2. TYPES OF DIABETES:

There are three main types of diabetes, they are as follows

· Type 1 diabetes(beta–cell destruction, usually leading to absolute insulin deficiency)

· Type 2 diabetes (predominantly insulin resistance with relative insulin deficiency or predominantly an insulin secretory defect with/without insulin resistance)

· Gestational diabetes

2.1. Type I Diabetes:

Type I diabetes is an autoimmune disease. In type 1 diabetes, the immune system attacks and destroys the insulin-producing beta cells in the pancreas resulting in decreased or nil production of diabetes. At present, scientists do not know exactly what causes the body’s immune system to attack the beta cells, but they believe that autoimmune, genetic, and environmental factors are involved. It develops most often in children and young adults but can appear at any age. Symptoms of type I diabetes usually develop over a short period. Symptoms may include polyphagia, polydypsia, poluurea, weight loss, blurred vision, and extreme fatigue. If not diagnosed and treated with insulin, a person with type I diabetes can lapse into a life-threatening diabetic coma, also known as diabetic ketoacidosis. Stem cells are a new choice for the treatment of this disorder. The major cells in interest are haemopoietic and mesenchymal cells(6).

2.2. Type II diabetes:

NIDDM is a complex disease that is currently thought to be influenced by more than a single gene or environmental factor. Although the relative contribution of genetic and environmental factors to the development of NIDDM differs among individuals, patients generally have two common metabolic abnormalities, insulin resistance, the failure of peripheral tissues; including liver, muscle, and adipose tissue, to respond to physiologic doses of insulin, and failure of pancreatic cells to properly secrete insulin in response to elevated blood glucose levels. Obesity is a significant risk factor for the development of NIDDM. An extremely lean and lipoatrophic models have revealed a similar predisposition to developing diabetes. Although it may seem paradoxical that both increased adiposity and severely reduced fat mass cause diabetes, a common pathophysiologic process in fat may be responsible for the predisposition to develop hyperglycemia in both conditions (7).

2.3 Gestational Diabetes:

Some women develop gestational diabetes late in pregnancy. Although this form of diabetes usually disappears after the birth of the baby, women who have had gestational diabetes have a 20 to 50% chance of developing type II diabetes within 5 to 10 years. Maintaining a reasonable body weight and being physically active may help prevent development of type 2 diabetes. As with type 2 diabetes, gestational diabetes occurs more often in some ethnic groups and among women with a family history of diabetes. Gestational diabetes is caused by the hormones of pregnancy or a shortage of insulin. Women with gestational diabetes may not experience any symptoms (8). The complications of gestational diabetes can be classified broadly into two

a) Maternal complications

b) Fetal complications (9)

3. ETIOLOGY:

The etiology of diabetes include the following

i) Metabolic syndrome – a syndrome with 4 key features (diabetes, hypertension, obesity, hyperlipedemia )

ii) Insulin resistance

iii) Hemochromatosis- iron overload causes pancreas damage that can mimic type 1 or type 2 diabetes

iv) Chronic pancreatitis- causes damage of the pancreas that can mimic diabetes

v) Polycystic ovarian syndrome- ovary cysts inhibit natural female hormone causing insulin resistance

vi) Carcinoid syndrome- glucose intolerance, protein manifestation, serotonin inhibits insulin production

vii) Pancreatic insufficiency, pancreatitis & pancreatic surgery

viii) Over active pituitary glands

ix) Over active adrenal glands (10)

4. PATHOPHYSIOLOGY:

Type 1 diabetes mellitus:

Resident antigen presenting cells phagocytose beta cells, become activated, and migrate to draining lymph nodes where they present antigen to circulating T cells. Upon activation beta cell specific T cells gain access to islet tissue through the vasculature and accumulate in the islet causing insulitis. Additional antigen presentation may occur locally leading to destruction of beta cells with subsequent hyperglycemia. At present, it remains unclear if a single common autoantigen elicits the initial immune response directed against pancreatic beta cells. To firmly accept or refute this idea, a better understanding of the earliest events in disease as well as those events that mark the transition from insulitis to diabetes may be required.(11)

Type 2 diabetes mellitus:

· The type 2 diabetes accounts for many as 90% of DM cases and u=is usually characterized by the presence of both insulin resistance and relative insulin insufficiency. Insulin resistance is manifested by increased lipolysis and free fatty acids production, increased hepatic glucose production and decreased skeletal muscle uptake of glucose. B-cell dysfuction is progressive and contributes to worsening blood glucose control over time. Type 2 DM occurs when a diabetogenic lifecycle is superimposed upon a susceptible genotype

· Uncommon causes of diabertses (1-2% of the cases) include endocrine disorder (acromegaly, Cushing syndrome), gestational diabetes mellitus, diseases of the endocrine and exocrine pancreas and the effects of medication

· Impaired fasting glucose and impaired glucose tolerance are the terms used to describe patients whose plasma glucose levels are higher than the normal but not diagnostic of DM are associated with insulin resistance syndrome

· Microvascular complications include retinopathy, neuropathy and nephropathy. Macro vascular complications include heart diseases, stroke, and peripheral vascular diseases (12).

Role of Acetylcholine and interleukins in diabetes.

Acetylcholinesterase (AChE) expression is pivotal during apoptosis. Indeed, AChE inhibitors partially protect cells from apoptosis. Insulin-dependent diabetes mellitus (IDDM) is characterized in part by pancreatic β-cell apoptosis (13). Several interleukins (ILs) attracted considerable attention as potential effectors in the pathology and physiology of insulin resistance associated with type 2 diabetes mellitus (T2DM) and obesity. IL-1, a major proinflammatory cytokine, is present at increased levels in patients with diabetes mellitus, and could promote beta-cell destruction and alter insulin sensitivity. IL-6 has been suggested to be involved in the development of obesity-related and T2DM-related insulin resistance. The action of IL-6 on glucose homeostasis is also complex and integrates central and peripheral mechanisms. Both experimental and clinical studies now converge to show that several ILs contribute to the pathology and physiology of T2DM through their interaction with insulin signaling pathways and beta-cell function (14).

5. ROLE OF MEDICINAL PLANTS IN THE MANAGEMENT OF DIABETES:

5.1. Mechanisms of anti diabetic activity:

The herbal drugs act via one of these mechanisms insulin like , increasing insulin secretion from beta cells of pancreas, acting by regeneration of γ-cells of the islets of Langerhans, inhibiting glucagon secretion from β- cells in pancreas, inhibiting aldose reductase activity, increasing glucose utilization, Drugs reducing lactic dehydrogenase and γ-glutamyl transpeptidase, inhibiting glycogen-metabolizing enzymes, increasing glyoxalase 1 activity in liver,increasing glucose uptake in lipocytes,inhibiting glucose-6-phosphate system, increasing the creatine kinase levels in tissues, acting as antioxidant [15 ].

5.2. Herbals in diabetes

5.2.1 Abelmoschus moschatus Medik (Malvaceae)

It is an aromatic medicinal plant, native to India. Myricelin, the active chemical constituent of A. moschatus, enhances insulin sensitivity via increase in post-receptor insulin signaling mediated by enhancements in IRS-1-associated PI3-kinase and GLUT 4 activity in muscles of obese Zucker rats. Myricetin can also be used as a model substance for the development of antidiabetic compounds [16].

5.2.2 Acacia arabica (Lam) Wild. (Mimosaceae):

It is distributed all over India. The plant extract exhibits antidiabetic agent by acting as secretagouge to release insulin. Powdered seeds of A. Arabica, administered to normal rabbits, induces hypoglycemic effect by initiating release of insulin from pancreatic beta cells [17].

5.2.3 Achyranthes aspera L (Amaranthaceae):

It is distributed throughout the tropical world. Oral administration of A. aspera powder exhibits dose-related hypoglycemic effect in normal as well as in diabetic rabbits. The water and methanol extracts also exhibit same activity in normal and alloxan diabetic rabbits. The plant may act by providing certain necessary elements like zinc, magnesium, manganese, calcium and copper to the beta-cells [18].

5.2.4 Achyrocline satureioides (Less) DC (Asteraceae)

It is a medicinal plant of Brazil. The results obtained from animal studides with the aqueous extract of A. satureioides supports its use in medicine as hypoglycemic, hepatoprotective and digestive agent and these are mediated by its antioxidant and choleretic activities [19].

5.2.5 Acosmium panamense Schott. (Leguminosae):

Oral administration of water extracts ( 20 and 200 mg/kg) and of butanol extracts(20 and 100 mg/kg) lowers the plasma glucose levels in diabetic rats within 3 h in streptozotocin-induced diabetic rats [20].

5.2.6 Aegle marmelose (L) Corr. (Rutaceae)

It is widely distributed in India and Southeast Asia. A significant decrease in liver glycogen of diabetic rats is reversed nearly to normal level by the leaf extract and it also reduces the blood urea and serum cholesterol. A similar effect is seen with insulin treatment and the results indicate that the active principle in A. marmelos leaf extract has insulin mimicing activity [21].

5.2. 7 Agrimony eupatoria L. (agrimony) (Rosaceae):

Aqueous extract (1mg/mL) induces insulin secretion from the BRIN-BDII pancreatic B-cell line, 2-deoxy-glucose transport, glucose oxidation and incorporation of glucose into glycogen in mouse abdominal muscle comparable with 0.1µM-insulin. This demonstrates the presence of antihyperglycemic, insulin-releasing and insulin-mimicing activity of A. eupatoria [22].

5.2.8 Ajuga iva L. Schreberr (Medit) (Lamiaceae);

A species native to Europe, Asia and Africa. Oral administration of the aqueous extract of A. iva L (10 mg/kg) produces decrease in plasma glucose levels in normal rats, 6 h after administration. It shows rapid normalization, which concludes A.iva exhibits a strong hypoglycemic effect in diabetic rats, and supports its traditional use in diabetes mellitus management [23].

5.2.9 Allium cepa L. (onion): (Liliaceae):

Various ether soluble fractions as well as insoluble fractions of dried onion powder exhibits hypoglycemic activity in diabetic rabbits. A.cepa also shows antioxidant and hypolipidemic activity. It normalizes the activities of liver hexokinase, glucose 6-phosphatase and HMG Co A reductase [24, 25]. When diabetic patients were given single oral dose of 50 g of onion juice it controls post-prandial glucose levels [26].

5.2.10 Allium sativum L. (garlic): (Liliaceae):

It is a perennial herb cultivated throughout India. Injestion via enteral route of the garlic extract lowers serum glucose, total cholesterol, triglycerides, urea, uric acid, creatinine, AST and ALT levels but increases serum insulin. The hypoglycemic activity is better in diabetic rats than with normal rats when compared with glibenglemide [27].

5.2.11 Aloe barbadensis Mill.(Liliaceae):

The species grows well throughout the world. Treatment with multiple doses of exudates of Aloe barbadensis leaves shows hypoglycemic effect in alloxan induced diabetic rats. Single as well as chronic doses of bitter principle of the same plant also show hypoglycemic effect in diabetic rats. This action is by stimulation or synthesis and/or release of insulin from pancreatic beta cells [28].

5.2.12 Aloe vera (L) Burm.(Asphodelaceae):

It grows in arid climates and is distributed in Africa, India and other arid areas. Aloe vera gel at 200 mg/kg1 demonstrates significant antidiabetic, cardioprotective activity, reduces the increased TBARS, maintains the Superoxide dismutase and Catalase activity to normal level and increases reduced glutathione by four times in diabetic rats [29]. The leaf pulp extract shows hypoglycemic activity on IDDM and NIDDM rats. [30].

5.2.13 Andrographis paniculata Burm. (Acanthaceae):

It is a herbaceous plant distributed mainly in India, Sri Lanka and southern Asia. It decreases blood glucose levels due to its antioxidant properties [31]. The ethanolic extract of A. paniculata demonstrates antidiabetic property and may be due to increase glucose metabolism. Its hypotriglyceridemic effect is also beneficial in the diabetic state [32].

5.2.14 Annona squamosa L (Annonaceae):

It is a well-branched tree or shrub, growing at lower altitudes. Administration of 15 mg/kg/day of isolated juercetin-3-O-glucoside from Annona squamosa leaves for 10 consecutive days to the hyperglycemic animals reverse these effects and simultaneously inhibits the activity of hepatic GIucose-6-phosphatase. It also decreases hepatic and renal lipid peroxidation with a simultameous increase in the activities of antioxidative enzymes, such as Catalase and Superoxide dismutase as well as glutathione content[33].

5.2.15 Artemisia herba-alba Asso (Med).(Asteraceae):

It is a perennial shrub of the steppes of Northern Africa, Arabian Peninsula and Western Asia. Oral administration of 0.39 g/kg body weight of aqueous extract of leaves or barks show significant reduction in blood glucose level. The extract of the aerial parts of the plant seem to have minimal adverse effect and high LD50 value [34].

5.2.16 Artemisia dracunculus L. (Asteraceae):

The hypoglycemic activity of the extract enhances 3-5 folds with bio-enhancers like Labrasol, and can be compared with the activity of metformin [35]. Tarralin, an ethanolic extract lowers elevated blood glucose levels by 24% relative to control animals. [36].

5.2.17 Astragalus membranaceus Bunge (Fisch.): (Leguminosae):

It is a traditional Chinese medicine. The protective mechanism of AGS-IV, a new glycoside of cycloartane-type triterpene isolated from the root of A. membranaceus (Fisch.) decreases the blood glucose concentration and HbAlC levels, and increases plasma insulin levels. AGS-IV increases the activity of glutathione peroxidase in nerves, depress the activation of aldose reductase in erythrocytes, and decreases the accumulation of advanced glycation end products in both nerves and erythrocytes. Moreover, elevates Na+, K+- ATPase activity in both the nerves and erythrocytes of diabetic rats. These results indicate that AGS-IV exerts protective effects against the progression of peripheral neuropathy in STZ-induced diabetes in rats through several interrelated mechanisms [37].

5.2.18 Averrhoa bilimbi L (Oxalidaceae):

The plant is distributed in Asia. It produces significant blood glucose-lowering effect in the diabetic rats when compared to the vehicle (distilled water). Aqueous fraction lowers Hepatic glucose-6-phosphatase activity. Results also show that the aqueous fraction shows potent activity than the butanol fration in the amelioration of hyperglycemia in STZ-diabeiic rats and is a potential source for the isolation of new orally active agent(s) for anti-diabetic therapy [38].

5.2.19 Azadirachta-indica A. Juss. (Meliaceae)

It is a tree native to India, Burma, Sri Lanka, Malaysia and Pakistan, growing in tropical and semi-tropical regions. A low (0.5g tid) and high (2g tid) doses of powdered part aqueous or alcoholic extract of A.indica shows hypoglycemic activity in high dose and can be combined with oral hypoglycemic agents in type-2 diabetic patients. The activity may be due to The activity may be due to inhibition of insulinase activity and insulin mimicing activity [39].

5.2.20 Bauhinia candicans Benth (Leguminosae)

The effect of methanolic extract of B. candicans leaves (8 mg/kg) exhibits hypoglycemic activity along with a reduced urinary glucose excretion. The results suggest may be due to B. candicans increased peripheral metabolism of glucose [40].

5.2.21 Bauhinia forficate Link. (Caesalpinaceae)

Oral administration of kaempferilrin , a major flavonoid compound of the n-butanol fraction from B. forficata leaves results in significant hypoglycemic effect in normal and in alloxan-induced diabetic rats. It also shows antioxidant properties [41]. Administration of aqueous, ethanolic and hexanic extracts for 7 days (doses: 200 and 400 mg/kg) to the alloxan-diabetic rats exhibit significant reductions in plasma glucose, triglycerides, total cholesterol and HDL-cholesterol after treatment with extracts and glibenclamide as compared to the diabetic controls [42].

5.2.22 Bidens pilosa L (Asteraceae)

The butanol fraction of B.pilosa inhibits differentiation of naive helper T (ThO) cells into Thl cells but enhances their transition into type II helper T (Th2) cells, thus can prevent diabetes possibly via suppressing the differentiation of ThO cells into Thl cells and promoting that of ThO cells into Th2 cells, thus preventing autoimmune diabetes in non-obese diabetic mice [43].

5.2.23 Biophytum sensitivum (L) DC. (Oxalidaceae)

The leaves exhibit hypoglycemic activity. Initial dose-response studies shows that 200 mg/kg body weight is optimum for hypoglycemia. In 16-h fasted non-diabetic rabbits, a single administration results in 15.1% fall in fasting plasma glucose at the end of 1 and 2 h, and the hypoglycemic effect persists at the end of 6 h (13.8% fall). Serum insulin level rises in the treated animals, which suggests insulinotropic effect suggesting that the hypoglycemic response of B. sensitivum may be mediated through stimulating the synthesis/release of insulin from the beta cells of Langerhans [44].

5.2.24 Bixa orellana L. (Bixaceae)

It is a shrub or small tree of the tropical region of the Americas. Annatto extract decreases blood glucose levels in fasting normoglycaemic and streptozotocin-induced diabetic dogs.

Increased insulin levels are not due to increased insulin synthesis as after 1h residence time and half-hour postprandial, decreases C-peptide levels. It was confirmed that B. orellana lowers blood glucose by stimulating peripheral utilization of glucose [45].

5.2.25 Brassica nigra (L) Koch (Brassicaceae)

It is native to the southern Mediterranean region of Europe. Administration of 200 mg/kg body weight of aqueous extract of the seeds to diabetic animals daily once for one month brings down fasting serum glucose (FSG) levels while in the untreated group FSG remains at a higher value. In treated animals the increase in glycosylated hemoglobin (HbAlc) and serum lipids is much less compared to untreated diabetic controls [46].

5.2.26 Bryonia alba L. (Cucurbitaceae)

Trihydroxyoctadecadienoic acids obtained from the roots of the native Armenian plant B. alba L. (0.05 mg/kg/day for 15 days. Lin.) restores the disordered lipid metabolism of alloxan-diabetic rats. Metabolic changes induced in diabetes significantly restores towards their normal values with the exception of diminished triglyceride content of muscle which does not get restored. Thus, they can influence the profile of the formation of stable prostaglandins by actions downstream of prostaglandin endoperoxides [47].

5.2.27 Bumelia sartorum Mart. (Sapotaceae)

Bassic acid, an unsaturated triterpene acid is obtained from ethanolic extract of B. sartorum root bark. This shows hypoglycemic activity and increases plasma insulin levels in alloxan-diabetic rats and alters the glucose tolerance pattern [48]. They also exhibit anti-inflammatory activity [49].

5.2.28 Caesalpinia bonducella (L) Roxb. (Caesalpinaceae)

The oral administration of the seed extracts results in significant antihyperglycemic action as well as diabetic dyslipidemia significantly by lowering the elevated cholesterol as well as LDL level. The antihyperglycemic action of the extracts may be due to the blocking of glucose absorption. The drug has the potential to act as antidiabetic as well as antihyperlipidemic [50].

5.2.29 Cajanus cajan (L) Millsp. (Papilionaceae)

Single doses of unroasted seeds (60% and 80%) on administration to alloxanized mice shows significant reduction in the serum glucose levels after 1-2 hr and a significant rise at 3 hr. [51].

5.2.30 Carum carvi L.(CC) (Apiaceae) / Capparis spinosa

L. (CS) (Capparidaceae)

Carum carvi is a biennial plant native to western Asia, Europe and Northern Africa and Capparis spinosa is native to Israel and eastern part of Mediterranean. After 14 daily doses, oral administration of the aqueous CC and CS extracts (20 mg/kg) elicits decrease in blood glucose levels in STZ diabetic rats. [52].

5.2.31 Casearia esculenta Roxb. (Flacourtiaceae):

Casearia esculenta root is widely used in traditional system of medicine as anti diabetic drug in India. Oral administration of aqueous extract of root for 45 consecutive days results in a significant reduction in blood glucose by lowering the activity of glucose-6-phosphatase and fructose-1,6-bisphosphatase and an increase in the activity of liver hexokinase. Its activity is compared to that of glibenclamide [53].

5.2.32 Cassia auriculata L.(Caesalpinaceae):

It grows well in dry regions of India and Sri Lanka. Oral administration of CLEt- to mildly diabetic (MD) and severely diabetic (SD) rats at a dose of 400 mg/kg once a day for 15 days shows reduction in FBG, by increasing the activity of hepatic hexokinase, phosphofructokinase, suppresses glucose-6-phosphatase and fructose-l,6-bisphosphatase. Histopathological studies of pancreatic sections reveal that there is an increase in number of islets and beta-cells in CLEt-treated rats [54].

5.2.33 Catharanthus roseus (L)G.Don.(Apocynaceae):

Oral administration at dose-dependent of 0.5, 0.75 and 1.0 mL/kg body weight reduced the blood glucose of diabetic rabbits which was found comparable with that of the standard drug, glibenclamide. The result indicates that a reduction of blood glucose by C. roseus and the mode of action of the active compound is probably by enhancing secretion of insulin from the beta- cells of Langerhans or through extra pancreatic mechanism [55].

5.2.34 Chamaemelum nobile (L) All. (Asteraceae):

It is a distributed in Europe, North America and Argentina. Single dose of oral administration at a dose of 20mg/kg body weight of C. nobile aqueous extract reduces blood glucose levels after 6h in normal rats and in STZ diabetic rats. After 15 days of treatment, Basal plasma insulin concentrations remain unchanged [56].

5.2.35 Cichorium intybus L.(Asteraceae)

A dose of 125 mg of plant extract/kg body weight exhibits the most potent hypoglycemic effect. Daily administration of Cichorium intybus (C1E) for 14 succesive days to diabetic rats attenuates serum glucose by 20%, triglycerides by 91% and total cholesterol by 16%. It acts by reducing the hepatic glucose 6 phosphatase [57].

5.2.36 Clausena anisata (Willd) Benth. (Rutaceae)

At a dose of 800 mg/kg p.o., Clausena anisata (Wild) Hook (CAME) reduces the mean basal blood glucose concentrations of fasted normal and fasted diabetic rats by 57.52 and 51.30%, respectively [58].

5.2.37 Coccinia indica Wt & Arn. (Cucurbitaceae):

An indigenous plant of India used in ayurvedic system of medicine. Dried extracts of C. indica administered to diabetic patients for 42 days restores the activities of enzyme lipoprotein lipase (LPL), glucose-6- phosphatase and lactate dehydrogenase, which helps in reversal of diabetics [59].

5.2.38 Coriandrum sativum L (Apiaceae):

It is an annual herb native of southern Europe and North Africa. Its seed extract significantly increases the activity of the beta cells and increases the release of insulin [60]. The extract shows antihyperglycemic, insulin-releasing and insulin-like activity [61].

5.2.39 Cuminum cyminum L (Apiaceae)

A flowering plant native from the East Mediterranean to East India. The seeds extract results in reduction in blood glucose, glycosylated hemoglobin, creatinine, blood urea nitrogen and improved serum insulin and glycogen content. It shows reduction in renal oxidative stress when compared to diabetic control and glibenclamide groups. CC and glibenclamide improve antioxidant status of kidney and pancreas of diabetic rats [62].

5.2.40 Cuminum nigrum L (Apiaceae)

It is distributed in Central Asia and India. Oral administration of the flavonoid fraction of the plant causes hypoglycemic effect at a dose range of 0.5 to 1.5 g/kg, both in normal and alloxan-diabetic rabbits [63]. It acts by AMPK activation and increasing glucose uptake with increased insulin sensitivity in muscle cells[64].

5.2.41 Cyamopsis tetragonoloba (L) Taubert. (Papilionaceae)

They are distributed across Africa, Asia and the Pacific. The aqueous extract of beans results in significant lowering of blood glucose levels in alloxan-induced diabetic rats within 3 h of administration. A 10 days therapy produces statistically significant reduction in the blood glucose levels [65].

5.2.42 Dioscorea dumetorum (Kunth) Pax. (Dioscoreaceae)

At a dose of 20 mg/kg, methanol extract reduces the fasting blood sugar in normoglycemic rabbits reduces from 112 mg/100 mL to 55 mg/100 mL after 4h. In alloxan diabetic rabbits, the blood sugar lowers from 520 mg/100 mL to 286 mg/100 mL in 4 hours. The aqueous fraction of the methanol extract produces comparable effects at 100 mg/kg. The hypoglycemic effects are compared to tolbutamide [66].

5.2.43 Eclipta alba (L) Hassk. (Asteraceae)

It is distributed in India, China, Thailand, and Brazil. Oral administration of leaf suspension of E. alba for 60 days results in significant reduction in blood glucose, glycosylated hemoglobin HbA(l)c. it acts by decreasing the activities of glucose-6- phosphatase and fructose-1,6-bisphosphatase, and enhances liver hexokinase activity. Thus, oral administration of E. alba possess potent antihyperglycemic activity [67].

5.2.44 Emblica officinalis Gaertn. (Euphorbiaceae)

Different extracts of E. officinalis acts as α-amylase and α-glucosidase inhibitor. Its antiglycation activity confirms therapeutic potential of extracts against diabetes. Methanol extracts significantly inhibits the oxidation of LDL under in vitro conditions [68].

5.2.45 Enicostema littorale blume (Gentianaceae)

Dried plant equivalent extract of 1.5 g/100 g body weight produces significant reduction in the glycosylated haemoglobin level, liver glucose-6-phosphatase activity and increase in serum insulin levels of the diabetic rats. The above results suggest that E. littorale is a potent antidiabetic agent [69].

5.2.46 Ficus bengalensis L. (Moraceae)

Commoly known as "banyan tree" in Ayurvedic literature. At a dose of 100 mg/kg for 30 days, it produces significant decrease in blood and urine sugar, certain lipid components in serum, tissues and glucose-6- phosphatase activity in liver. The activities of hexokinase and HMG-COA reductase in tissues as compared to diabetic control. The mechanism of action of the principle is related to protective/inhibitory action against the insulin degradative processes [70].

5.2.47 Fraxinus excelsior L (Oleaceae)

The aqueous extract produces a significant decrease in blood glucose levels in diabetic rats. A potent increase of glycosuria concludes inhibition of renal glucose reabsorption. This renal effect might be at least one mechanism explaining the hypoglycemic activity of this plant [71].

5.2.48 Garcinia kola Heckel (Clusiaceae)

It is found in Africa . The extract decreases the activity of glucose-6-phosphatase and lipid peroxidation (LPO) products [72]. At a dose of 100 mg/kg, alloxan induced diabetic rabbits, the blood sugar lowers from 506 mg/100 mL to 285 mg/100 mL at 12 h. the chief constituent producing this activity is Kolaviron, a mixture of C-3/C-8 linked biflavonoids obtained from Garcinia kola produces significant hypoglycemic effects [73].

5.2.49 Gongronema latifolium Endl. (Asclepiadaceae)

The plant is native of Nigeria in West Africa. The aqueous extract of G. latifolium leaves produces significant increase in the activity of hepatic hexokinase and decreases the activities of glucokinase[74]. The aqueous extract increases the activity of glutathione reductase while the ethanolic extract causes a significant increase in the activity of glutathione peroxidase. The results suggest that the extracts from G.latifolium leaves could exert their antidiabetic activities through their antioxidant properties [75].

5.2.50 Helicteres isora L., As.(Sterculiaceae)

Distributed widely throughout India. The hot water extract of fruit of H. isora exhibits significant antioxidant activity and antidiabetic activity [76], shows glucose uptake activity and found to be active comparable with insulin and metformin [77]. The ethanolic extract has insulin-sensitizing and hypolipidemic activity and can be used in the treatment of type-2 diabetes [78].

5.2.51 Hypoxis hemerocallidea conn Corm (African potato) (Hypoxidaceae)

At a dose of 800 mg/kg, the plant extract causes 30.20% and 48.54% reductions in the blood glucose concentrations of fasted normal and STZ-treated diabetic rats respectively.

Thus, the plant tubers possesses hypoglycemic activity [79].

5.2.52 Inula racemosa Hook.f.(Asteraceae)

It grows in the Alpine and Western Himalayas. The petroleum ether extract of roots reduces plasma insulin and glucose levels within 75 min of oral administration to albino rats and it significantly counteracts adrenaline-induced hyperglycemia in rats. All these findings indicate that constituents I. racemosa may have adrenergic beta-antagonist activity [80].

5.2.53 Lagerstroemia speciosa (L) Pers.(Lythraceae)

L. speciosa shows significant reduction in the blood glucose levels. Glucosol in a soft gel capsule formulation exhibiting a 30% reduction in blood glucose levels compared to 20% drop with dry-powder filled hard gelatin capsule formulation.[81].

5.2.54 Lepidium sativum L. (Brassicaceae)

The aqueous LS extract at a dose of 10 mg/kg/h produces a potent inhibition of renal glucose reabsorption resulting in reversal of diabetes. This renal effect is at least one mechanism explaining the hypoglycemic activity of this herb [82].

5.2.55 Mangifera indica L.(Anacardiaceae)

The aqueous extract produces reduction of blood glucose level in normoglycemic and glucose-induced hyperglycemia, but does not have any effect on streptozotocin-induced diabetic mice under the same conditions. The hypoglycaemic effect of the aqueous extract was compared with that of an oral dose of chlorpropamide under the same conditions. The result indicates that the aqueous extract of the leaves of M. indica possess hypoglycemic activity [83].

5.2.56 Momordica charantia L. (Cucurbitaceae)

M. charantia is commonly known as vegetable insulin. The administration of aqueous extract (AE), methanol fraction (MF) or methanol insoluble fraction (MIF) each significantly suppresses plasma glucose levels at 30 min as compared with control. The mechanism of action is by the inhibition of α-glucosidase activity [84].

5.2.57 Morinda lucida Benth.(Rubiaceae)

The extract demonstrates a significant dose- dependent hypoglycemic activity in hyperglycemic rats, the extract produces a significant anti-diabetic effect from day 3 after oral administration, with 400 mg/kg extract-treated groups. These results suggest that the leaves of M. lucida have a strong glucose lowering property when administered to streptozotocin-treated rats [85].

5.2.58 Myrcia uniflora Barb., Rods.(Myricaceae)

A plant is widely distributed in northern Brazil and used for treatment of diabetes. The aqueous extracts of Myrcia elicits beneficial effect in diabetic condition, mainly by improving metabolic parameters of glucose homeostasis. Myrcia on administration for 3 weeks has no effect on the weight of epididymal and retroperitoneal adipose tissue [86].

2.2.59 Nigella sativa L (Ranunculaceae)

Ethanol extract of Nigella sativa seeds (300 mg/kg body weight/day) administered to streptozotocin induced diabetic rats for 30 days shows significant fall in the elevated levels of blood glucose, lipids, plasma insulin and improves altered levels of lipid peroxidation products (TBARS and hydroperoxides) and antioxidant enzymes in liver and kidney. The results confirm the antidiabetic activity of N. sativa ethanolic seeds extract [87].

5.2.60 Ocimum sanctum L. (Lamiaceae)

Traditional known as Tulsi. Aqueous extract of leaves shows significant reduction in blood sugar level in normal and alloxan induced diabetic rats [88]. Significant reduction in diabetic parameters indicate the hypoglycemic and hypolipidemic effects of tulsi in diabetic rats [89]. Oral administration of plant extract (200 mg/kg) for 30 days results in decrease in the plasma glucose level. Renal glycogen content increases 10 fold while skeletal muscle and hepatic glycogen levels decreases by 68 and 75% respectively in diabetic rats when compared to control [90]. It also elicits gastric antiulcer activity, antimutagenic, antibacterial, antifungal, antiviral, antiasthemitic, antistress, antitumor, antioxidant and immunostimulant activities.

5.2.61 Origanum vulgare L. (Lamiaceae)

It is native western and south-western Eurasia and the Mediterranean region. Oral administration of aqueous extract of dose 20 mg/kg body weight results in significant decrease on blood glucose levels in STZ diabetic rats. The blood glucose levels gets normalised from the fourth day after daily repeated oral administration of aqueous OV extract (20 mg/kg). This concludes that an aqueous extract of O. Vulgare exhibits anti-hyperglycemic activity in STZ rats [91].

5.2.62 Otholobium pubescens L. (Papilionaceae)

A chemical compound bakuchiol, isolated from an extract of O. pubescens reduces blood glucose levels by dose- dependent response in db/db mice. An oral dose of bakuchiol at 150 mg/kg q.d. in the fat-fed, streptozotocin (STZ)-treated rat, significantly lowers plasma glucose and triglyceride levels [92].

5.2.63 Paeonia lactiflora Pall.(Paeoniaceae)

Paeoniflorin and 8-debenzoylpaeoniflorin are two anti-diabetic compounds isolated from the dried root of P.lactiflora pall causes significant blood sugar reduction in streptozotocin-treated rats and has a maximum effect, 25 min after treatment. Plasma insulin does not change in paeoniflorin-treated normoglycemic rats indicating an insulin-independent action [93].

5.2.64 Panax ginseng C. Meyer. (Araliaceae)

The roots are taken orally in the treatment of type II diabetes. Extracts of ginseng species shows antihyperglycemic activity associated with increased peroxisome proliferator-activated receptor gamma expression and adenosine monophosphate-activated protein kinase phosphorylation in liver and muscle. It also improves insulin sensitivity [94].

5.2.65 Phyllanthus amarus Schum & Thonn. (Euphorbiaceae)

Methanolic extract of Phyllanthus amarus has potent anti-oxidant activity as it also inhibit lipid peroxidation, and scavenge hydroxyl and superoxide radicals in vitro. This extract also reduces the blood sugar in alloxanized diabetic rats [95].

5.2.66 Psidium guajava L. (Myrtaceae)

It is traditionally used in India for the treatment of type 2 diabetes mellitus. Ethanolic stem bark extract exhibits statistically potent hypoglycemic activity in alloxan-induced hyperglycemic rats [96]. Aqueous extract shows hypolipidaemic activity in addition to its hypoglycemic and antidiabetic activity [97].

5. 2.67 Pterocarpus marsupium Roxb.(Papilionaceae)

It is widely used as 'Rasayana' for management of various metabolic disorders in the ayurvedic system of medicine. An aqueous extract of P.marsupium wood, at an oral dose of 250 mg/kg, shows significant hypoglycemic activity [98]. Marsupin, pterosupin and Iiquiritigenin obtained from this plant show antihyperlipidemic activity [99]. (-) Epicatechin, active principle, has been found to be insulinogenic, enhancing insulin release and conversion of proinsulin to insulin in vitro. (-)epicatechin has insulin-like activity in a dose- dependent manner [100].

5.2.68 Retama raetam (RR) (Forssk) Webb. (Papilionaceae)

Its aqueous extract in a dose of 20mg/kg reduces the blood glucose in diabetic rats after 6 hours of oral administration. This hypoglycemic effect is more pronounced in streptozotocin (STZ) induced diabetic rats [101]. It also shows a potent inhibition of renal glucose reabsorption [102]. These findings suggest that the aqueous extract elicits significant hypoglycemic effect.

5. 2.69 Salacia reticulate W. (Celastraceae)

Administration of 0.01 % solution of the extract in drinking water prevents the increase of plasma glucose level and intestinal α-glucosidase activities in type 1 diabetic mice. It prevents elevation of plasma, pancreatic, and kidney LPL( lipid peroxide levels ), lowering of the plasma insulin level, and elevation of the kidney aldose reductase activities in diabetic mice. These results prove that aueous extract of leaves of S. reticulata could be asupplementary product for the prevention of diabetes and obesity[103].

5.2.70 Spergularia purpurea (SP) (Pers) G, Donf. (Caryophyllaceae)

The aqueous extract (10 mg/kg) elicits a significant decrease in blood glucose levels in diabetic rats. This hypoglycemic effect might be due to an extra-pancreatic action of the aqueous extract of SP. This demonstrates that the aqueous extract perfusion of SP inhibits endogenous glucose production in mice [104].

5. 2.71 Suaeda fruticosa (SF) Euras (Chenopodiaceae) – to be checked

The aqueous extract at a dose of 192 mg/kg produces a significant decrease in blood glucose levels in normal rats, and even more in diabetic rats. This hypoglycemic effect might be due to an extra-pancreatic action of the aqueous extract of SF, since that the levels of plasma insulin unchange between the values before and after treatment. The effect of the aqueous extract on the plasma cholesterol is significant in both normal and diabetic rats but, there is no significant effect of SF on plasma triglycerides in both groups [105].

5. 2.72 Syzigium cumini (L) Skeels.(Myrtaceae)

Commonly known as 'Jamun’, is widely used in Indian folk medicine for the treatment of diabetes mellitus. Oral administration of 2.5 and 5.0 g/kg body weight of the aqueous extract of the seed for 6 weeks results in significant reduction in blood glucose and an increase in total haemoglobin, but in the case of 7.5 g/kg body weight the effect is not significant. The aqueous extract also decreases free radical formation which clearly shows the antioxidant property. Thus the study shows that Jamun seed extract (JSEt) has hypoglycemic action [106].

5. 2.73 Tamarindus indica L. (Caesalpinaceae)

Aqueous extract of seed of T. indica when given to mild diabetic (MD) and severe diabetic (SD) rats at the dose of 80 mg and 120 mg/0.5 mL distilled water/100 g body weight/d respectively for 14 days, the extract shows attenuation of hyperglycemia and hyperlipidemia in streptozotocin-induced diabetic rats [107].

5. 2.74 Telfaria occidentalis Hook. (Cucurbitaceae)

It is a tropical vine grown in West Africa as a leaf vegetable and for its edible seeds. The aqueous extract given orally in 1 g/kg to the mice 60 minutes before glucose administration reduces the blood glucose level from day two when compared with that of chlorpropamide (200 mg/kg) under the same conditions. The results of this study indicates that the aqueous extract of the leaves of T. occidentalis possess hypoglycemic activity [108].

5. 2.75 Tinospora cordifolia Miers. (Menispermaceae)

Commonly known as Guduchi, an herbaceous vine indigenous to the tropical areas of India, Myanmar and Sri Lanka. Oral administration of an aqueous T. cordifolia root extract to alloxan diabetic rats causes a significant reduction in blood glucose and brain lipids. Though the aqueous extract at a dose of 400 mg/kg could elicit significant antihyperglycemic effect in different animal models, its effect is equivalent to only one unit/kg of insulin [109].

5.2.76 Trigonella foenum graecum L. (fenugreek) (Papilionaceae)

Used both as an herb (the leaves) and as a spice (the seed) and cultivated worldwide as a semi-arid crop. Oral administration of 2 and 8 g/kg of plant extract produces dose dependent decrease in the blood glucose levels in both normal as well as diabetic rats [110]. Administration of fenugreek seeds improves glucose metabolism and normalizes creatinine kinase activity in heart, skeletal muscle and liver of diabetic rats. It also reduces hepatic and renal glucose-6-phosphalase and fructose -1, 6-biphosphatase activity [111]

5.2.77. Withania somnifera (solanaceae)

Withania somnifera is an important medicinal plant, which is used in traditional medicine to cure many diseases. Hypoglycaemic and hypolipidaemic effects were also investigated in alloxan-induced diabetic rats. Treatment of the diabetic rats with Withania somnifera root and leaf extracts and glibenclamide restored the changes of the above parameters to their normal level after eight weeks of treatment, indicating that both the extracts possess hypoglycaemic and hypolipidaemic activities in alloxan-induced diabetes rats.(112)

5.2.78. Withania coagulans (solanaceae)

Withania coagulans fruit is used in the traditional system of medicine for various diseases. Isolated alkaloids and steroids from this plant sources are responsible for hypoglycemic activity. The aqueous and chloroform extracts of the fruits decreased the blood glucose levels. The fruits of W. coagulans was determined about 25 mg/kg in streptozotocin-induced diabetic rats, which is comparable to the standard antidiabetic drug metformin. It has been already reported that higher concentrations of Mg and lower con-centrations of K play a vital roles in diabetes management. The significant antidiabetic potential of W. coagulans could be due to the high concentration of Mg along with Ca. The Ca ion activates insulin gene expression via. CREB and is responsible for exocytose of stored insulin. (113)

LIST OF HERBS HAVING ANTI DIABETIC ACTIVITY

S.No	Name of the plant	Parts used	Mechanism of action	Reference number
1.	Abelmoschus moschatus (Malvaceae)	Whole plant extract	improves insulin sensitivity	16
2.	Acacia arabica (Lam) Wild. (Mimosaceae)	Whole Plant extract	acting as secretagouge to release insulin	17
3.	Achyranthes aspera L (Amaranthaceae)	Whole olant extract	Provides necessary elements to β cells	18
4.	Achyrocline satureioides (Asteraceae)	aerial parts	By inhibition of liver AST and ALT	19
5.	Aegle mannelose (Rutaceae)	Leaf	Insulin mimicing activity	21
6.	Agrimony eupatoria L. (Rosaceae)	Aqueous extract of whole plant	Insulin mimicing activity	22
7.	Allium sativum (Liliaceae)	Rhizome	increases serum insulin	27
8.	Aloe vera (Liliaceae)	Exudates of leaves	stimulation or synthesis and/or release of insulin from pancreatic beta cells	29
9.	Andrographis paniculata (Acanthaceae)	Aerial parts	By increasing SOD and catalase activity and increase in glucose metabolism	31,32
10.	Annona squamosa (Annonaceae)	Leaves	Inhibition of hepatic GIucose-6-phosphatase	33
11.	Artemisia herba-alba (Asteraceae)	Leaves	Insulin mimic activity	34
12.	Averrhoa bilimbi (Oxalidaceae)	Aerial parts	Inhibition of hepatic GIucose-6-phosphatase	38
13.	Azadirachta-indica . (Meliaceae)	Aqueous extract of leaves	Inhibition of insulinase activity and insulin mimicking activity	39
14.	Bauhinia candicans (Leguminosae)	Leaves	Increased peripheral metabolism of glucose	40
15.	Bidens pilosa (Asteraceae)	Aerial parts	Suppressing the differentiation of ThO cells into Thl cells	43
16.	Biophytum sensitivum (Oxalidaceae)	Leaves	Insulinotropic effect	44
17.	Bixa orellana (Bixaceae)	Aerial parts	stimulating peripheral utilization of glucose	45
18.	Brassica nigra (Brassicaceae)	Seeds	Insulinotropic effect	46
19.	Bryonia alba (Cucurbitaceae)	Root	Inhibiting glycogen-metabolizing enzymes	47
20.	Caesalpinia bonducella(Caesalpinaceae)	Seed	blocking of glucose absorption	50
21.	Cajanus caja (Papilionaceae)	Seed	Increasing the secretions of insulin	51
22.	Carum carvi (Capparidaceae)	Seed	inhibition of hepatic glucose production and/or stimulation of glucose utilization	52
23.	Casearia esculenta(Flacourtiaceae)	Root	Lowering the activity of G-6-P and increasing the activity of hexokinase	53
24.	Cassia auriculata (Caesalpinaceae)	Leaf	Suppresses glucose-6-phosphatase	54
25.	Catharanthus roseus(Apocyanaceae)	Leaves	Increased secretion of insulin	55
26.	Chamaemelum nobile(Asteraceae)	Full plant	Alters the activity of HMG coenzyme a	56
27.	Cichorium intybus(Asteraceae)	Full plant	reduction in the hepatic Glc-6-Pase activity	57
28.	Clausena anisata(Rutaceae)	Hook and root	Insulin mimicking activity	58
29.	Corriandrum sativum (Apiaceae)	Seed	Insulin releasing and insulin like activity	60,61
30.	Cuminum cyminum(Apiaceae )	Seed	Antioxidant activity on the kidney	62
31.	Cuminum nigrum(apiaceae)	Seed	AMPK activation and increased glucose uptake.	64
32.	Cyamopsis tetragonoloba(Papilionaceae )	Beans	Potentiates insulin secretion	65
33.	Dioscorea dumetorum( Dioscoraceae)	Tubers	Insulinotropic activity	66
34.	Eclipta officinalis ( Eupharbiaceae )	Leaves	α-amylase and α-glucosidase inhibitor	68
35.	Eclipta alba (Asteraceae )	Leaves	Inhibition of Glucose-6- phosphate	67
36.	Enicostema littorale blume (Gentianaceae)	Aerial parts	Antiglycosylation activity	69
37.	Ficus bengalences (Moraceae )	Bark	Inhibition of insulin degradation	70
38.	Fraxcinus excelsior(Oleaceae )	Seed	Inhibition of renal glucose absorption	71
39.	Garcinia kola(Clusiaceae)	Seeds	Inhibition of glucose-6-phosphatase and lipid peroxidation	73
40.	Gongronema latifolium(Asclepiadaceae)	Leaves	Anti-oxidant property	75
41.	Helicteres isora (Sterculiaceae)	Fruit	Insulin sensitizing activity	76
42.	Inula racemosa (Asteraceae)	Hook	Adrenergic antagonist activity	80
43.	Lepidium sativum (Brassicaceae)	Seed	Inhibition of renal resorption of glucose	82
44.	Mangifera indica (Anacardiaceae)	Leaves , kernals of seeds	Increase release of insulin from pancreatic beta cells.	83
45.	Momordica charantia(Cucurbitaceae)	Fruit	Inhibition of α-glucosidase activity	84
46.	Morinda lucida (Rubiaceae)	Leaves	Anti oxidant property	85
47.	Ocimum sanctum(Lamiaceae)	Leaves	Antioxidant property	90
48.	Panax ginseng (Araliaceae)	Root	increased peroxisome proliferator-activated receptor gamma expression	94
49.	Phyllantus amarus(Euphorbiaceae)	Fruit	Inhibit lipid peroxidation, and scavenge hydroxyl and superoxide radicals	96
50.	Pterocarpus marsupium.(Papilionaceae)	Bark , wood	Insulinogenic and insulin like activity	99
51.	Retama raetam(Papilionaceae)	Aerial parts	inhibition of renal glucose reabsorption	103
52.	Spergularia purpurea.(Caryophyllaceae)	leaves	inhibits endogenous glucose production	105
53.	Trigonella foenum graecum (Papilionaceae)	Leaves and seeds	Partial or complete inhibition of hepatic and renal glucose-6-phosphalase	111
54.	Withania somnifera (Solanaceae)	Root and leaf extracts	Anti oxidant property	112
55.	Withania coagulans	Bud, fruit	Activates insulin gene expression via. CREB	113

6. CONCLUSION:

In conclusion, this review has presented a list of anti diabetic plants used in the treatment of diabetes mellitus. Many new bioactive drugs isolated from plants having hypoglycaemic effects showed anti-diabetic activity equal and sometimes even more potent than known oral hypoglycaemic agents. However, many other active agentsobtained from plants have not been well characterized. More investigations must be conducted to evaluate the mechanism of action of medicinal plants with anti-diabetic effect. Consequently, it is necessary to perform toxicological investigation of all plants empirically used in order to avoid the risk of the side effects related to phytotherapy.

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Received on 17.03.2013

Modified on 28.03.2013

Accepted on 03.04.2013

Research Journal of Pharmacognosy and Phytochemistry. 5(3): May-June 2013, 155-168

A systematic Review on Antidiabetic medicinal Plants