancement of insulin secretion from the clonal pancreatic
-cell line21.
Eugenia uniflora L. (Family: Myrtaceae)
Commonmly known as Surinam Cherry or Brazilian Cherry in
English. Ethanolic extract of the leaves of E.
uniflora inhibited the increase in plasma glucose level and plasma
triglyceride level48.
Ficus bengalensis (Family: Moraceae)
It
is known as bargad in Hindi and Banyan in English. 50 mg/kg of hot water extract of F. bengalensis was given orally to normal rabbits and rabbits with
alloxan induced alloxan-recovered, mildly diabetic and severely diabetic states
daily for three days. After a gap of five days, the water extract was
readministered for three days at the same dose level. There was no significant
change in fasting blood glucose (FBG), or glucose tolerance test (GTT) in
normal rabbits. There was no fall in FBG but improvement in glucose tolerance
in alloxanrecovered rabbits. In mildly diabetic rabbits there was 55.8% fall in
FBG values and an improvement in glucose tolerance. The extract produced 68%
fall in FBG values in severely diabetic rabbits69. The bark and
aerial roots ethanolic extracts at a dose of 100 mg/kg

significantly (p<0.001), (p<0.01) lowered the blood sugar
level of hyperglycemic rats respectively. Barks exhibited better activity than
aerial roots17. Leucodelphinidin, isolated from the bark of F. bengalensis has been reported for its
hypoglycemic activity.
Ficus
racemosa (Family: Moraceae)
It is commonly known as
‘Gular’ in

weight, lowered the
blood glucose levels by 18.4 and 17.0% at 5 and 24 hour, respectively, in
sucrose challenged streptozotocin induced diabetic rat (STZ-S) model. Its
p-chlorobenzoic acid derivative and nicotinic acid derivative showed potent
antihyperglycemic activity at 100 mg/kg body weight52.
Glycyrrhiza glabra L. (Family: Fabaceae)
Commonly known as Licorice. Glycyrrhizin, isolated from
licorice root, is composed of one molecule of glycyrrhetinic acid and two
molecules of glucuronic acid. After oral administration, glycyrrhizin has been
shown to be hydrolyzed by the glucuronidase of intestinal bacteria to its

principal aglycone,
18β-glycyrrhetinic acid. 18β-glycyrrhetinic acid when administered
orally at 100mg/kg of bodyweight, showed potential antihyperglycemic effect
that is comparable with glibenclamide34.
Gymnema montanum Hook.f. (Family: 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 glucose and an increase in plasma insulin. The decrease in lipid
peroxides and increase in reduced glutathione (GSH), ascorbic acid (Vitamin C)
and a -tocopherol (Vitamin E)
showed its antioxidant properties6.
Gymnema sylvestre R. Br. (Family: Asclepiadaceae)
G. sylvestre leaf extract lowers the blood glucose level in normal fasting,
glucose-fed hyperglycemic and diabetic rats compared with placebo-treated
animals. The maximum glucose suppression occurred after 2 hour of treatment by
the effective dose of 200 mg/kg,
Helicteres isora L. (Family: Sterculiaceae)
Administration of the bark extract of H. isora at the
doses of 100 and 200 mg/kg body weight for 21 days resulted in significant
reduction in serum and tissue cholesterol, phospholipids, free fatty acids and
triglycerides in STZ diabetic rats. Significant (p< 0.05) decrease in
high-density lipoprotein (HDL) whereas significant increase (p<0.05)
low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) were
observed in STZ diabetic rats. The bark extract possesses definite hypotriglyceridemic
and antiatherogenic properties in STZ diabetic rats after 3 weeks of treatment39.
Hibiscus
rosa-sinensis (Family: Malvaceae)
Commonly known as Gudhal in
Hindi and shoe flower in English. In streptozotocin induced
diabetic rats, oral administration of an ethanol flower extract of Hibiscus
Hygrophila auriculata (Family:
Acanthaceae)
It is a wild herb widely used in ‘Ayurveda’ as ‘Rasayana’ drug
for treatment of various disorders. aerial parts of H. auriculata extract
possesses significant antidiabetic activity along with potent antioxidant
potential in diabetic conditions. Treatment of diabetic rats at the doses of
100 and 250 mg/kg body weight for 3 weeks showed significant reduction in blood
glucose, thiobarbituric acid reactive substances (TBARS) and hydroperoxide in
both liver and kidney78.
Indigofera mysorensis (Family:
Fabaceae)
In insulin resistant db/db mice extract of the whole shrub of
Indigofera at 300 mg/kg for 10 days, produced a 63% reduction in plasma
glucose, 41% reduction in plasma triglyceride and 77% reduction in
plasma insulin levels, which is better than insulin sensitizer, troglitazone
(400 mg/kg). Study showed that the antidiabetic effect of the ethanolic extract
of Indigofera is due to its insulin
sensitizing property and is clearly different from that of sulfonylurea or
acarbose10.
Ipomoea batatas (Family: Convolvulaceae)
Commonly known as sweet potato.
White-skinned sweet potato is useful in
the prevention and improvement of
diabetic symptoms by stimulating human immunity. It increased phagocytic
activity and phagosome-lysosome fusion in neutrophils and monocytes in a
dose-dependent manner46.
Lantana camara (Family:
Verbenaceae)
In
Hindi, it is known as Caturang. Administration at the dose of 1500 mg/kg/day for 14 days showed significant hypoglycemic
effect in rats23.
Lactuca indica (Family: Asteraceae)
Commonly known as Indian
Lettuce. Lactucain C and lactucaside have shown significant hypoglycemic
activity48.

Mangifera indica L. (Family: Anacardiaceae)
It is known as Aam in Hindi and Mango in English. Aqueous leaf
extract at the dose of 1 g/kg p.o. showed hypoglycemic effect when given 60
mins prior to glucose administration in streptozotocin-induced diabetic rats2.
The chronic intraperitoneal administration of mangiferin, a xanthone glucoside
isolated from the leaves of Mangifera indica at
the doses of 10 and

20 mg/kg once daily
for 28 days exhibited antidiabetic activity by significantly lowering fasting
plasma glucose level at different time intervals in STZ-diabetic rats. At the
same doses, mangiferin showed significant antihyperlipidemic and
antiatherogenic activities as evidenced by significant decrease in plasma total cholesterol, triglycerides,
low-density lipoprotein cholesterol (LDL-C) levels coupled together with
elevation of high-density lipoprotein cholesterol (HDL-C) level and diminution
of atherogenic index in diabetic rats50.
Memecylon umbellatum Burm. f. (Family:
Melastomataceae)
Commonly known as Anjani
in Hindi. Oral administration of alcoholic extract of the leaves of M. umbellatum (250 mg/kg) caused a
significant reduction in the serum glucose levels in normal and alloxanized
rats at 30, 60 and 90 min after administration23.
Momordica charantia L. (Family:
Cucurbitaceae)
Common
name is karela in Hindi and bittergourd
in English.
The anti-diabetic potential of Momordica charantia is well
established in streptozocin or alloxan induced diabetic animals. Momordica
charantia displays insulin-like properties, remarkably stimulates glycogen
storage by the liver and improves peripheral glucose uptake62.
Charantin, a steroidal saponin isolated have hypoglycemic potential.
Momordica
cymbalaria Fenzl ex Naudin (Family: Cucurbitaceae)
Commonly known as Kadavanchi in Hindi. It exhibited both
hypoglycemic as well as hypolipidemic properties. Its powdered fruit exhibited
significant reduction in fasting blood glucose levels in alloxanized rats23.
Morus alba L. (Family: Moraceae)
Commonly known as Shetut in Hindi and White Mulberry in
English. Hot water extract of leaves of M.
alba showed hypoglycemic activity in fasted and non-fasted STZ diabetic
mice at the dose of 200 mg/kg23.
Mucuna pruriens (L.) DC. (Family: Leguminosae)
It is called as Kavach in Hindi and Cowitch in English. In
normal rats, at the the oral administration of 100 and 200 mg/kg body weight,
the aqueous extract of the seeds of M.
pruriens significantly reduced the blood glucose levels after an oral
glucose load from 127.5±3.2 to 75.6±4.8 mg %. It also significantly lowered the
blood glucose in STZ diabetic rats from 240.5±7.2 to 90.6±5.6 mg % after 21
days of daily oral administration of the extract (Pb0.001)9.
Murraya koeingii (L.) Spreng. (Family: Rutaceae)
One month oral administration of M. koenigii aqueous
leaves extract in STZ induced severe diabetic rats, at the dose of 300 mg/kg
body weight fasting blood glucose (FBG) levels reduced by 48.2% after 30 days
treatment with the aqueous leaves extract. A fall of 19.2 and 30.8% in total
cholesterol (TC) and 22.97 and 37.1% in triglyceride (TG) levels were also
observed in the case of treated normal as well as diabetic rats, respectively.
Feeding the extract increased the HDL-cholesterol level by 16 and 29.4% in
normal and diabetic rats, respectively, as compared with their initial values.
In the normal rats after 1 month of oral administration of the extract serum
glutamate oxaloacetate and pyruvate transaminases (SGOT and SGPT) levels
were decreased by 21.7 and 25.0%. Serum alkaline phosphatase values of the
treated normal animals were also reduced by 33% while negligible change was
observed in the normal control animals. In the case of diabetic rats, SGOT and
SGPT levels were reduced by 36.7 and 32.2%, respectively, whereas phosphatase
(ALKP) levels decreased by 39.7%. The serum creatinine levels decrease in
normal as well as in the diabetic animals by 17.75 and 18.2%, respectively, as
compared to initial values. In the diabetic control animals the urinary sugar
remains at +4 level but there was a decrease of 75% in urine sugar in the case
of treated diabetic rats 37.
Musa sapientum L. (Family: Musaceae)
Commonly known as Kela in Hindi and
Banana in English. Oral administration of
0.15, 0.20 and 0.25 g/kg of chloroform extract of the M. sapientum flowers
for 30 days resulted in a significant reduction in blood glucose, glycosylated
haemoglobin and an increase in total haemoglobin, but in the case of 0.25 g/kg
the effect was highly significant. It also prevents decrease in body weight.
There was a significant improvement in glucose tolerance in treated animals and
the effect was compared with glibenclamide57.
Nelumbo nucifera Gaertn. (Family: Nymphaeaceae)
This
is aquatic plant known as Kamal in Hindi and Lotus in English. Ethanolic extract of the rhizome of N. nucifera suppressed
blood glucose levels in normal, glucose-fed hyperglycemic, insulin-treated and
diabetic rats. The extract improved glucose tolerance and potentiated the
action of exogenously injected insulin, The hypoglycemic potential of the
extract was comparable with that of tolbutamide in normal and diabetic rats. It
was observed that in normal and diabetic rats, the activity of the extract was
73 and 67% compared with that of tolbutamide, respectively49.
Nigella sativa (Family: Ranunculaceae)
Nigella sativa seeds, commonly known as Black cumin have been used
traditionally for treating diabetes. The aqueous extract of N. sativa
at 0.1 pg/ml to 100 ng/ml, exerted dose-dependent inhibition of
sodium-dependent glucose transport across isolated rat jejunum. Chronic N.
sativa treatment improved glucose tolerance as efficiently as metformin. It also reduced body weight without
any toxic effect45.
Ocimum sanctum (Family: Lamiaceae)
Common
name is tulsi in Hindi and Basil in English.
The hypoglycemic effect of the alcoholic extract of leaves of Ocimum sanctum
was investigated in both normal and alloxan-induced diabetic rats.
Alcoholic extract of leaves of O.
sanctum reduced blood sugar levels 204.48 ± 11.0 to 131.43 ± 7.86 in normal
rats and 73.54 ± 3.7 to 61.44 ± 2.3 in diabetic rats significantly
(p<0.001). In addition, the extract also showed a favorable effect on
glucose disposition in glucose fed hyperglycemic rats77.
Phyllanthus amarus Schumach. & Thonn./Phyllanthus niruri (Family:
Euphorbiaceae)
Commonly known as Jangli Amla in Hindi. Oral administration of
5 g/day of a preparation of the whole plant for 10 days reduces blood glucose
in diabetic as well as nondiabetic subjects23.
Picrorrhiza kurroa Royle ex Benth. (Family:
Scrophulariaceae)
Alcoholic extract of P.
kurroa at the dose of 75 mg/kg reduced serum glucose by 43 % and at 150
mg/kg reduced by 60%33.
Pongamia pinnata (Family: Fabaceae)
Commonly known as
Karanja in Hindi. The oral administration of ethanolic extract of Pongamia
pinnata flowers at a dose of 300 mg/kg body weight showed significant
antihyperglycemic, and antilipidperoxidative effects and enhancement in
antioxidants defense system in alloxan induced diabetic rats. It considerably
reduced the blood glucose concentration in a similar extent to that of the
reference drug glibenclamide (600 g/kg body weight) in alloxan induced diabetic
rats60.
Antidiabetic potential of the compounds
pongamol and karanjin isolated from Pongamia
have been proved. In streptozotocin-induced diabetic rats, single dose
treatment of pongamol and karanjin lowered the blood glucose level by 12.8% (p<0.05)
and 11.7% (p<0.05) at 50mg /kg dose and 22.0% (p<0.01)
and 20.7% (p<0.01) at 100 mg/kg dose, respectively after 6 h
post-oral administration. The compounds also significantly lowered blood
glucose level in db/db mice with percent activity of 35.7 (p<0.01)
and 30.6 (p<0.01), respectively at 100 mg/kg dose after
consecutive treatment for 10 days. The compounds were observed to exert a
significant inhibitory effect on enzyme protein tyrosine phosphatase-1B. The results
showed that pongamol and karangin isolated from the

fruits of P. pinnata
possesses significant antihyperglycemic activity in Streptozotocin-induced
diabetic rats and type 2 diabetic db/db mice and protein tyrosine
phosphatase-1B may be the possible target for their activity75.
Pterocarpus marsupium Roxb.
(Family: Fabaceae)
Common
name is Vijaysar in Hindi and Indian Malabar in English. Pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene),
a constituent derived from wood of Pterocarpus
marsupium caused hypoglycemia in dogs (at the dose of 10 mg/kg IV). Higher
dose (20, 30 and 50 mg/kg) caused initial hyperglycemia followed by
hypoglycemia lasting for nearly 5h26. (-) Epicatechin, Marsupsin,
Pterosupin, Pterostilbene, isolated from the bark and heartwood of the plant
possess blood sugar lowering activity (Mukherjee et al., 2006).

Punica granatum L. (Family: Punicaceae)
Commonly known as Pomegranate. 50% ethanolic extract of flower
showed blood glucose lowering activity in glucose fed and alloxanized
hyperglycemic rats. At the doses of 150, 300, 600 mg/kg showed hypoglycemic
activity 12 hour after administration in STZ- diabetic rats48.
Ricinus communis (Family: Euphorbiaceae)
Commonly known as Eranda or Gandharva hasta
in Hindi and Castor in English. 50% ethanolic extract of roots of R. communis at the dose of
five-hundred milligram per kilogram body weight caused maximum lowering of the
fasting blood glucose, both in normal as well as type 1 diabetic animals. It
was considered as effective dose. Administration of the effective dose to the
diabetic rats for 20 days showed favorable effects not only on fasting blood glucose,
but also on total lipid profile and liver and kidney functions on 10th and 20th
day68.
Rosmarinus officinalis (Family:
Labiatae)
Commonly known as Rosemary. Hypoglycaemic effects of oral
administration of various doses (50, 100 and 200 mg/kg) of the extract were
examined in normoglycaemic and glucose-hyperglycaemic rabbits. Optimal effect
was observed in both of the animal groups with a dose of 200 mg/kg of the
extract and this activity was independent from the effects of insulin. Acute
effect of various doses of the R. officinalis extract on blood glucose
and serum insulin levels was studied in alloxan-induced diabetic rabbits. Of
the three doses of extract, the highest dose (200 mg/kg) significantly lowered
blood glucose level and increased serum insulin concentration in
alloxan-diabetic rabbits. At the doses of 100 and 200 mg/kg, antihyperglycaemic
effect of extract was accompanied by a significant increase in serum insulin
levels in diabetic rabbits. Furthermore, during 1 week of treatment of diabetic
rabbits with a dose of 200 mg/kg of the extract showed that the extract
possessed a capability to inhibit the lipid peroxidation and activate the
antioxidant enzymes7.
Salacia oblonga Wall. (Family: Celastaceae)
S. oblonga root is an Ayurvedic medicine with anti-diabetic and
anti-obese properties. Chronic oral administration of the water extract from
the root of S. oblonga to
Zucker diabetic fatty rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total
cholesterol levels, increased plasma high-density lipoprotein levels and
reduced the liver contents of triglyceride, non-esterified fatty acids and the
ratio of fatty droplets to total tissue. By contrast, the extract had no effect
on plasma triglyceride and total cholesterol levels in fasted Zucker diabetic
fatty rats29.
Salacia reticulata Wight. (Family: Celastaceae)
Commonly known as Kothala himbutu. Aqueous extracts of Kothala
himbutu stems decreases fasting blood glucose levels. Results demonstrate that
it exerts its effect by gluconeogenic gene regulation in traditional diabetic
medicine30.
Scoparia dulcis L. (Family: Scrophulariaceae)
Commonly
known as Sweet Broomweed. The
administration of an aqueous extract of . S. dulcis at a dose of 200 mg/kg body weight significantly
decreased the blood glucose with significant increase in plasma insulin level
in streptozotocin diabetic rats at the end of 15 days treatment. S. dulcis plant extract protected
against streptozotocin- mediated cytotoxicity (88%) and NO production in rat
insulinoma cell line (RINm5F). Results suggest its glucose lowering effect to
be associated with potentiation of insulin release from pancreatic islets41.
Sida cordifolia L. (Family: Malvaceae)
Commonly known as Bala. It is used in Ayurvedic medicine. S. cordifolia extracts of the aerial and
root parts showed good analgesic, antiinflammatory and hypoglycaemic
activities. The methanol extract of root was found to possess significant
hypoglycaemic activity36.
Swertia chirayita (Roxb. ex Fleming) H. Karst. (Family:
Gentianaceae)
Hexane fraction of S.
chirayita at the dose of 250 mg/kg body weight induced significant fall in
blood sugar in albino rats. Daily administration for 28 days resulted in
significant lowering of blood sugar and increase in plasma IRI along with a
significant rise in liver glycogen. Intestinal absorption of glucose was not
inhibited by hexane fraction. It is suggested that hexane fraction of S.
chirayita possibly acts through its insulin releasing effect11. A
xanthone was isolated from the hexane fraction of the plant, identified as
1,8-dihydroxy-3,5-dimethoxy-xanthone (swerchirin). It has a very significant
blood sugar lowering effect in fasted, fed, glucose loaded, and tolbutamide
pretreated albino rat models. The ED50 for 40% blood sugar lowering
in CF male albino rats (body weight 140-165 g) is 23.1 mg/kg/oral8.

Syzigium cumini/
Eugenia jambolana Lam. (Family:
Myrtaceae)
Administration of the
extract for 6 weeks resulted in significant reductions in plasma lipid
peroxide, ceruloplasmin and α-tocopherol and a significant elevation in
plasma reduced glutathione and vitamin C in alloxan diabetic rats. Insulin
restored all the parameters to their normal values. The seed extract was also
more effective than glibenclamide in restoring the values of these parameters58,59.
Oral administration of 2.5 and 5.0 g/kg body weight of the aqueous extract of
the seed for 6 weeks resulted in a significant reduction in blood glucose and
an increase in total haemoglobin, but in the case of 7.5 g/kg body weight the
effect was not significant. It also prevents decrease in body weight. The
aqueous extract also resulted in decreased free radical formation in tissues
studied. Thus the study shows that Jamun seed extract (JSEt) has hypoglycaemic
action. The decrease in thiobarbituric acid reactive substances (TBARS) and
increase in reduced glutathione (GSH), superoxide dismutase (SOD) and catalase
(CAT) clearly show the antioxidant property of the JSEt. The effect of JSEt was
most prominently seen in the case of animals given 5.0 g/kg body weight. JSEt
was more effective than glibenclamide. 58,59
Terminalia catappa L. (Family: Combretaceae)
Commonly known as Badam in Hindi and Indian Almond Tree in
English. Terminalia catappa fruit extracts have good antidiabetic
activity. Petroleum ether, methanol and aqueous extracts of T. catappa produced
a 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.
Terminalia pallida Brandis (Family: Combretaceae)
Different doses of ethanolic fraction of fruits of Terminalia
pallida were evaluated for hypoglycemic and antihyperglycemic activity in
normal and alloxan diabetic rats. The oral administration of ethanolic extract
at a dosage of 0.5 g/kg body weight exhibited a significant antihyperglycemic
activity in alloxan diabetic rats, whereas in normal rats no hypoglycemic
activity was observed61.
Trigonella foenum
graecum L. (Family: Fabaceae)
Commonly known as fenugreek. Galactomannan, extracted from T. foenum reported
to reduce postprandial blood glucose response. Using this fiber, extracted from
The segments of jejunum and ileum from genetically determined lean and obese
rats were incubated with labeled glucose (2 or 32 mmol/L) in the presence of
different concentrations of galactomannan ranging from 0.1% to 0.5% (wt/wt).
The uptake of low or high concentration of glucose was significantly and
progressively reduced by increasing concentrations of galactomannan in both
lean and obese rats. No significant difference was observed in the uptake of
glucose between the 2 groups. The viscosity of various concentrations of
galactomannan solutions was determined after stirring for 60 minutes at a
temperature-controlled (37°C) fixed sheer rate of 1.29 (1/s). The inhibitory
effect of galactomannan on glucose uptake was found to be in parallel with the
degree of viscosity of the fiber solutions. Because of its viscous property,
galactomannan has the potential to reduce intestinal absorption of low or high
concentrations of glucose and hence for the benefit of blood glucose management72
.
Tinospora
cordifolia (Family: Menispermaceae)
Commonly known as Giloe in Hindi. Treatment with plant extract
showed significant anti-hyperglycemic activity in mild to moderate degree of
hyperglycemia. In mild diabetes, the maximum percent reduction in glucose levels
was 70.37%, seen in groups receiving 400 mg/kg/day of aqueous extract of T. cordifolia. In moderate
diabetes, 4 months of T. cordifolia
treatment resulted in a moderate reduction in plasma glucose level of 48.81%.
In severe diabetes, it did not show any reduction in plasma glucose level.
Since the percentage fall in plasma glucose levels was different in models with
varying intensity of hyperglycemia, it implies that the anti-hyperglycemic
effect of these plants is dependent upon the dose of diabetogenic agent and
therefore on the degree of b-cell destruction23.
Withania coagulans (Family:
Solanaceae)
Commonly
known as “Paneer ke phool” in Hindi and Vegetable Rennet in English. At the
dose of 1 g/kg of aqueous extract of fruits of W.
coagulans significantly lowered the blood sugar, serum cholesterol, serum
LPO and hepatic LPO levels in streptozotocin induced diabetic rats after 7 days
of treatment (p<0.001). It also significantly (p<0.01) decreased blood
glucose level in normal rats (at the dose 1 g/kg; po)28. Coagulin C, 17β- hydroxywithanolide K,
withanolide F, coagulanolide and coagulin L, isolated from the fruits, showed
significant inhibition on postprandial rise in hyperglycemia post sucrose load
in normoglycemic rats and in streptozotocin-induced diabetic rats. Coagulin L
showed significant fall in peripheral blood glucose profile and also improved
the glucose tolerance of db/db mice. It also showed antidyslipidemic activity
in db/db mice that is comparable to median effective dose of fenofibrate i.e., 50 mg/kg body weight. The median
effective dose of the coagulin L was determined to be around 25 mg/kg in
streptozotocin-induced diabetic rats, which is better than the standard drug
metformin. Beside this, coagulin L also showed antidyslipidemic activity in
db/db mice44.

Zingiber officinale Roscoe
(Family: Zingiberaceae)
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 test, treatment with Z. officinale was found to decrease significantly the area under
the curve of glucose and to increase the area under the curve of insulin in
STZ-diabetic rats. Treatment with Z.
officinale also caused a decrease in serum cholesterol, serum triglyceride
and blood pressure in diabetic rats3. 6-shogaol (6S) and 6-gingerol
(6G), present in Z. officinale
significantly inhibited the tumor necrosis factor-α (TNF-α) mediated
downregulation of the adiponectin expression in 3T3-L1 adipocytes. 6S functions
as a PPARγ agonist with its inhibitory mechanism due to the PPARγ
transactivation, and 6G is an effective inhibitor of TNF-α induced
c-Jun-NH2-terminal kinase signaling activation and thus, its
inhibitory mechanism is due to this inhibitory effect99.

Conclusion
Treatment of diabetes with synthetic drugs is associated with
several complications. The most severe complication associated is condition of
hypoglycemia. Plants and natural products are in use to prevent and cure
diabetes since past. They show comparatively less or no side effects. As far as
cost is concerned, herbal treatment is cheaper than synthetic drugs. A wide and
diverse range of plants is reported to prevent and treat diabetes. A lot of
work has been done on the antidiabetic potential of various plants by numerous
workers. We have worked on Pongamia
pinnata, Pterocarpus marsupium, Withania
coagulans, Zingiber officinale and
Ficus racemosa and have isolated antidiabetic 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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Development of the Thiazolidinediones
as PPAR γ Agonists for the Treatment of Type 2 Diabetes
Saman Raza and Seturam B. Katti*
Medicinal and Process Chemistry Division,
Central Drug Research Institute,
Introduction
Diabetes mellitus (DM) is a major and
growing public health problem throughout the world. Diabetes has reached
epidemic proportions and affects more than 170 million individuals worldwide.
It is a disease characterized by high levels of blood glucose resulting from
defects in: insulin production, insulin action or both. The basic types of
diabetes mellitus are type 1 and type 2. Type 1 (insulin dependant) DM can
occur at any age and is characterized by the marked and progressive inability
of the pancreas to secrete insulin because of autoimmune destruction of the
beta cells. Therefore, these patients are dependent on exogenous insulin.
Type 2 (non-insulin-dependent) DM, which
affects 90% of diabetic individuals, is more of a lifestyle related disorder,
with obesity being a major risk factor for its development. It is characterized
by insulin resistance: the inability of insulin-sensitive tissues to respond to
normal circulating concentrations of insulin. To offset resistance to insulin,
the beta cells of the pancreas increase insulin secretion. However over time,
beta-cell function deteriorates, less insulin is secreted and hyperglycemia
develops. Treatment of type 2 diabetes is aimed at lowering insulin resistance
and increasing function of beta cells. Current therapeutic approaches for type
2 DM include: 1) insulin; 2) enhancers of insulin release eg. Sulfonylureas,
Dipeptidyl Peptidase IV (DPP-4) Inhibitors and Meglitinides; 3) inhibitors of
hepatic glucose production eg. biguanides; 4) inhibitors of glucose uptake eg. α-glucosidase
inhibitors; and 5) insulin sensitizers eg. peroxisome proliferator-activated
receptor γ (PPAR γ) agonists [1]. As the
number and types of the therapeutic options are so vast and varied, it is not
possible to elaborate on all of them and hence we have chosen to focus on the
one which is of particular interest to researchers today, that is: PPAR γ
PPAR γ agonists, dual and pan agonists as well as PPAR γ
modulators have become exciting therapeutic targets for type 2 diabetes
as they also address the complications related with diabetes.
Peroxisome
Proliferator-activated Receptor Gamma (PPAR γ ) Role in Type 2
Diabetes
The peroxisome proliferator-activated
receptors belong to the superfamily of nuclear receptors and are
ligand-activated transcription factors. There are three PPAR isoforms, which are the products of
distinct genes and are commonly designated as PPAR α, PPAR γ and PPAR
δ/b. The three subtypes of
PPAR bind to fatty acids and fatty acid metabolites and regulate the expression
of genes involved in the transport, metabolism and buffering of these ligands
within the cells. PPARs are 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].
While PPAR α
regulates fatty acid oxidation and PPAR δ is involved in cholesterol homeostasis, PPAR γ agonists regulate
adipogenesis and are effective insulin sensitizers. Thus, the PPARs possess the
ability to address many features of the diabetic phenotype. PPAR γ agonists
and PPAR α / γ dual agonists are interesting
compounds for the development of anti-diabetic agents. PPAR γ agonists
reduce plasma glucose, lipids and insulin levels in type 2 diabetic patients
while PPAR α/γ dual agonists improve both lipid metabolism and
glucose tolerance- two key factors in the treatment of type 2 diabetes.
Synthetic
Agonists of PPAR γ -General Structure
As
the role of PPAR γ
in adipogenesis, energy storage and insulin sensitization came into
light, it quickly evolved over the last decade from a new orphan receptor to
one of the best characterized nuclear receptors. Structures of the ligand
binding domain (LBD) of the PPARs in the absence and presence of ligands have
been solved by x-ray crystallography. The solved structures for ligand-bound PPARs reveal that
its agonists, such as TZDs, fibrates and fatty acids, share a common binding
mode in which their acidic head groups participate in a hydrogen bonding
network within a Y-shaped ligand binding pocket in the ligand binding domain of
the receptor [3].
Guided
by the mutual pharmacophore, the general structure of PPAR γ as well as α
/γ agonists can be divided into three regions:
A
is the acidic head group,
B
is the central spacer group, and
C
is the linear lipophilic tail group (figure 1).

Figure 1: General structure of PPAR γ and
α /γ agonists
The spacer connecting the lipophilic
heterocyclic tail and the central ring of the molecule has been examined. The
compounds with three carbon spacer seem to be favorable for agonism of PPAR γ
over those with two carbon atoms [4]. Variation of the length of the
spacer could alter its in vitro functional activity profile without regularity.
For the lipophilic tail a variety of aryl
and heteroaryl groups such as, pyridyl, oxazoyl, benzoxazoyl have been found to
be tolerated. Also, when one tries to rationalize the shape of the heterocyclic
moiety, the planar heterocycle is preferred.
The desired linker fragment between the
head group (2,4-thiazolidinedione) and the central spacer group has been
suggested to be the methylene moiety. Any deviation in the linker fragment
length has been reported to reduce the PPAR γ activity.
Based on the chemical structure, some of
the PPAR γ agonists have been broadly classified as follows:
1.The
first generation thiazolidinediones
2.The second generation glitazones:
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”
The TZDs (figure 2) were developed
over a period of 15 years through empirical compound screening in rodent models
of insulin resistance. Ever since a thiazolidinedione-based compound,
ciglitazone, was developed from a class of fibrate lipid-lowering agents and
was reported
as a novel anti-diabetic agent that enhanced insulin sensitivity in patients
with type-2 diabetes, many studies on new analogues have been carried out.
The molecular mechanism of action of the
TZDs remained unknown until several reports in the mid-1990s suggested a
possible connection between these agents and the PPARs. In 1995,
Lehmann et al [5] made the important
discovery that the TZDs were potent and selective activators of PPAR γ.
Troglitazone
was derived from ciglitazone by replacing the lipophilic tail (which is a
methylcyclohexylmethyl ether moiety), with a vitamin E residue [6]. Troglitazone (Rezulin), was
the first TZD to
reach the market as an anti-diabetic agent, but was withdrawn from clinical use
in 2000 due to reports of severe, idiosyncratic hepatotoxicity [7].
Two TZDs approved for clinical use today
are rosiglitazone (Avandia) and pioglitazone (Actos); both have a pyridyl tail
group.
In general, pioglitazone and rosiglitazone
have similar clinical efficacy with both demonstrating improvements in insulin
sensitivity and the ability to lower fasting plasma glucose levels [8].
However one potential area of distinction between these two TZDs is the greater
impact of pioglitazone on diabetic dyslipidemia. Although pioglitazone was
initially found to be a PPAR γ agonist, additional preclinical data show
that this compound has some, although minimal, activity on PPAR γ as well
in standard cotransfection (CTF) assays [9]. Consistent with these
data are clinical findings showing that pioglitazone has beneficial effects on
lipids not seen with rosiglitazone, which is a pure PPAR γ agonist.
In addition to the improvement in
glycemic control, the glitazones have a beneficial effect on many of the
traditional as well as the new risk factors and can help inpreventing or
lessening the impact of the cardiovascular consequences of type 2 diabetes.
They have been shown to lower the levels of atherogenic dyslipidemia, lower
blood pressure [10] as well as visceral obesity, lessen the levels
of the pro-inflammatory and pro-thrombotic cytokines and adipokines as well as
increase the levels of the anti-atherogenic adinopectin. Unfortunately, these
compounds are also associated with the side effects of obesity, hemodilution
and edema [8]. Thus, there is significant interest in the design of novel PPAR γ
modulating drugs that retain efficacious insulin sensitizing properties while
minimizing potential adverse side effects.
DRF-2189 BRL-48482 PAT5A Englitazone KRP-297 Netoglitazone (X=C, R=F) CLX-0921


