Drugs and Pharmaceuticals

Current R & D Highlights

(Diabetes)

 

 

 

 

Contents

 


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

     Abstracts

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, Lucknow


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.

 

 

 

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 beta -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 India. α-amyrin acetate, isolated from the fruits of F. racemosa at the dose of 100 mg/kg body

 

 

 

 

 

 

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, PO, of the extract 12,13.

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 rosa sinensis lowered the total cholesterol and serum triglycerides by 22 and 30%, respectively. Maximal diminution in blood glucose (41–46%) and insulin level (14%) was noticed after 21 days. The hypoglycemic activity of this extract is comparable to that of glibenclamide63  .

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, Lucknow

 


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