Indian Medicinal Plants with Hypoglycemic Potential
P.K. Mukherjee, N.K. Nema, S. Pandit, K. Mukherjee School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
1. INTRODUCTION Diabetes mellitus (DM) is described as ‘Madhumeha’ in Sanskrit in the ancient Indian literature dealing with the human healthcare systems. It is a metabolic disease caused by genetic or environmental factors. This chronic disease is supposed to occur when there is a deficient production of insulin from the pancreas (type-1 diabetes) or when the body does not respond to the produced insulin (type-2 diabetes). This results in raised uncontrolled blood glucose level. DM is also a maharoga (major disease) because it affects most part of the body and every cell of the human physiology. Pathophysiology of diabetes is described in Figure 23.1. The increased blood glucose level results in some classical symptoms such as polyurea (frequent urination), polyphagia (increased hunger), and polydipsia (increased thrust). These symptoms develop readily in type-1 diabetes but develop slowly in type-2 diabetes (Chen et al., 2010). DM has become a global problem in spite of advances in modern science which accounts for 5% deaths per year and this is supposed to increase by 50% in next 10 years as per who estimations. India has been projected byWHO as the country with the fastest growing population of diabetic patients and estimated that in between 1995 and 2025, diabetic patients will increase by 195%. Several classes of synthetic drugs are available for therapeutic treatment of the disease. The plant-derived products have been proved to be a good source for the treatment of diabetic complications, as these are used traditionally from thousands of years and are well described in ancient literature like Ayurveda (Mukherjee, 2002). Along with this the naturally occurring leads have shown good acceptability in the human system with the well-known fact that natural products have less side/toxic effects than synthetic molecules. The ethnobotanical information reports that out of an estimated 250000 higher plants, about 800 plants may possess antidiabetic potential (Grover et al., 2002). The plants of Indian origin have been well explored for their possible use in various diabetic complications using various experimental models and along with isolated leads (Mukherjee, 2001). Several Indian medicinal plants have pharmacologically established hypoglycemic potential. They have been investigated for their beneficial use in different types of diabetes and reported in numerous scientific journals (Mukherjee et al., 2006). The present work highlights 80 potential plants that are used as hypoglycemic, which have been proved for their efficacy and reported in journals. This will highlight the respective plants of individual families and their bioactive phytomolecules useful as hypoglycemic obtained from natural sources along with their inhibitory concentration and type of enzyme and substrate used. 2. PLANT FAMILIES WITH ANTIDIABETIC POTENTIAL 2.1 Family: Acanthaceae 2.1.1 Adhatoda vasica Nees Adhatoda vasica Nees is a small evergreen tree which grows in India prominently in the lower Himalayan region. This plant is an important part of the Ayurvedic system of medicine where it is mainly used to treat respiratory tract disorder viz. asthma, bronchitis, cough, etc. Methanolic extract of the leaves of the plant has shown inhibition of the rat intestinal a-glucosidase enzyme using sucrose as substrate. Bioactivity-guided isolation of vasicine [1] and vasicinol [2] have shown reversible inhibition of the enzyme with IC50 values of 125 and 250 mM, respectively (Hao et al., 2008). 2.1.2 Andrographis paniculata Nees Andrographis paniculata Nees, commonly known as Kalmegh or ‘King of Bitters’, is a herbaceous plant native to India and Sri Lanka having a wide spectrum of biological activities. Its extract and isolated compound have demonstrated hypoglycemic and antihyperglycemic activity along with antioxidant property in normal and streptozotocin (STZ)-induced diabetic rats. 2.1.3 Barleria lupulina Lindl. It is a popular folklore medicinal plant distributed in the mountains of southern and western India. The methanolic extract of the aerial parts of Barleria lupulina Lindl. (300 mg kg 1 ) have been found to possess significant hypoglycemic activity. 2.2 Family: Alliaceae 2.2.1 Allium sativum L. It is an essential dietary supplement known as garlic. The ethanol, petroleum ether, and ethyl acetate extract exerted antihyperglycemic activity in alloxanized rabbits at a dose of 0.25 mg kg 1 orally, and it has strong antioxidant activity and rapid reactivity with thiol-containing proteins, which is responsible for the hypoglycemic property. The S-allyl cysteine [4] sulfoxide significantly lowers blood glucose in experimental diabetic animals. Another constituent allicin [5] (thio-2-propene-1-sulfinic acid S-allyl ester) Indian Medicinal Plants with Hypoglycemic Potential 237 reported hypoglycemia in mildly diabetic rabbits upon oral administration (0.25 mg kg 1 ) (Sheela and Augusti, 1992). 2.3 Family: Aloaceae 2.3.1 Aloe vera (L.) Burm.f. Aloe vera is cultivated all over the world for its various medicinal properties. Mukherjee et al. (2006) included antidiabetic activity in their review article. In a study, the extract of aloe gum was found to be effective in enhancing glucose tolerance in normal and diabetic rats. It maintains glucose homeostasis by controlling the carbohydrate-metabolizing enzymes and stimulates pancreatic beta cells to release insulin. Aloin A [6], the bitter principle of aloe, is found to be hypoglycemic in alloxanized mice. 2.4 Family: Amaranthaceae 2.4.1 Aerva lanata (L.) Juss. ex Schult. Aerva lanata (L.) Juss. ex Schult. is a part of the Indian folk medicine system for the treatment of DM and it is commonly known as Sunny Khur. The alcoholic extract of A. lanata reduced the increase of blood glucose level in alloxanized rats by 42% at a dose of 375 mg kg 1 and 48% at 500 mg kg 1 body weight (Vetrichelvan and Jegadeesan, 2002). 2.5 Family: Anacardiaceae 2.5.1 Mangifera indica L. It is a well-known perennial tree commonly known as Mango, widely cultivated throughout in India. It is the national fruit of India (Mukherjee et al., 2006). The aqueous leaf extract (1 g kg 1 p.o.) showed hypoglycemic potential when given along with as well as 60 min before glucose administration in STZ-induced diabetic rats. It is found to act possibly through intestinal reduction of the absorption of glucose by inhibiting the a-glucosidase enzyme and as well as pancreatic and extrapancreatic mechanisms. Hypoglycemic activity of mangiferin [7] (10 and 20 mg kg 1 , i.p. once daily for 28 days) in STZ-induced diabetic rats and improvement in oral glucose tolerance in glucose-loaded normal rats upon chronic administration (10 and 20 mg kg 1 , i.p.) for 14 days have also been reported. 2.6 Family: Annonaceae 2.6.1 Annona squamosa L. Annona squamosa L. is a 10–20 ft long tree commonly known as sugar apple found in different parts of India. Ethanolic leaf extract (350 mg kg 1 , orally) shows hypoglycemic and antihyperglycemic activities in normal, STZ-diabetic rats and alloxanized rabbits. Quercetin-30 -O-glucoside [8] isolated from leaves of the plant has been reported to regulate alloxan-induced hyperglycemia and lipid peroxidation in rats (Gupta et al., 2005). 238 P.K. Mukherjee et al. 2.7 Family: Apocynaceae 2.7.1 Alstonia scholaris (L.) R. Br. It is commonly known as devil tree. It is an evergreen, tropical, small, and glabrous tree with perfumed flowers. Two isolated molecules from aqueous methanolic extract, quercetin 3-O-b-D-xylopyranosyl (1!2)-b-D-galactopyranoside [9] and ( )-lyoniresinol 3-O-b-D-glucopyranoside [10], were assayed for the inhibition of the rat intestinal a-glucosidase using sucrose and maltose as substrate. Among these two isolated molecules compound ( )-lyoniresinol 3-O-b-D-glucopyranoside is more potent and exhibited inhibitory activity against both substrates, sucrase IC50 1.95 mM and maltase IC50 1.43 mM, while the former compound exhibited only maltase inhibitory activity at an IC50 of 1.96 mM (Channa et al., 2005). 2.7.2 Catharanthus roseus (L.) G. Don. It is used as a folk remedy for treatment of diabetes in various parts of India. The hypoglycemic activity of dichloromethane: methanol extract of leaves and twigs was found in STZ-induced diabetic rats (500 mg kg 1 p.o., for 7 and 15 days). It increases metabolization of glucose and enhances secretion of insulin either from the beta cells of Langerhans or through extrapancreatic mechanism (Singh et al., 2001). 2.8 Family: Arecaceae 2.8.1 Areca catechu L. Areca catechu L. commonly known as betel nut is cultivated throughout India. Arecoline [11], a natural alkaloidal constituent of the nut, was investigated and reported to have hypoglycemic activity. 2.9 Family: Asclepiadaceae 2.9.1 Gymnema montanum Hook. f. It is an endemic plant species of India found mainly in Western Ghats. The ethanolic leaf extract showed competitive inhibition against yeast a-glucosidase and noncompetitive inhibition against salivary a-amylase in a concentration-dependent manner and the long-term administration (12 weeks) of the leaf extract effectively reduced the blood glucose level and also increased the insulin level. The blood glucose-lowering activity of alcoholic leaf extract (200 mg kg 1 orally) was studied in alloxan-induced diabetic rats along with an increase in plasma insulin level (Ananthan et al., 2004). 2.9.2 Gymnema Sylvestre R. Br. It is commonly known as the ‘sugar destroyer’ because the leaves effectively block sweet taste in the mouth when chewed. The plant has been used in the treatment of DM for a long time in India and reported by different workers for its blood glucose-lowering activity both in vitro and in vivo (Mukherjee et al., 2006). Indian Medicinal Plants with Hypoglycemic Potential 239 2.10 Family: Bombacaceae 2.10.1 Bombax ceiba L. Bombax ceiba L., commonly known as silk cotton tree, is distributed throughout India. Shamimin, a flavonol glucoside isolated from the leaves of the plant, has been reported to possess significant hypoglycemic activity at 500 mg kg 1 in rats. 2.11 Family: Brassicaceae 2.11.1 Brassica juncea (L.) Czern. The spice is used as foodstuff in India and it is a small herb cultivated throughout India. It has been reported to possess significant hypoglycemic activity in normal rats upon oral administration in diet (10%w/w) for 60 days. It increases the concentration of hepatic glycogen and glycogenesis and suppresses the activity of glycogen phosphorylase and gluconeogenic enzymes, leading to reduction in glycogenolysis and gluconeogenesis (Khan et al., 2002). 2.12 Family: Capparidaceae 2.12.1 Capparis decidua (Forsk.) Edgew. It is commonly known as ‘Kair,’ found in the western part of India. The powdered fruit of the plant showed significant hypoglycemic potential in alloxan-induced diabetic rats. Treatment of diabetic mice with alkaloid rich fraction for 28 days significantly inhibited the acute elevation of blood glucose level during oral glucose tolerance test (Sharma et al., 2010). 2.13 Family: Celastaceae 2.13.1 Salacia oblonga Wall. This is a woody plant found in the forests of Sri Lanka and India. The plant, root, and stems are an important part of Aryuveda and traditional Indian medicine for the treatment of diabetes. Serum glucose-lowering activity and a-glucosidase and aldose reductase inhibitory activities of hydroalcoholic extract of the roots were established in sucrose and maltose-loaded rats. 2.14 Family: Cesalpinaceae 2.14.1 Caesalpinia bonducella (L.) Roxb. Traditionally this plant is used to control blood sugar level. The aqueous and 50% ethanolic seed extracts showed hypoglycemic and antihyperglycemic activities in normal and STZ-diabetic rats and increase the release of insulin from pancreatic cells. 2.15 Family: Chenopodiaceae 2.15.1 Beta vulgaris L. It is commonly known as garden beet, which is used traditionally in the management of diabetes. The beta vulgarosides II [12] and IV [13] isolated from the root have been 240 P.K. Mukherjee et al. investigated for hypoglycemic activity in an oral glucose tolerance test and lowers the blood glucose level. The extract of the plant was also found to be effective in inhibiting nonenzymatic glycolization of skin proteins in STZ-induced diabetic rats (Tunali et al., 1998). 2.16 Family: Combretaceae 2.16.1 Terminalia catappa L. It is a large deciduous tropical tree from India. In a study by Nagappa et al. (2003) the petroleum ether, methanol, and aqueous extracts of the fruit were examined on fasting blood sugar levels and serum biochemical parameters in alloxan-induced diabetic rats and produced significant hypoglycemic activity. 2.16.2 Terminalia pallida Brandis It is an evergreen endemic tree found in various parts of India. The ethanolic extract of fruits exhibits significant antihyperglycemic activity in alloxan diabetic rats at a dose of 0.5 g kg 1 orally.
2.17 Family: Compositae 2.17.1 Artemisia pallens Wall. ex DC. It is a shrub used in the treatment of DM in the southern parts of India and commonly known as ‘Dhavanam.’ The methanolic extract (100 mg kg 1 , orally) of aerial parts of the plant exhibited antihyperglycemic activity in glucose-fed hyperglycemic and alloxaninduced diabetic rats. It is supposed to act by inhibiting glucose reabsorption or increasing peripheral glucose utilization (Subramoniam et al., 1996). 2.18 Family: Convolvulaceae 2.18.1 Ipomoea batatas (L.) Lam. It is an important food crop commonly known as Sweet Potato cultivated in many tropical and subtropical countries. The plant has showed hypoglycemic effect in diabetic Zucker fatty rats and inhibition of the increased blood glucose level in a glucose tolerance test in rats. It reduces insulin resistance and possibly acts by maltase inhibition. Onidin 3-O-[2-O-(6-O-E-feruloyl-beta-D-glucopyranosyl)-6-O-ecaffeoyl-betaD-glucopyranoside]-5-O-beta-D-glucopyranoside, a diacylated anthocyanin, isolated from storage roots reduced blood glucose level by 16.5% at 30 min in male 8-weekold Sprague–Dawley rats upon single oral administration (Matsui et al., 2002). 2.19 Family: Cucurbitaceae 2.19.1 Citrullus colocynthis (L.) Schrad. It is a vine plant commonly known as ‘Bitter apple,’ distributed and cultivated throughout India. The hypoglycemic activity of aqueous extract (300 mg kg 1 ), and glycosidic Indian Medicinal Plants with Hypoglycemic Potential 241 and saponin extract (50 mg kg 1 ) was evaluated orally in normal rabbits and exerted an insulinotropic effect. The aqueous seed extract showed blood glucose-lowering activity in normal and STZ-induced diabetic rats upon daily oral administration for 2 weeks (Nmila et al., 2000). 2.19.2 Momordica charantia L. It is commonly known as bitter melon or Karela, widely grown in tropical and subtropical regions for fruits which are the most bitter among all the fruits; it is commonly used as vegetable. The plant is well known for its antidiabetic potential with many scientific reports in past four to five decades. Charantin [14] is major constituent that has antidiabetic potential. D-(+)-trehalose, an active principle isolated from the seeds of M. charantia, showed alpha glucosidase inhibitory activity at concentration of 0.002 M (Matsuura et al., 2002). 2.19.3 Momordica cymbalaria Fenzl ex Naudin. It is commonly known as Karchikayee, well known for its medicinal properties in different parts of India. Fruit powder and aqueous fruit extract possess blood glucose level reducing activity in fasting alloxan-induced diabetic rats in a treatment for 15 days (Rao et al., 2001). It may act by increasing hepatic glycogen. 2.20 Family: Euphorbiaceae 2.20.1 Phyllanthus amarus Schumach. & Thonn. It is an annual globrous herb. Oral administration of the whole plant extract with a dose of 5 g per day for 10 days produced reduction in blood glucose in diabetic and nondiabetic subjects. The methanolic extract was found to reduce the blood sugar in alloxan diabetic rats at 4th hour by 6% at a dose of 200 mg kg 1 and 18.7% at a concentration of 1000 mg kg 1 and produced significant reduction in blood sugar upon continued administration for 15 days (Raphael et al., 2002). 2.21 Family: Fabaceae 2.21.1 Cajanus cajan (L.) Millsp. Perennial woody shrub grows throughout India and commonly known as Pigeon Pea. The roasted and unroasted seeds of this plant lower plasma glucose levels of normal and alloxan diabetic mice. The aqueous leaf extract has glucose-lowering activity in oral glucose tolerance test (Esposito Avella et al., 1991). 2.21.2 Derris scandens Benth. D. scandens Benth. is commonly known as Gonj. From the hexane and chloroform extract of the plant, three molecules, scandinone [15], scandenone [16], and scandenin 242 P.K. Mukherjee et al. A [17], were investigated for a-glucosidase inhibition against PNP-G as substrate at IC50 values of 34.74, 33.83, and 25.17 mg ml 1 , respectively (Rao et al., 2007). 2.21.3 Glycyrrhiza glabra L. Glycyrrhiza glabra L., commonly known as Licorice, is a flavorful perennial herb used for food and medicinal purposes for thousands of years. The hydrophobic flavonoids from this plant possess abdominal fat-lowering and hypoglycemic effects, possibly mediated through activation of peroxisome proliferator-activated receptor-gamma in obese diabetic KK-A (y) mice (Nakagawa et al., 2004). 2.21.4 Pterocarpus marsupium Roxb. It is commonly known as Vijaysar, found throughout India. Different parts of the plant (bark, latex, etc.) were investigated and reported to have hypoglycemic activity. ( )-Epicatechin [18] isolated from the bark and heartwood of the plant were identified to possess blood sugar-lowering activity (Sheehan et al., 1983). 2.21.5 Trigonella foenum graecum L. It is commonly known as fenugreek and is a well-known hypoglycemic agent used in traditional system of Indian medicines. Various extracts of different parts of this plant, fibers, proteins, and saponins isolated from the seeds, were investigated and found to possess significant hypoglycemic potential (Mukherjee et al., 2006). Trigonelline [19], the major alkaloid component, exerted a mild hypoglycemic effect (Vats et al., 2002). 2.22 Family: Flacourtiaceae 2.22.1 Casearia esculenta Roxb. It is a shrub which is well distributed throughout India. The plant extract produced an alleviative effect in liver and renal damage associated with STZ-induced diabetes in rats. The roots are also reported to have antihyperglycemic activity (300 mg kg 1 p.o. for 45 days) in normal and STZ-induced diabetic rats by decreasing the activities of glucose-6-phosphatase and fructose-1, 6-bishosphatase, and also increasing the activity of liver hexokinase (Prakasam et al., 2002). 2.23 Family: Gentiaceae 2.23.1 Enicostemma littorale Blume It is a perennial herb which grows throughout India. A clinical study involving 84 patients with type 2 diabetes showed that pills prepared from Enicostemma littorale Blume administered for 3 months reduced blood glucose as well as serum insulin levels and prevented the progression of complications in diabetic patients. It is found to enhance glucose-induced insulin release from isolated rat pancreatic islets, mediated through K (þ)-ATP channel-dependent pathway. Aqueous extract reduces glucose level and Indian Medicinal Plants with Hypoglycemic Potential 243 decreases the elevated cholesterol, triglyceride, and creatinine levels when administered daily (2 g kg 1 p.o.) for 6 weeks in neonatal non-insulin-dependent diabetes mellitus (NIDDM) rats (Maroo et al., 2002). 2.24 Family: Gentianaceae 2.24.1 Swertia chirayita (Roxb. ex Fleming) H. Karst. It is commonly known as Chiretta. The hypoglycemic and antihyperglycemic efficacy of the plant extract as well as the active constituent swerchirin (1,8-dihydroxy3,5-dimethoxyxanthone) [20], isolated from the hexane fraction of the plant, is found to exert potent hypoglycemic activity. The hexane fraction of ethanolic extract (250 mg kg 1 ) showed blood glucose-lowering activity in fed, glucose-loaded and tolbutamide-pretreated animals. It stimulates insulin release from islets of Langerhans by depleting aldehyde-fuchsin stained beta-granules and immunostained insulin. Insulinreleasing effect was established for hexane fraction of the plant (250 mg kg 1 body weight p.o. per day for 28 days) in albino rats along with a significant rise in liver glycogen (Chandrasekar et al., 1990). 2.25 Family: Hippocrateaceae 2.25.1 Salacia reticulate Wight Salacia reticulta is a woody climber of Sri Lankan and Indian region. The plant is reported to lower blood glucose in fasted animals with improved glucose tolerance in laboratory animals and also inhibits alpha-glucosidase activity (Yoshikawa et al., 1998). Salacinol [21], Kotalanol [22], and de-O-sulfonated kotalanol [23] inhibited N-terminal catalytic domain of maltase-glucoamylase (ntMGAM). Among these compounds, de-Osulfonated Kotalanol is most potent with Ki¼0.03 mM (Sim et al., 2010). 2.26 Family: Lamiaceae 2.26.1 Ocimum sanctum L. It is commonly known as ‘Holy Basil’ distributed throughout India. It is thought that the plant exhibits hypoglycemic effect mediated by its cortisol-inhibiting potency and the plant may be used effectively in regulating corticosteroid-induced DM. The 70% ethanolic leaf extracts showed hypoglycemic activity in normal, glucose-fed, and STZ diabetic rats orally, and potentiated the action of exogenous insulin in normal rats. Plasma glucose-lowering activity of plant extract (200 mg kg 1 for 30 days) in STZ-induced diabetic animals revealed the effect of the extract on three important enzymes of carbohydrate metabolism, namely glucokinase, hexokinase, and phosphofructokinase (Vats et al., 2002). 244 P.K. Mukherjee et al. 2.26.2 Salvia moorcraftiana Wall. It grows in temperate Himalayas from Kashmir to Kumann. Two molecules have been isolated from the acetone extract of the aerial parts of the plant, which showed inhibition of the glucosidase type VI against p-nitrophenyl a-D-glucopyranoside as substrate. The two isolated molecules, 5-hydroxy-7, 40 -dimethoxyflavone [24], and oleanolic acid [25], inhibited enzyme at 4.38 and 5.64 mM concentration (Khan et al., 2002). 2.27 Family: Leguminosae 2.27.1 Cassia auriculata L. The evergreen Indian shrub commonly known as Tanner’s Cassia has hypoglycemic potential. The flowers of the plant have been reported to be the most potent in controlling blood glucose level. Researchers have established antihyperglycemic and antihyperlipidemic activity of aqueous flower extract in STZ-induced diabetic rats upon oral administration at different doses for 30 days (Latha and Pari, 2003). It regulates gluconeogenesis during diabetes and enhances utilization of glucose through increased glycolysis and also inhibits alpha-glucosidase resulting in a significant reduction of blood glucose levels. 2.27.2 Pterocarpus santalinus L. f. The traditionally used plant grows throughout India. Along with diabetes the plant is used traditionally for treating bleeding piles, dysentery, and all skin inflammations. The bark extracts of Pterocarpus santalinus L. (0.25 g kg 1 body weight) showed maximum antihyperglycemic activity (Kameswara et al., 2001). 2.27.3 Mucuna pruriens (L.) DC. The powdered seeds (0.5, 1, and 2 g kg 1 ) lowered blood glucose in normal and alloxaninduced diabetic rabbits. It acts probably by stimulating the release of insulin and/or by a direct insulin-like action due to the presence of trace elements like manganese, zinc, etc. The long-term use (40 days) of plant extract (200 mg kg 1 ) lowered blood glucose upon daily oral feeding in STZ-induced diabetic mice. Antihyperglycemic effect of alcoholic extract of the plant (100, 200, and 400 mg kg 1 per day) is also reported in alloxanized rats (Rathi et al., 2002). 2.28 Family: Liliaceae 2.28.1 Allium cepa L. Allium cepa L., commonly known as Onion, is an essential part of diet. A study with the seedling parts and callus cultures suggested that it exhibited much higher hypoglycemic activity as compared to natural bulbs of onion and the same can be used as an alternative source for the isolation of hypoglycemic compounds. Presence of a sulfur containing amino acid, S-methyl cysteine sulfoxide, has showed potent hypoglycemic activity when administered at a dose of 200 mg kg 1 for 45 days to alloxan-induced diabetic rats Indian Medicinal Plants with Hypoglycemic Potential 245 (Kumari et al., 1995). Another compound S-allyl cysteine sulfoxide was also found to be effective in reducing the blood glucose level of alloxan-induced diabetic rats. 2.29 Family: Malvaceae 2.29.1 Hibiscus rosa sinensis L. These large shrubs or small trees have potent blood glucose-lowering activity. Hypoglycemic activity was found in alcoholic leaf extract (250 mg kg 1 p.o. for seven consecutive days) against glucose-induced hyperglycemia model in rats and suggested that this is because of increased utilization of glucose, either by direct stimulation of glucose uptake or via the mediation of enhanced insulin secretion (Sachdewa et al., 2001). 2.29.2 Sida cordifolia L. It is a perennial shrub. The methanol extract of the root of this plant has been reported to possess significant hypoglycemic activity (Kanth and Diwan, 1999). 2.30 Family: Menispermaceae 2.30.1 Tinospora cordifolia (Willd.) Hook. f. & Thomson It is commonly known as ‘Guduchi’ found throughout India. The hypoglycemic activities of various extracts of the leaves have been investigated in normal and alloxanized rabbits for potent blood sugar-lowering activity. The antihyperglycemic activity of major alkaloid berberine [26] is due to its ability to inhibit alpha-glucosidase and decrease glucose transport through the intestinal epithelium (Pan et al., 2003). 2.31 Family: Melastomataceae 2.31.1 Memecylon umbellatum Burm. f. It is a small tree which grows in the Deccan coastal region. The oral administration of alcoholic extract of the leaves (250 mg kg 1 ) significantly lowered serum glucose level in normal and alloxan-induced diabetic mice. 2.32 Family: Meliaceae 2.32.1 Azadirachta indica A. Juss. Azadirachta indica A. Juss., commonly referred to as the Neem tree, is found throughout India and is widely recognized for its potential as insecticide. Hydroalcoholic plant extracts exerted hypoglycemic activity in normal and STZ-induced diabetic rats. b-Sitosterol, a steroid, may be responsible for its hypoglycemic property. It is due to the inhibition action of epinephrine on glucose metabolism, resulting in increased utilization of peripheral glucose and altering the serum cortisol concentration level (Chattopadhyay, 1999). 246 P.K. Mukherjee et al. 2.33 Family: Mimosaceae 2.33.1 Acacia arabica (Lam.) Muhl. ex Willd. Acacia arabica (Lam.) Muhl. ex Willd. is found throughout the drier parts of India and is commonly known as Babool. The powdered seeds have shown hypoglycemic effect in normal rabbits (2, 3, and 4 mg kg 1 ) when it is administered orally. The account for its hypoglycemic potential is probably through the release of insulin from pancreatic beta cells (Wadood et al., 1989). 2.34 Family: Moraceae 2.34.1 Ficus bengalensis L. It is widely distributed throughout India. Various active components isolated from the plant including the dimethoxy derivative of leucocyandin 3-O-beta-D-galactosyl cellobioside, dimethoxy derivative of perlargonidin 3-O-alpha-l rhamnoside, glycoside of leucopelargonidin, leucodelphinidin, isolated from the bark of this plant, have been reported for their hypoglycemic activity (Mukherjee et al., 2006). Kumar and Augusti (1989) proposed that blood sugar-lowering activity of a dimethoxy derivative of leucocyandin 3-O-beta-D-galactosyl cellobioside isolated from the bark is due to increase of serum insulin in normal and moderately diabetic rats at a dosage of 250 mg kg 1 for a 2 h period upon oral administration. 2.34.2 Morus alba L. It is commonly known as ‘Mulberry’ extensively grown in India for its leaves as food for silkworms. Chronic subcutaneous administration of leaf extract has showed degranulation effect on the beta cells of islets of langerhans of rabbits. Chen et al. (1995) established hypoglycemic activity of hot water extract of leaves in fasted and nonfasted STZ-induced diabetic mice at a dose of 200 mg kg 1 , i.p. It is found to act by increasing glucose uptake. 2.35 Family: Musaceae 2.35.1 Musa sapientum L. It is a potential fruit, commonly known as ‘Banana’ used extensively as food stuff. It is a good folklore medicine for the treatment of diabetes. Flower extracts (0.15, 0.20, and 0.25 g kg 1 p.o. for 30 days) have showed blood glucose-lowering activity in experimental animals (Pari and Maheswari, 1999). 2.36 Family: Myrtaceae 2.36.1 Eucalyptus globulus Labill. It is an ornamental tree which grows in subtropical parts of India. Aqueous extract of eucalyptus (0.5 g l 1 ) enhanced 2-deoxy-glucose transport by 50%, glucose oxidation by 60%, and increases the incorporation of glucose into glycogen by 90% in mouse Indian Medicinal Plants with Hypoglycemic Potential 247 abdominal muscle. It also enhanced insulin secretion from the clonal pancreatic beta-cell line which contributes for its antihyperglycemic activity (Gray and Flatt, 1998). 2.36.2 Eugenia jambolana Lam. It is a large evergreen tree of Indian subcontinent, also known as Syzygium cumini L. commonly known as ‘Jamun’ in India. The decoction of kernels of Eugenia jambolana is used as a household remedy for diabetes. The seeds and decoction of dry leaves were found to produce hypoglycemic effect. The protective effect of the alcoholic (100 mg kg 1 ) and the aqueous (5 g kg 1 ) extracts of the seed of this plant against tissue damage in diabetic rat brain was studied, and it was observed that both the extracts effectively protected the tissues, the alcoholic extract having more pronounced effect than the water extract (Prince et al., 2004). 2.36.3 Eugenia uniflora L. It is a small tree or shrub commonly known as Surinam Cherry or Brazilian Cherry. Seventy percent ethanol leaf extracts were evaluated and found to inhibit plasma glucose level. The antidiabetic activity of the extract may be due to the inhibition of the decomposition of carbohydrates and fats in the intestine (Arai et al., 1999). 2.36.4 Psidium guajava L. It is an evergreen shrub or small tree commonly known as guava. Bioactivity-guided fractionation of the 75% ethanol extract from guava leaves showed high inhibition of a-glucosidase and a-amylase. Quercetin [27], kaempferol [28], and myricetin [29] showed inhibition of a-glucosidase at IC50 values of 3.5, 5.2, and 3.0 mM against sucrose and with IC50 values of 4.8, 5.6, and 4.1 mM against maltase as substrate, respectively. These compounds also showed inhibition of a-amylase at IC50 values of 4.8, 5.3, and 4.3 mM, respectively. Among these myricetin is most potent for the activity (Wanga et al., 2010). 2.36.5 Syzygium alternifolium Walp. It is an endemic aromatic tree. Locally it is known as mogi/movi. The aqueous, ethanolic, and hexane extracts of the seeds of this plant were evaluated in normal and alloxan diabetic rats and the extracts showed significant hypoglycemic and antihyperglycemic activity. The aqueous extract was most potent among all the tested fractions (Rao and Rao, 2001). 2.37 Family: Nyctaginaceae 2.37.1 Boerhavia diffusa L. It is a commonly known as ‘Punarnava’ which means rejuvenates or renews the body. The aqueous leaf extract of Boerhaavia diffusa L. was showed to produce significant 248 P.K. Mukherjee et al. hypoglycemic activity at doses of 100, 200, and 400 mg kg 1 in alloxan-induced diabetic rats (Chude et al., 2001). It increases the plasma insulin levels and improves glucose tolerance. 2.38 Family: Nymphaeaceae 2.38.1 Nelumbo nucifera Gaertn. It is an aquatic perennial herb commonly known as sacred lotus, found throughout India. The ethanolic extract of rhizome of the plant on oral administration markedly reduced the blood sugar level of normal, glucose-fed hyperglycemic, and STZ-induced diabetic rats. The extract also improved the glucose tolerance and potentiated the action of exogenously injected insulin in normal rats (Mukherjee et al., 1995, 2006). 2.38.2 Nymphaea stellata Willd. It is commonly known as water lily or blue lotus. 1,2,3,4,6-penta-O-galloyl-b-D-glucose [30] isolated from flower extract showed inhibition of rat intestinal a-glucosidase enzyme using maltose as substrate at an ED50 of 0.1 mg ml 1 (Huang et al, 2010). 2.39 Family: Oxalidaceae 2.39.1 Biophytum sensitivum (L.) DC. It is a small flowering annual herb found throughout tropical India and commonly known as ‘Mukkutti.’ The leaf extract showed hypoglycemic activity in alloxan diabetic male rabbits. It stimulates pancreatic beta cells to release insulin (Puri and Baral, 1998). 2.40 Family: Piperaceae 2.40.1 Piper longum L. Piper longum L., commonly known as Pippali, is used as a spice and preservative in food stuff. Yeast a-glucosidase-I enzyme inhibited IC50 of 32.10, 34.39, 36.39, 34.09, and 19.26, by isolated compounds pipataline [31], pellitorine [32], sesamine [33], brachystamide B [34], and guineensine [35] respectively, from methanolic extract of the fruits against p-nitrophenyl-a-D-glucopyranoside as substrate (Pullela et al., 2006). 2.41 Family: Polygonaceae 2.41.1 Rheum emodi Wall It is commonly known as Himalayan rhubarb. Methanolic extract of the rhizome inhibited yeast a-glucosidase and mammalian a-glucosidase enzyme with p-nitrophenyl-aD-glucopyranoside as substrate. Yeast a-glucosidase inhibitors such as rhapontigenin [36], desoxyrhapontigenin [37], chrysophanol-8-O-b-D-glucopyranoside [38], torachrysone-8-O-b-D-glucopyranoside [39], and mammalian a-glucosidase inhibitors such as chrysophanol-8-O-b-D-glucopyranoside, desoxyrhaponticin [40], and torachrysone8-O-b-D-glucopyranoside have been isolated from the methanolic extract. Indian Medicinal Plants with Hypoglycemic Potential 249 2.42 Family: Punicaceae 2.42.1 Punica granatum L. It is a fruit-bearing deciduous shrub commonly known as pomegranate. The fruit juice has been reported to possess significant antihyperlipidemic activity in type II diabetic patients. The extract improves postprandial hyperglycemia in type II diabetes by inhibiting intestinal alpha-glucosidase. The methanolic seed extract showed hypoglycemic activity (150, 300, and 600 mg kg 1 p.o.) in strepotozotocin diabetic rats (Das et al., 2001). 2.43 Family: Rhamnaceae 2.43.1 Zizyphus sativa Gaertn. It is a small spreading tree with drooping branches. An alcoholic extract of the leaves showed dose-dependent reduction in blood glucose level but failed to produce significant hypoglycemic activity in alloxan diabetic rats (Mukherjee et al., 2006). 2.44 Family: Rutaceae 2.44.1 Aegle marmelos (L.) Correa ex Roxb. A moderate-sized tree found throughout the deciduous forests of India. Different extracts obtained from the leaves, bark, and fruit of this plant have been investigated for possible hypoglycemic activity in various experimental animal models of diabetes like STZ- and alloxan-induced diabetes along with possible mechanism of action (Mukherjee et al., 2006). Aegelin [41] is major compound responsible for the hypoglycemic activity. 2.44.2 Murraya koeingii (L.) Spreng. It is commonly known as curry-leaf tree and is a native of India and Sri Lanka. Fasting as well as postprandial blood sugar-lowering effect has been reported for leaf-powder in type II diabetic patients upon administration for a period of 1 month. It increases glycogenesis and decreases glycogenolysis and gluconeogenesis. The leaves lower the blood sugar in normal rats when administered as a diet (10%, v/v) for 60 days (Khan et al., 1995). Mahanine [42] and Mahanimbine [43], carbazole alkaloids isolated from leaves, showed hypolipidemic, antidiabetic property by inhibition of a-glucosidase and a-amylase enzymes in vitro. 2.45 Family: Saxifragaceae 2.45.1 Bergenia ciliate Haw. Bergenia ciliate Haw. is a perennial herb having rhizomes. Isolated compound from the plant inhibited rat intestinal glucosidase, when sucrose and maltose were used as substrate. ( )-3-O-Galloylepicatechin [44] inhibited sucrase, maltase, and a-amylase activity at 250 P.K. Mukherjee et al. IC50 values of 560, 334, and 739 mM, respectively, and ( )-3-O-galloylcatechin [45] inhibited at IC50 values of 297, 150, and 401 mM, respectively (Bhandaria et al., 2008). 2.45.2 Bergenia ligualata Wall. It is a perennial herb grown in North India commonly known as Pashanbheda in India. Ethanolic extract and ethyl acetate fraction of the rhizome showed inhibition of the enzyme using p-nitrophenyl-a-D-glucopyranoside as substrate, from which a compound (þ)-afzelechin [46] found to be responsible for the activity with IC50 of 0.13 mM was identified (Saijya et al., 2008). 2.46 Family: Scrophulariaceae 2.46.1 Picrorrhiza kurroa Royle ex Benth. It is a small herb which grows in the Himalayas at 3000–5000 m and is used extensively in the ayurvedic system of medicine. Alcoholic extract (75 mg kg 1 ) reduces serum glucose to the maximum extent. It reduced the enhanced glucose level in serum and blood urea nitrogen and serum lipid peroxides in alloxan-induced diabetic animals (Joy and Kuttan, 1999). 2.46.2 Scoparia dulcis L. It is commonly known as ‘Sweet Broomweed’ widely used in Indian folk medicine. Various extracts of the plant have been reported to increase the activities of insulin and to reduce the blood glucose level in STZ-diabetic rats. It binds to insulin receptor, which significantly increases plasma insulin level. 2.47 Family: Solanaceae 2.47.1 Solanum torvum Swartz Solanum torvum Swartz is a wild, herbaceous perennial plant. This plant is native to India but also distributed to South east Asia. Methyl caffeate isolated as rat intestinal sucrose and maltase inhibitor at IC50 of 1.5 and 2.0 mM, respectively (Takahashi et al., 2010). 2.48 Family: Sterculiaceae 2.48.1 Helicteres isora L. It is a well-known plant of the Indian subcontinent. The root extracts have showed (300 mg kg 1 , after 9 days of administration) plasma glucose-lowering activity in insulin-resistant and diabetic C57BL/KsJdb/db mice associated with a reduction in plasma triglyceride level. It acts through insulin-sensitizing activity (Chakrabarti et al., 2002). Indian Medicinal Plants with Hypoglycemic Potential 251 2.49 Family: Theaceae 2.49.1 Camellia sinensis Kuntze Camellia sinensis Kuntze is commonly known as tea. It is a small evergreen tree. The hot water extract is reported for antihyperglycemic activity in STZ-induced diabetes in rats. Epigallocatechin gallate, a constituent of tea which increases insulin activity and prevents oxidative damages, may contribute toward the hypoglycemic activity (Anderson and Polansky, 2002). 2.50 Family: Verbenaceae 2.50.1 Lantana camara L. It is a rugged evergreen shrub found throughout India. The leaf juice of this plant at a dose of 1500 mg kg 1 p.o. daily for 14 days produced significant hypoglycemic activity in rats (Garg et al., 1997). 2.51 Family: Zingiberceae 2.51.1 Curcuma longa L. Curcuma longa L. is a rhizomatous herbaceous perennial herb, which grows to a height of three to five feet and is cultivated extensively in Asia, India, China, and other countries with a tropical climate. Naturally occuring Curcumin [47], demethoxycurcumin [48], and bisdemethoxycurcumin [49] isolated from C. longa have been showed to inhibit the glucosidase enzyme. Among these naturally occuring compounds, bisdemethoxycurcumin is most potent and shows inhibition at a concentration twofold lower than that of acarbose with an IC50 value of 23 mM. Further, kinetic studies suggested that the mode of inhibition is noncompetitive. The enzyme inhibition activity was assayed using p-nitrophenyl-a-D-glucopyranoside as substrate (Du et al., 2006). 2.51.2 Hedychium spicatum Smith. It is a perennial small, hard ginger, commonly known as ginger lily and Kapoorkachari in India (Satyavati, 1987). Labdane-type triterpenoids, Spicatanol [50] and Spicatanol methyl ether [51], isolated from the rhizome of the plant have showed inhibition of intestinal a-glucosidase enzyme using p-nitrophenyl-a-D-glucopyranoside as substrate. Among the two isolated molecules, Spicatanol is more potent. 2.51.3 Kaempferia parviflora Wall. ex Baker It is a native plant of Southeast Asia. Ethyl acetate-soluble fraction of dichloromethane extract has showed inhibition of a-glucosidase enzyme. 5,7,30 ,40 -Tetramethoxyflavone [52] (IC50¼20.4 mM), 5,7,40 trimethoxyflavone [53] (IC50¼54.3 mM), and 3,5,7,30 ,40 - pentamethoxyflavone [54] (IC50¼64.3 mM) were found to be responsible for the activity (Azuma et al., 2011). 252 P.K. Mukherjee et al. 2.51.4 Zingiber officinale Roscoe It is commonly known as ginger and widely consumed as food stuff. The rhizome juice significantly prevented hyperglycemia and hypoinsulinemia in STZ-induced type I diabetic rats on administration at a dose of 4 ml kg 1 p.o. daily for 6 weeks. It is suggested that the hypoglycemic activity of the juice of Zingiber officinale in type I diabetic rats possibly involved 5-HT receptors (Akhani et al., 2004). 3. BIOACTIVE PHYTOCONSTITUENTS WITH ANTIDIABETIC POTENTIAL Several plant-derived active principles representing numerous chemical compounds like alkaloids, glycosides, polysaccharides, peptidoglycans, hypoglycans, steroids, carbohydrates, glycopeptides, terpenoids, amino acids, and inorganic ions showed prominent antidiabetic activity. A number of alkaloids isolated from several Indian medicinal plants have potent hypoglycemic activity, for example, berberine from Tinospora cordifolia, and catharanthine, vindoline, and vindolinine obtained from Catharanthus roseus. Imidazoline compounds like beta-carbolines, harmane, norharmane, and pinoline were found to increase insulin secretion two- to threefold from isolated human islets of Langerhans. Aloe vera and Ocimum sanctum are found to contain polysaccharides which increased the levels of serum insulin, reduced the blood glucose levels, and improved tolerance of glucose. Some flavonoids improved altered glucose and oxidative metabolisms of diabetic states, for example, quercetin, naringenin, chrysin, and genistein. Proanthocyanidins are found to improve the pathological oxidative state of a diabetic situation. Another flavonoid glycoside kaempferitrin (kaempferol-3, 7-O-(alpha)-L-dirhamnoside) was found to have an acute lowering effect on blood glucose in diabetic rats. Epigallocatechin gallate and ( )-epicatechin are reported to have glucose-lowering effects in animals. Increased amounts of fiber-rich low-glycemic index natural foods improve blood glucose levels and reduce the number of hypoglycemic events in diabetic patients. Consumption of dietary fiber like fenugreek significantly affects insulin binding and reduces plasma glucose concentration (Mukherjee et al, 2006). Triterpenoid and steroidal glycosides are potential classes of naturally occurring bioactive antidiabetic compounds found in several plants like charantin in Momordica charantia, lactucain-C, furofuran lignin in Lactuca indica, and many other isolated compounds are available which have been reported to possess significant hypoglycemic activity (Table 23.1). 4. CONCLUSION Many oral antidiabetic agents are available to treat this worldwide health problem and its associated complications but they have a number of serious adverse effects; thus, managing diabetes without any side effects is still a challenge. Therefore, the search for more effective and safer hypoglycemic agents from botanicals or natural resources has continued to be an important area of investigation. Medicinal plants offer a great opportunity for the discovery of new antidiabetic drugs from traditional and natural resources. Several bioactive components have been reported from natural resources as antidiabetic. These natural resources can be explored further for discovery and development of potentially useful new antidiabetic leads.
Structures of active chemicals
P.K. Mukherjee, N.K. Nema, S. Pandit, K. Mukherjee School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
1. INTRODUCTION Diabetes mellitus (DM) is described as ‘Madhumeha’ in Sanskrit in the ancient Indian literature dealing with the human healthcare systems. It is a metabolic disease caused by genetic or environmental factors. This chronic disease is supposed to occur when there is a deficient production of insulin from the pancreas (type-1 diabetes) or when the body does not respond to the produced insulin (type-2 diabetes). This results in raised uncontrolled blood glucose level. DM is also a maharoga (major disease) because it affects most part of the body and every cell of the human physiology. Pathophysiology of diabetes is described in Figure 23.1. The increased blood glucose level results in some classical symptoms such as polyurea (frequent urination), polyphagia (increased hunger), and polydipsia (increased thrust). These symptoms develop readily in type-1 diabetes but develop slowly in type-2 diabetes (Chen et al., 2010). DM has become a global problem in spite of advances in modern science which accounts for 5% deaths per year and this is supposed to increase by 50% in next 10 years as per who estimations. India has been projected byWHO as the country with the fastest growing population of diabetic patients and estimated that in between 1995 and 2025, diabetic patients will increase by 195%. Several classes of synthetic drugs are available for therapeutic treatment of the disease. The plant-derived products have been proved to be a good source for the treatment of diabetic complications, as these are used traditionally from thousands of years and are well described in ancient literature like Ayurveda (Mukherjee, 2002). Along with this the naturally occurring leads have shown good acceptability in the human system with the well-known fact that natural products have less side/toxic effects than synthetic molecules. The ethnobotanical information reports that out of an estimated 250000 higher plants, about 800 plants may possess antidiabetic potential (Grover et al., 2002). The plants of Indian origin have been well explored for their possible use in various diabetic complications using various experimental models and along with isolated leads (Mukherjee, 2001). Several Indian medicinal plants have pharmacologically established hypoglycemic potential. They have been investigated for their beneficial use in different types of diabetes and reported in numerous scientific journals (Mukherjee et al., 2006). The present work highlights 80 potential plants that are used as hypoglycemic, which have been proved for their efficacy and reported in journals. This will highlight the respective plants of individual families and their bioactive phytomolecules useful as hypoglycemic obtained from natural sources along with their inhibitory concentration and type of enzyme and substrate used. 2. PLANT FAMILIES WITH ANTIDIABETIC POTENTIAL 2.1 Family: Acanthaceae 2.1.1 Adhatoda vasica Nees Adhatoda vasica Nees is a small evergreen tree which grows in India prominently in the lower Himalayan region. This plant is an important part of the Ayurvedic system of medicine where it is mainly used to treat respiratory tract disorder viz. asthma, bronchitis, cough, etc. Methanolic extract of the leaves of the plant has shown inhibition of the rat intestinal a-glucosidase enzyme using sucrose as substrate. Bioactivity-guided isolation of vasicine [1] and vasicinol [2] have shown reversible inhibition of the enzyme with IC50 values of 125 and 250 mM, respectively (Hao et al., 2008). 2.1.2 Andrographis paniculata Nees Andrographis paniculata Nees, commonly known as Kalmegh or ‘King of Bitters’, is a herbaceous plant native to India and Sri Lanka having a wide spectrum of biological activities. Its extract and isolated compound have demonstrated hypoglycemic and antihyperglycemic activity along with antioxidant property in normal and streptozotocin (STZ)-induced diabetic rats. 2.1.3 Barleria lupulina Lindl. It is a popular folklore medicinal plant distributed in the mountains of southern and western India. The methanolic extract of the aerial parts of Barleria lupulina Lindl. (300 mg kg 1 ) have been found to possess significant hypoglycemic activity. 2.2 Family: Alliaceae 2.2.1 Allium sativum L. It is an essential dietary supplement known as garlic. The ethanol, petroleum ether, and ethyl acetate extract exerted antihyperglycemic activity in alloxanized rabbits at a dose of 0.25 mg kg 1 orally, and it has strong antioxidant activity and rapid reactivity with thiol-containing proteins, which is responsible for the hypoglycemic property. The S-allyl cysteine [4] sulfoxide significantly lowers blood glucose in experimental diabetic animals. Another constituent allicin [5] (thio-2-propene-1-sulfinic acid S-allyl ester) Indian Medicinal Plants with Hypoglycemic Potential 237 reported hypoglycemia in mildly diabetic rabbits upon oral administration (0.25 mg kg 1 ) (Sheela and Augusti, 1992). 2.3 Family: Aloaceae 2.3.1 Aloe vera (L.) Burm.f. Aloe vera is cultivated all over the world for its various medicinal properties. Mukherjee et al. (2006) included antidiabetic activity in their review article. In a study, the extract of aloe gum was found to be effective in enhancing glucose tolerance in normal and diabetic rats. It maintains glucose homeostasis by controlling the carbohydrate-metabolizing enzymes and stimulates pancreatic beta cells to release insulin. Aloin A [6], the bitter principle of aloe, is found to be hypoglycemic in alloxanized mice. 2.4 Family: Amaranthaceae 2.4.1 Aerva lanata (L.) Juss. ex Schult. Aerva lanata (L.) Juss. ex Schult. is a part of the Indian folk medicine system for the treatment of DM and it is commonly known as Sunny Khur. The alcoholic extract of A. lanata reduced the increase of blood glucose level in alloxanized rats by 42% at a dose of 375 mg kg 1 and 48% at 500 mg kg 1 body weight (Vetrichelvan and Jegadeesan, 2002). 2.5 Family: Anacardiaceae 2.5.1 Mangifera indica L. It is a well-known perennial tree commonly known as Mango, widely cultivated throughout in India. It is the national fruit of India (Mukherjee et al., 2006). The aqueous leaf extract (1 g kg 1 p.o.) showed hypoglycemic potential when given along with as well as 60 min before glucose administration in STZ-induced diabetic rats. It is found to act possibly through intestinal reduction of the absorption of glucose by inhibiting the a-glucosidase enzyme and as well as pancreatic and extrapancreatic mechanisms. Hypoglycemic activity of mangiferin [7] (10 and 20 mg kg 1 , i.p. once daily for 28 days) in STZ-induced diabetic rats and improvement in oral glucose tolerance in glucose-loaded normal rats upon chronic administration (10 and 20 mg kg 1 , i.p.) for 14 days have also been reported. 2.6 Family: Annonaceae 2.6.1 Annona squamosa L. Annona squamosa L. is a 10–20 ft long tree commonly known as sugar apple found in different parts of India. Ethanolic leaf extract (350 mg kg 1 , orally) shows hypoglycemic and antihyperglycemic activities in normal, STZ-diabetic rats and alloxanized rabbits. Quercetin-30 -O-glucoside [8] isolated from leaves of the plant has been reported to regulate alloxan-induced hyperglycemia and lipid peroxidation in rats (Gupta et al., 2005). 238 P.K. Mukherjee et al. 2.7 Family: Apocynaceae 2.7.1 Alstonia scholaris (L.) R. Br. It is commonly known as devil tree. It is an evergreen, tropical, small, and glabrous tree with perfumed flowers. Two isolated molecules from aqueous methanolic extract, quercetin 3-O-b-D-xylopyranosyl (1!2)-b-D-galactopyranoside [9] and ( )-lyoniresinol 3-O-b-D-glucopyranoside [10], were assayed for the inhibition of the rat intestinal a-glucosidase using sucrose and maltose as substrate. Among these two isolated molecules compound ( )-lyoniresinol 3-O-b-D-glucopyranoside is more potent and exhibited inhibitory activity against both substrates, sucrase IC50 1.95 mM and maltase IC50 1.43 mM, while the former compound exhibited only maltase inhibitory activity at an IC50 of 1.96 mM (Channa et al., 2005). 2.7.2 Catharanthus roseus (L.) G. Don. It is used as a folk remedy for treatment of diabetes in various parts of India. The hypoglycemic activity of dichloromethane: methanol extract of leaves and twigs was found in STZ-induced diabetic rats (500 mg kg 1 p.o., for 7 and 15 days). It increases metabolization of glucose and enhances secretion of insulin either from the beta cells of Langerhans or through extrapancreatic mechanism (Singh et al., 2001). 2.8 Family: Arecaceae 2.8.1 Areca catechu L. Areca catechu L. commonly known as betel nut is cultivated throughout India. Arecoline [11], a natural alkaloidal constituent of the nut, was investigated and reported to have hypoglycemic activity. 2.9 Family: Asclepiadaceae 2.9.1 Gymnema montanum Hook. f. It is an endemic plant species of India found mainly in Western Ghats. The ethanolic leaf extract showed competitive inhibition against yeast a-glucosidase and noncompetitive inhibition against salivary a-amylase in a concentration-dependent manner and the long-term administration (12 weeks) of the leaf extract effectively reduced the blood glucose level and also increased the insulin level. The blood glucose-lowering activity of alcoholic leaf extract (200 mg kg 1 orally) was studied in alloxan-induced diabetic rats along with an increase in plasma insulin level (Ananthan et al., 2004). 2.9.2 Gymnema Sylvestre R. Br. It is commonly known as the ‘sugar destroyer’ because the leaves effectively block sweet taste in the mouth when chewed. The plant has been used in the treatment of DM for a long time in India and reported by different workers for its blood glucose-lowering activity both in vitro and in vivo (Mukherjee et al., 2006). Indian Medicinal Plants with Hypoglycemic Potential 239 2.10 Family: Bombacaceae 2.10.1 Bombax ceiba L. Bombax ceiba L., commonly known as silk cotton tree, is distributed throughout India. Shamimin, a flavonol glucoside isolated from the leaves of the plant, has been reported to possess significant hypoglycemic activity at 500 mg kg 1 in rats. 2.11 Family: Brassicaceae 2.11.1 Brassica juncea (L.) Czern. The spice is used as foodstuff in India and it is a small herb cultivated throughout India. It has been reported to possess significant hypoglycemic activity in normal rats upon oral administration in diet (10%w/w) for 60 days. It increases the concentration of hepatic glycogen and glycogenesis and suppresses the activity of glycogen phosphorylase and gluconeogenic enzymes, leading to reduction in glycogenolysis and gluconeogenesis (Khan et al., 2002). 2.12 Family: Capparidaceae 2.12.1 Capparis decidua (Forsk.) Edgew. It is commonly known as ‘Kair,’ found in the western part of India. The powdered fruit of the plant showed significant hypoglycemic potential in alloxan-induced diabetic rats. Treatment of diabetic mice with alkaloid rich fraction for 28 days significantly inhibited the acute elevation of blood glucose level during oral glucose tolerance test (Sharma et al., 2010). 2.13 Family: Celastaceae 2.13.1 Salacia oblonga Wall. This is a woody plant found in the forests of Sri Lanka and India. The plant, root, and stems are an important part of Aryuveda and traditional Indian medicine for the treatment of diabetes. Serum glucose-lowering activity and a-glucosidase and aldose reductase inhibitory activities of hydroalcoholic extract of the roots were established in sucrose and maltose-loaded rats. 2.14 Family: Cesalpinaceae 2.14.1 Caesalpinia bonducella (L.) Roxb. Traditionally this plant is used to control blood sugar level. The aqueous and 50% ethanolic seed extracts showed hypoglycemic and antihyperglycemic activities in normal and STZ-diabetic rats and increase the release of insulin from pancreatic cells. 2.15 Family: Chenopodiaceae 2.15.1 Beta vulgaris L. It is commonly known as garden beet, which is used traditionally in the management of diabetes. The beta vulgarosides II [12] and IV [13] isolated from the root have been 240 P.K. Mukherjee et al. investigated for hypoglycemic activity in an oral glucose tolerance test and lowers the blood glucose level. The extract of the plant was also found to be effective in inhibiting nonenzymatic glycolization of skin proteins in STZ-induced diabetic rats (Tunali et al., 1998). 2.16 Family: Combretaceae 2.16.1 Terminalia catappa L. It is a large deciduous tropical tree from India. In a study by Nagappa et al. (2003) the petroleum ether, methanol, and aqueous extracts of the fruit were examined on fasting blood sugar levels and serum biochemical parameters in alloxan-induced diabetic rats and produced significant hypoglycemic activity. 2.16.2 Terminalia pallida Brandis It is an evergreen endemic tree found in various parts of India. The ethanolic extract of fruits exhibits significant antihyperglycemic activity in alloxan diabetic rats at a dose of 0.5 g kg 1 orally.
2.17 Family: Compositae 2.17.1 Artemisia pallens Wall. ex DC. It is a shrub used in the treatment of DM in the southern parts of India and commonly known as ‘Dhavanam.’ The methanolic extract (100 mg kg 1 , orally) of aerial parts of the plant exhibited antihyperglycemic activity in glucose-fed hyperglycemic and alloxaninduced diabetic rats. It is supposed to act by inhibiting glucose reabsorption or increasing peripheral glucose utilization (Subramoniam et al., 1996). 2.18 Family: Convolvulaceae 2.18.1 Ipomoea batatas (L.) Lam. It is an important food crop commonly known as Sweet Potato cultivated in many tropical and subtropical countries. The plant has showed hypoglycemic effect in diabetic Zucker fatty rats and inhibition of the increased blood glucose level in a glucose tolerance test in rats. It reduces insulin resistance and possibly acts by maltase inhibition. Onidin 3-O-[2-O-(6-O-E-feruloyl-beta-D-glucopyranosyl)-6-O-ecaffeoyl-betaD-glucopyranoside]-5-O-beta-D-glucopyranoside, a diacylated anthocyanin, isolated from storage roots reduced blood glucose level by 16.5% at 30 min in male 8-weekold Sprague–Dawley rats upon single oral administration (Matsui et al., 2002). 2.19 Family: Cucurbitaceae 2.19.1 Citrullus colocynthis (L.) Schrad. It is a vine plant commonly known as ‘Bitter apple,’ distributed and cultivated throughout India. The hypoglycemic activity of aqueous extract (300 mg kg 1 ), and glycosidic Indian Medicinal Plants with Hypoglycemic Potential 241 and saponin extract (50 mg kg 1 ) was evaluated orally in normal rabbits and exerted an insulinotropic effect. The aqueous seed extract showed blood glucose-lowering activity in normal and STZ-induced diabetic rats upon daily oral administration for 2 weeks (Nmila et al., 2000). 2.19.2 Momordica charantia L. It is commonly known as bitter melon or Karela, widely grown in tropical and subtropical regions for fruits which are the most bitter among all the fruits; it is commonly used as vegetable. The plant is well known for its antidiabetic potential with many scientific reports in past four to five decades. Charantin [14] is major constituent that has antidiabetic potential. D-(+)-trehalose, an active principle isolated from the seeds of M. charantia, showed alpha glucosidase inhibitory activity at concentration of 0.002 M (Matsuura et al., 2002). 2.19.3 Momordica cymbalaria Fenzl ex Naudin. It is commonly known as Karchikayee, well known for its medicinal properties in different parts of India. Fruit powder and aqueous fruit extract possess blood glucose level reducing activity in fasting alloxan-induced diabetic rats in a treatment for 15 days (Rao et al., 2001). It may act by increasing hepatic glycogen. 2.20 Family: Euphorbiaceae 2.20.1 Phyllanthus amarus Schumach. & Thonn. It is an annual globrous herb. Oral administration of the whole plant extract with a dose of 5 g per day for 10 days produced reduction in blood glucose in diabetic and nondiabetic subjects. The methanolic extract was found to reduce the blood sugar in alloxan diabetic rats at 4th hour by 6% at a dose of 200 mg kg 1 and 18.7% at a concentration of 1000 mg kg 1 and produced significant reduction in blood sugar upon continued administration for 15 days (Raphael et al., 2002). 2.21 Family: Fabaceae 2.21.1 Cajanus cajan (L.) Millsp. Perennial woody shrub grows throughout India and commonly known as Pigeon Pea. The roasted and unroasted seeds of this plant lower plasma glucose levels of normal and alloxan diabetic mice. The aqueous leaf extract has glucose-lowering activity in oral glucose tolerance test (Esposito Avella et al., 1991). 2.21.2 Derris scandens Benth. D. scandens Benth. is commonly known as Gonj. From the hexane and chloroform extract of the plant, three molecules, scandinone [15], scandenone [16], and scandenin 242 P.K. Mukherjee et al. A [17], were investigated for a-glucosidase inhibition against PNP-G as substrate at IC50 values of 34.74, 33.83, and 25.17 mg ml 1 , respectively (Rao et al., 2007). 2.21.3 Glycyrrhiza glabra L. Glycyrrhiza glabra L., commonly known as Licorice, is a flavorful perennial herb used for food and medicinal purposes for thousands of years. The hydrophobic flavonoids from this plant possess abdominal fat-lowering and hypoglycemic effects, possibly mediated through activation of peroxisome proliferator-activated receptor-gamma in obese diabetic KK-A (y) mice (Nakagawa et al., 2004). 2.21.4 Pterocarpus marsupium Roxb. It is commonly known as Vijaysar, found throughout India. Different parts of the plant (bark, latex, etc.) were investigated and reported to have hypoglycemic activity. ( )-Epicatechin [18] isolated from the bark and heartwood of the plant were identified to possess blood sugar-lowering activity (Sheehan et al., 1983). 2.21.5 Trigonella foenum graecum L. It is commonly known as fenugreek and is a well-known hypoglycemic agent used in traditional system of Indian medicines. Various extracts of different parts of this plant, fibers, proteins, and saponins isolated from the seeds, were investigated and found to possess significant hypoglycemic potential (Mukherjee et al., 2006). Trigonelline [19], the major alkaloid component, exerted a mild hypoglycemic effect (Vats et al., 2002). 2.22 Family: Flacourtiaceae 2.22.1 Casearia esculenta Roxb. It is a shrub which is well distributed throughout India. The plant extract produced an alleviative effect in liver and renal damage associated with STZ-induced diabetes in rats. The roots are also reported to have antihyperglycemic activity (300 mg kg 1 p.o. for 45 days) in normal and STZ-induced diabetic rats by decreasing the activities of glucose-6-phosphatase and fructose-1, 6-bishosphatase, and also increasing the activity of liver hexokinase (Prakasam et al., 2002). 2.23 Family: Gentiaceae 2.23.1 Enicostemma littorale Blume It is a perennial herb which grows throughout India. A clinical study involving 84 patients with type 2 diabetes showed that pills prepared from Enicostemma littorale Blume administered for 3 months reduced blood glucose as well as serum insulin levels and prevented the progression of complications in diabetic patients. It is found to enhance glucose-induced insulin release from isolated rat pancreatic islets, mediated through K (þ)-ATP channel-dependent pathway. Aqueous extract reduces glucose level and Indian Medicinal Plants with Hypoglycemic Potential 243 decreases the elevated cholesterol, triglyceride, and creatinine levels when administered daily (2 g kg 1 p.o.) for 6 weeks in neonatal non-insulin-dependent diabetes mellitus (NIDDM) rats (Maroo et al., 2002). 2.24 Family: Gentianaceae 2.24.1 Swertia chirayita (Roxb. ex Fleming) H. Karst. It is commonly known as Chiretta. The hypoglycemic and antihyperglycemic efficacy of the plant extract as well as the active constituent swerchirin (1,8-dihydroxy3,5-dimethoxyxanthone) [20], isolated from the hexane fraction of the plant, is found to exert potent hypoglycemic activity. The hexane fraction of ethanolic extract (250 mg kg 1 ) showed blood glucose-lowering activity in fed, glucose-loaded and tolbutamide-pretreated animals. It stimulates insulin release from islets of Langerhans by depleting aldehyde-fuchsin stained beta-granules and immunostained insulin. Insulinreleasing effect was established for hexane fraction of the plant (250 mg kg 1 body weight p.o. per day for 28 days) in albino rats along with a significant rise in liver glycogen (Chandrasekar et al., 1990). 2.25 Family: Hippocrateaceae 2.25.1 Salacia reticulate Wight Salacia reticulta is a woody climber of Sri Lankan and Indian region. The plant is reported to lower blood glucose in fasted animals with improved glucose tolerance in laboratory animals and also inhibits alpha-glucosidase activity (Yoshikawa et al., 1998). Salacinol [21], Kotalanol [22], and de-O-sulfonated kotalanol [23] inhibited N-terminal catalytic domain of maltase-glucoamylase (ntMGAM). Among these compounds, de-Osulfonated Kotalanol is most potent with Ki¼0.03 mM (Sim et al., 2010). 2.26 Family: Lamiaceae 2.26.1 Ocimum sanctum L. It is commonly known as ‘Holy Basil’ distributed throughout India. It is thought that the plant exhibits hypoglycemic effect mediated by its cortisol-inhibiting potency and the plant may be used effectively in regulating corticosteroid-induced DM. The 70% ethanolic leaf extracts showed hypoglycemic activity in normal, glucose-fed, and STZ diabetic rats orally, and potentiated the action of exogenous insulin in normal rats. Plasma glucose-lowering activity of plant extract (200 mg kg 1 for 30 days) in STZ-induced diabetic animals revealed the effect of the extract on three important enzymes of carbohydrate metabolism, namely glucokinase, hexokinase, and phosphofructokinase (Vats et al., 2002). 244 P.K. Mukherjee et al. 2.26.2 Salvia moorcraftiana Wall. It grows in temperate Himalayas from Kashmir to Kumann. Two molecules have been isolated from the acetone extract of the aerial parts of the plant, which showed inhibition of the glucosidase type VI against p-nitrophenyl a-D-glucopyranoside as substrate. The two isolated molecules, 5-hydroxy-7, 40 -dimethoxyflavone [24], and oleanolic acid [25], inhibited enzyme at 4.38 and 5.64 mM concentration (Khan et al., 2002). 2.27 Family: Leguminosae 2.27.1 Cassia auriculata L. The evergreen Indian shrub commonly known as Tanner’s Cassia has hypoglycemic potential. The flowers of the plant have been reported to be the most potent in controlling blood glucose level. Researchers have established antihyperglycemic and antihyperlipidemic activity of aqueous flower extract in STZ-induced diabetic rats upon oral administration at different doses for 30 days (Latha and Pari, 2003). It regulates gluconeogenesis during diabetes and enhances utilization of glucose through increased glycolysis and also inhibits alpha-glucosidase resulting in a significant reduction of blood glucose levels. 2.27.2 Pterocarpus santalinus L. f. The traditionally used plant grows throughout India. Along with diabetes the plant is used traditionally for treating bleeding piles, dysentery, and all skin inflammations. The bark extracts of Pterocarpus santalinus L. (0.25 g kg 1 body weight) showed maximum antihyperglycemic activity (Kameswara et al., 2001). 2.27.3 Mucuna pruriens (L.) DC. The powdered seeds (0.5, 1, and 2 g kg 1 ) lowered blood glucose in normal and alloxaninduced diabetic rabbits. It acts probably by stimulating the release of insulin and/or by a direct insulin-like action due to the presence of trace elements like manganese, zinc, etc. The long-term use (40 days) of plant extract (200 mg kg 1 ) lowered blood glucose upon daily oral feeding in STZ-induced diabetic mice. Antihyperglycemic effect of alcoholic extract of the plant (100, 200, and 400 mg kg 1 per day) is also reported in alloxanized rats (Rathi et al., 2002). 2.28 Family: Liliaceae 2.28.1 Allium cepa L. Allium cepa L., commonly known as Onion, is an essential part of diet. A study with the seedling parts and callus cultures suggested that it exhibited much higher hypoglycemic activity as compared to natural bulbs of onion and the same can be used as an alternative source for the isolation of hypoglycemic compounds. Presence of a sulfur containing amino acid, S-methyl cysteine sulfoxide, has showed potent hypoglycemic activity when administered at a dose of 200 mg kg 1 for 45 days to alloxan-induced diabetic rats Indian Medicinal Plants with Hypoglycemic Potential 245 (Kumari et al., 1995). Another compound S-allyl cysteine sulfoxide was also found to be effective in reducing the blood glucose level of alloxan-induced diabetic rats. 2.29 Family: Malvaceae 2.29.1 Hibiscus rosa sinensis L. These large shrubs or small trees have potent blood glucose-lowering activity. Hypoglycemic activity was found in alcoholic leaf extract (250 mg kg 1 p.o. for seven consecutive days) against glucose-induced hyperglycemia model in rats and suggested that this is because of increased utilization of glucose, either by direct stimulation of glucose uptake or via the mediation of enhanced insulin secretion (Sachdewa et al., 2001). 2.29.2 Sida cordifolia L. It is a perennial shrub. The methanol extract of the root of this plant has been reported to possess significant hypoglycemic activity (Kanth and Diwan, 1999). 2.30 Family: Menispermaceae 2.30.1 Tinospora cordifolia (Willd.) Hook. f. & Thomson It is commonly known as ‘Guduchi’ found throughout India. The hypoglycemic activities of various extracts of the leaves have been investigated in normal and alloxanized rabbits for potent blood sugar-lowering activity. The antihyperglycemic activity of major alkaloid berberine [26] is due to its ability to inhibit alpha-glucosidase and decrease glucose transport through the intestinal epithelium (Pan et al., 2003). 2.31 Family: Melastomataceae 2.31.1 Memecylon umbellatum Burm. f. It is a small tree which grows in the Deccan coastal region. The oral administration of alcoholic extract of the leaves (250 mg kg 1 ) significantly lowered serum glucose level in normal and alloxan-induced diabetic mice. 2.32 Family: Meliaceae 2.32.1 Azadirachta indica A. Juss. Azadirachta indica A. Juss., commonly referred to as the Neem tree, is found throughout India and is widely recognized for its potential as insecticide. Hydroalcoholic plant extracts exerted hypoglycemic activity in normal and STZ-induced diabetic rats. b-Sitosterol, a steroid, may be responsible for its hypoglycemic property. It is due to the inhibition action of epinephrine on glucose metabolism, resulting in increased utilization of peripheral glucose and altering the serum cortisol concentration level (Chattopadhyay, 1999). 246 P.K. Mukherjee et al. 2.33 Family: Mimosaceae 2.33.1 Acacia arabica (Lam.) Muhl. ex Willd. Acacia arabica (Lam.) Muhl. ex Willd. is found throughout the drier parts of India and is commonly known as Babool. The powdered seeds have shown hypoglycemic effect in normal rabbits (2, 3, and 4 mg kg 1 ) when it is administered orally. The account for its hypoglycemic potential is probably through the release of insulin from pancreatic beta cells (Wadood et al., 1989). 2.34 Family: Moraceae 2.34.1 Ficus bengalensis L. It is widely distributed throughout India. Various active components isolated from the plant including the dimethoxy derivative of leucocyandin 3-O-beta-D-galactosyl cellobioside, dimethoxy derivative of perlargonidin 3-O-alpha-l rhamnoside, glycoside of leucopelargonidin, leucodelphinidin, isolated from the bark of this plant, have been reported for their hypoglycemic activity (Mukherjee et al., 2006). Kumar and Augusti (1989) proposed that blood sugar-lowering activity of a dimethoxy derivative of leucocyandin 3-O-beta-D-galactosyl cellobioside isolated from the bark is due to increase of serum insulin in normal and moderately diabetic rats at a dosage of 250 mg kg 1 for a 2 h period upon oral administration. 2.34.2 Morus alba L. It is commonly known as ‘Mulberry’ extensively grown in India for its leaves as food for silkworms. Chronic subcutaneous administration of leaf extract has showed degranulation effect on the beta cells of islets of langerhans of rabbits. Chen et al. (1995) established hypoglycemic activity of hot water extract of leaves in fasted and nonfasted STZ-induced diabetic mice at a dose of 200 mg kg 1 , i.p. It is found to act by increasing glucose uptake. 2.35 Family: Musaceae 2.35.1 Musa sapientum L. It is a potential fruit, commonly known as ‘Banana’ used extensively as food stuff. It is a good folklore medicine for the treatment of diabetes. Flower extracts (0.15, 0.20, and 0.25 g kg 1 p.o. for 30 days) have showed blood glucose-lowering activity in experimental animals (Pari and Maheswari, 1999). 2.36 Family: Myrtaceae 2.36.1 Eucalyptus globulus Labill. It is an ornamental tree which grows in subtropical parts of India. Aqueous extract of eucalyptus (0.5 g l 1 ) enhanced 2-deoxy-glucose transport by 50%, glucose oxidation by 60%, and increases the incorporation of glucose into glycogen by 90% in mouse Indian Medicinal Plants with Hypoglycemic Potential 247 abdominal muscle. It also enhanced insulin secretion from the clonal pancreatic beta-cell line which contributes for its antihyperglycemic activity (Gray and Flatt, 1998). 2.36.2 Eugenia jambolana Lam. It is a large evergreen tree of Indian subcontinent, also known as Syzygium cumini L. commonly known as ‘Jamun’ in India. The decoction of kernels of Eugenia jambolana is used as a household remedy for diabetes. The seeds and decoction of dry leaves were found to produce hypoglycemic effect. The protective effect of the alcoholic (100 mg kg 1 ) and the aqueous (5 g kg 1 ) extracts of the seed of this plant against tissue damage in diabetic rat brain was studied, and it was observed that both the extracts effectively protected the tissues, the alcoholic extract having more pronounced effect than the water extract (Prince et al., 2004). 2.36.3 Eugenia uniflora L. It is a small tree or shrub commonly known as Surinam Cherry or Brazilian Cherry. Seventy percent ethanol leaf extracts were evaluated and found to inhibit plasma glucose level. The antidiabetic activity of the extract may be due to the inhibition of the decomposition of carbohydrates and fats in the intestine (Arai et al., 1999). 2.36.4 Psidium guajava L. It is an evergreen shrub or small tree commonly known as guava. Bioactivity-guided fractionation of the 75% ethanol extract from guava leaves showed high inhibition of a-glucosidase and a-amylase. Quercetin [27], kaempferol [28], and myricetin [29] showed inhibition of a-glucosidase at IC50 values of 3.5, 5.2, and 3.0 mM against sucrose and with IC50 values of 4.8, 5.6, and 4.1 mM against maltase as substrate, respectively. These compounds also showed inhibition of a-amylase at IC50 values of 4.8, 5.3, and 4.3 mM, respectively. Among these myricetin is most potent for the activity (Wanga et al., 2010). 2.36.5 Syzygium alternifolium Walp. It is an endemic aromatic tree. Locally it is known as mogi/movi. The aqueous, ethanolic, and hexane extracts of the seeds of this plant were evaluated in normal and alloxan diabetic rats and the extracts showed significant hypoglycemic and antihyperglycemic activity. The aqueous extract was most potent among all the tested fractions (Rao and Rao, 2001). 2.37 Family: Nyctaginaceae 2.37.1 Boerhavia diffusa L. It is a commonly known as ‘Punarnava’ which means rejuvenates or renews the body. The aqueous leaf extract of Boerhaavia diffusa L. was showed to produce significant 248 P.K. Mukherjee et al. hypoglycemic activity at doses of 100, 200, and 400 mg kg 1 in alloxan-induced diabetic rats (Chude et al., 2001). It increases the plasma insulin levels and improves glucose tolerance. 2.38 Family: Nymphaeaceae 2.38.1 Nelumbo nucifera Gaertn. It is an aquatic perennial herb commonly known as sacred lotus, found throughout India. The ethanolic extract of rhizome of the plant on oral administration markedly reduced the blood sugar level of normal, glucose-fed hyperglycemic, and STZ-induced diabetic rats. The extract also improved the glucose tolerance and potentiated the action of exogenously injected insulin in normal rats (Mukherjee et al., 1995, 2006). 2.38.2 Nymphaea stellata Willd. It is commonly known as water lily or blue lotus. 1,2,3,4,6-penta-O-galloyl-b-D-glucose [30] isolated from flower extract showed inhibition of rat intestinal a-glucosidase enzyme using maltose as substrate at an ED50 of 0.1 mg ml 1 (Huang et al, 2010). 2.39 Family: Oxalidaceae 2.39.1 Biophytum sensitivum (L.) DC. It is a small flowering annual herb found throughout tropical India and commonly known as ‘Mukkutti.’ The leaf extract showed hypoglycemic activity in alloxan diabetic male rabbits. It stimulates pancreatic beta cells to release insulin (Puri and Baral, 1998). 2.40 Family: Piperaceae 2.40.1 Piper longum L. Piper longum L., commonly known as Pippali, is used as a spice and preservative in food stuff. Yeast a-glucosidase-I enzyme inhibited IC50 of 32.10, 34.39, 36.39, 34.09, and 19.26, by isolated compounds pipataline [31], pellitorine [32], sesamine [33], brachystamide B [34], and guineensine [35] respectively, from methanolic extract of the fruits against p-nitrophenyl-a-D-glucopyranoside as substrate (Pullela et al., 2006). 2.41 Family: Polygonaceae 2.41.1 Rheum emodi Wall It is commonly known as Himalayan rhubarb. Methanolic extract of the rhizome inhibited yeast a-glucosidase and mammalian a-glucosidase enzyme with p-nitrophenyl-aD-glucopyranoside as substrate. Yeast a-glucosidase inhibitors such as rhapontigenin [36], desoxyrhapontigenin [37], chrysophanol-8-O-b-D-glucopyranoside [38], torachrysone-8-O-b-D-glucopyranoside [39], and mammalian a-glucosidase inhibitors such as chrysophanol-8-O-b-D-glucopyranoside, desoxyrhaponticin [40], and torachrysone8-O-b-D-glucopyranoside have been isolated from the methanolic extract. Indian Medicinal Plants with Hypoglycemic Potential 249 2.42 Family: Punicaceae 2.42.1 Punica granatum L. It is a fruit-bearing deciduous shrub commonly known as pomegranate. The fruit juice has been reported to possess significant antihyperlipidemic activity in type II diabetic patients. The extract improves postprandial hyperglycemia in type II diabetes by inhibiting intestinal alpha-glucosidase. The methanolic seed extract showed hypoglycemic activity (150, 300, and 600 mg kg 1 p.o.) in strepotozotocin diabetic rats (Das et al., 2001). 2.43 Family: Rhamnaceae 2.43.1 Zizyphus sativa Gaertn. It is a small spreading tree with drooping branches. An alcoholic extract of the leaves showed dose-dependent reduction in blood glucose level but failed to produce significant hypoglycemic activity in alloxan diabetic rats (Mukherjee et al., 2006). 2.44 Family: Rutaceae 2.44.1 Aegle marmelos (L.) Correa ex Roxb. A moderate-sized tree found throughout the deciduous forests of India. Different extracts obtained from the leaves, bark, and fruit of this plant have been investigated for possible hypoglycemic activity in various experimental animal models of diabetes like STZ- and alloxan-induced diabetes along with possible mechanism of action (Mukherjee et al., 2006). Aegelin [41] is major compound responsible for the hypoglycemic activity. 2.44.2 Murraya koeingii (L.) Spreng. It is commonly known as curry-leaf tree and is a native of India and Sri Lanka. Fasting as well as postprandial blood sugar-lowering effect has been reported for leaf-powder in type II diabetic patients upon administration for a period of 1 month. It increases glycogenesis and decreases glycogenolysis and gluconeogenesis. The leaves lower the blood sugar in normal rats when administered as a diet (10%, v/v) for 60 days (Khan et al., 1995). Mahanine [42] and Mahanimbine [43], carbazole alkaloids isolated from leaves, showed hypolipidemic, antidiabetic property by inhibition of a-glucosidase and a-amylase enzymes in vitro. 2.45 Family: Saxifragaceae 2.45.1 Bergenia ciliate Haw. Bergenia ciliate Haw. is a perennial herb having rhizomes. Isolated compound from the plant inhibited rat intestinal glucosidase, when sucrose and maltose were used as substrate. ( )-3-O-Galloylepicatechin [44] inhibited sucrase, maltase, and a-amylase activity at 250 P.K. Mukherjee et al. IC50 values of 560, 334, and 739 mM, respectively, and ( )-3-O-galloylcatechin [45] inhibited at IC50 values of 297, 150, and 401 mM, respectively (Bhandaria et al., 2008). 2.45.2 Bergenia ligualata Wall. It is a perennial herb grown in North India commonly known as Pashanbheda in India. Ethanolic extract and ethyl acetate fraction of the rhizome showed inhibition of the enzyme using p-nitrophenyl-a-D-glucopyranoside as substrate, from which a compound (þ)-afzelechin [46] found to be responsible for the activity with IC50 of 0.13 mM was identified (Saijya et al., 2008). 2.46 Family: Scrophulariaceae 2.46.1 Picrorrhiza kurroa Royle ex Benth. It is a small herb which grows in the Himalayas at 3000–5000 m and is used extensively in the ayurvedic system of medicine. Alcoholic extract (75 mg kg 1 ) reduces serum glucose to the maximum extent. It reduced the enhanced glucose level in serum and blood urea nitrogen and serum lipid peroxides in alloxan-induced diabetic animals (Joy and Kuttan, 1999). 2.46.2 Scoparia dulcis L. It is commonly known as ‘Sweet Broomweed’ widely used in Indian folk medicine. Various extracts of the plant have been reported to increase the activities of insulin and to reduce the blood glucose level in STZ-diabetic rats. It binds to insulin receptor, which significantly increases plasma insulin level. 2.47 Family: Solanaceae 2.47.1 Solanum torvum Swartz Solanum torvum Swartz is a wild, herbaceous perennial plant. This plant is native to India but also distributed to South east Asia. Methyl caffeate isolated as rat intestinal sucrose and maltase inhibitor at IC50 of 1.5 and 2.0 mM, respectively (Takahashi et al., 2010). 2.48 Family: Sterculiaceae 2.48.1 Helicteres isora L. It is a well-known plant of the Indian subcontinent. The root extracts have showed (300 mg kg 1 , after 9 days of administration) plasma glucose-lowering activity in insulin-resistant and diabetic C57BL/KsJdb/db mice associated with a reduction in plasma triglyceride level. It acts through insulin-sensitizing activity (Chakrabarti et al., 2002). Indian Medicinal Plants with Hypoglycemic Potential 251 2.49 Family: Theaceae 2.49.1 Camellia sinensis Kuntze Camellia sinensis Kuntze is commonly known as tea. It is a small evergreen tree. The hot water extract is reported for antihyperglycemic activity in STZ-induced diabetes in rats. Epigallocatechin gallate, a constituent of tea which increases insulin activity and prevents oxidative damages, may contribute toward the hypoglycemic activity (Anderson and Polansky, 2002). 2.50 Family: Verbenaceae 2.50.1 Lantana camara L. It is a rugged evergreen shrub found throughout India. The leaf juice of this plant at a dose of 1500 mg kg 1 p.o. daily for 14 days produced significant hypoglycemic activity in rats (Garg et al., 1997). 2.51 Family: Zingiberceae 2.51.1 Curcuma longa L. Curcuma longa L. is a rhizomatous herbaceous perennial herb, which grows to a height of three to five feet and is cultivated extensively in Asia, India, China, and other countries with a tropical climate. Naturally occuring Curcumin [47], demethoxycurcumin [48], and bisdemethoxycurcumin [49] isolated from C. longa have been showed to inhibit the glucosidase enzyme. Among these naturally occuring compounds, bisdemethoxycurcumin is most potent and shows inhibition at a concentration twofold lower than that of acarbose with an IC50 value of 23 mM. Further, kinetic studies suggested that the mode of inhibition is noncompetitive. The enzyme inhibition activity was assayed using p-nitrophenyl-a-D-glucopyranoside as substrate (Du et al., 2006). 2.51.2 Hedychium spicatum Smith. It is a perennial small, hard ginger, commonly known as ginger lily and Kapoorkachari in India (Satyavati, 1987). Labdane-type triterpenoids, Spicatanol [50] and Spicatanol methyl ether [51], isolated from the rhizome of the plant have showed inhibition of intestinal a-glucosidase enzyme using p-nitrophenyl-a-D-glucopyranoside as substrate. Among the two isolated molecules, Spicatanol is more potent. 2.51.3 Kaempferia parviflora Wall. ex Baker It is a native plant of Southeast Asia. Ethyl acetate-soluble fraction of dichloromethane extract has showed inhibition of a-glucosidase enzyme. 5,7,30 ,40 -Tetramethoxyflavone [52] (IC50¼20.4 mM), 5,7,40 trimethoxyflavone [53] (IC50¼54.3 mM), and 3,5,7,30 ,40 - pentamethoxyflavone [54] (IC50¼64.3 mM) were found to be responsible for the activity (Azuma et al., 2011). 252 P.K. Mukherjee et al. 2.51.4 Zingiber officinale Roscoe It is commonly known as ginger and widely consumed as food stuff. The rhizome juice significantly prevented hyperglycemia and hypoinsulinemia in STZ-induced type I diabetic rats on administration at a dose of 4 ml kg 1 p.o. daily for 6 weeks. It is suggested that the hypoglycemic activity of the juice of Zingiber officinale in type I diabetic rats possibly involved 5-HT receptors (Akhani et al., 2004). 3. BIOACTIVE PHYTOCONSTITUENTS WITH ANTIDIABETIC POTENTIAL Several plant-derived active principles representing numerous chemical compounds like alkaloids, glycosides, polysaccharides, peptidoglycans, hypoglycans, steroids, carbohydrates, glycopeptides, terpenoids, amino acids, and inorganic ions showed prominent antidiabetic activity. A number of alkaloids isolated from several Indian medicinal plants have potent hypoglycemic activity, for example, berberine from Tinospora cordifolia, and catharanthine, vindoline, and vindolinine obtained from Catharanthus roseus. Imidazoline compounds like beta-carbolines, harmane, norharmane, and pinoline were found to increase insulin secretion two- to threefold from isolated human islets of Langerhans. Aloe vera and Ocimum sanctum are found to contain polysaccharides which increased the levels of serum insulin, reduced the blood glucose levels, and improved tolerance of glucose. Some flavonoids improved altered glucose and oxidative metabolisms of diabetic states, for example, quercetin, naringenin, chrysin, and genistein. Proanthocyanidins are found to improve the pathological oxidative state of a diabetic situation. Another flavonoid glycoside kaempferitrin (kaempferol-3, 7-O-(alpha)-L-dirhamnoside) was found to have an acute lowering effect on blood glucose in diabetic rats. Epigallocatechin gallate and ( )-epicatechin are reported to have glucose-lowering effects in animals. Increased amounts of fiber-rich low-glycemic index natural foods improve blood glucose levels and reduce the number of hypoglycemic events in diabetic patients. Consumption of dietary fiber like fenugreek significantly affects insulin binding and reduces plasma glucose concentration (Mukherjee et al, 2006). Triterpenoid and steroidal glycosides are potential classes of naturally occurring bioactive antidiabetic compounds found in several plants like charantin in Momordica charantia, lactucain-C, furofuran lignin in Lactuca indica, and many other isolated compounds are available which have been reported to possess significant hypoglycemic activity (Table 23.1). 4. CONCLUSION Many oral antidiabetic agents are available to treat this worldwide health problem and its associated complications but they have a number of serious adverse effects; thus, managing diabetes without any side effects is still a challenge. Therefore, the search for more effective and safer hypoglycemic agents from botanicals or natural resources has continued to be an important area of investigation. Medicinal plants offer a great opportunity for the discovery of new antidiabetic drugs from traditional and natural resources. Several bioactive components have been reported from natural resources as antidiabetic. These natural resources can be explored further for discovery and development of potentially useful new antidiabetic leads.
Structures of active chemicals
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