Asian Pacific Journal of Tropical Biomedicine (2012)320-330 320

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Document heading An overview on antidiabetic medicinal having insulin mimetic property Patel DK, Prasad SK, Kumar R, Hemalatha S* Pharmacognosy Research Laboratory, Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi-221005, India

ARTICLE INFO ABSTRACT

Article history: ’ Diabetes mellitus is one of the common metabolic disorders acquiring around 2.8% of the world s R 17 O 2011 eceived ctober population and is anticipated to cross 5.4% by the year 2025. Since long back herbal medicines 5 2011 Received in revised form November have been the highly esteemed source of medicine therefore, they have become a growing part of A 25 N 2011 ccepted ovember modern, high-tech medicine. In view of the above aspects the present review provides profiles of A 28 A 2012 vailable online pril plants (65 species) with hypoglycaemic properties, available through literature source from various database with proper categorization according to the parts used, mode of reduction in blood Keywords: glucose (insulinomimetic or insulin secretagogues activity) and active phytoconstituents having Diabetes insulin mimetics activity. From the review it was suggested that, showing hypoglycemic Insulin secretagogues potential mainly belongs to the family Leguminoseae, Lamiaceae, Liliaceae, AlliumCucurbitaceae, sativum, Insulin mimetics GymnemaAsteraceae, sylvestre, Moraceae, Citrullus Rosaceae colocynthis, and Araliaceae. Trigonella The foenum most active greacum, plants Momordica are charantia Phytoconstituents Ficus bengalensis Pancrease and . The review describes some new bioactive drugs and isolated compounds 1 Blood glucose from plants such as roseoside, epigallocatechin gallate, beta-pyrazol- -ylalanine, cinchonain 3 3 Insulin Ib, leucocyandin -O-beta-d-galactosyl cellobioside, leucopelargonidin- - O-alpha-L Beta cell rhamnoside, glycyrrhetinic acid, dehydrotrametenolic acid, strictinin, isostrictinin, pedunculagin, Antidiabetic activity epicatechin and christinin-A showing significant insulinomimetic and antidiabetic activity Medicinal plant with more efficacy than conventional hypoglycaemic agents. Thus, from the review majorly, the Metabolic disorder antidiabetic activity of is attributed to the presence of polyphenols, flavonoids, Herbal medicine terpenoids, coumarins and other constituents which show reduction in blood glucose levels. The Diabetes mellitus review also discusses the management aspect of diabetes mellitus using these plants and their Hypoglycaemic activity active principles.

1. Introduction have high blood glucose level[3]. Type 2 diabetes or non- insulin-dependent diabetes mellitus, is the most common Diabetes mellitus, one of the most common endocrine form of the disease, accounting for 90%-95% of cases in metabolic disorders has caused significant morbidity and which the body does not produce enough insulin or properly mortality due to microvascular (retinopathy, neuropathy, use it[4]. According to World Health Organization the and nephropathy) and macrovascular (heart attack, stroke diabetic population is likely to increase up to 300 million and peripheral vascular disease) complications[1]. Human or more by the year 2025[5]. Currently available therapies bodies possess enzymatic and non-enzymatic antioxidative for diabetes include insulin and various oral antidiabetic mechanisms which minimize the generation of reactive agents such as sulfonylureas, biguanides and glinides. Many oxygen species, responsible for many degenerative diseases of them have a number of serious adverse effects; therefore, including diabetes[2]. The disease is rapidly increasing the search for more effective and safer hypoglycemic agents worldwide and affecting all parts of the world. Due to is one of the important areas of investigation[6]. Aldose deficiency of the insulin people suffering from diabetes reductases, a key enzyme in the polyol pathway catalyze the reduction of glucose to sorbitol. Accumulation of *Corresponding author: Hemalatha S, Pharmacognosy Research Laboratory, Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, sorbitol in the body causes various complications including [7] Varanasi-221005, India. cataract, neuropathy and nephropathy . The hypoglycemic Tel: +91 9415256481 effect of several plants used as antidiabetic remedies has E-mail: [email protected] Foundation Project: This work was financially supported by University Grants been confirmed, and the mechanisms of hypoglycemic Commission, New Delhi. activity of these plants are being studied. Natural products Patel DK et al./Asian Pacific Journal of Tropical Biomedicine (2012)320-330 321 having antidiabetic potential which acts through either about the experimental studies performed on hypoglycaemic insulinomimetic or secretagogues properties are reviewed activity of the plant material and the bioactive components here. This review also focuses on the role of traditional related to the seceration of insulin or its action. Here all therapeutic and natural medicines from traditional the plant materials which are listed were tested for their medicinal plants for diabetes. Traditional medicines from insulinomimeticin vivo in vitro or secretogogues activity in the different readily available medicinal plants offer great potential for or model systems and represented according the discovery of new antidiabetic drugs[8]. to alphabetical order. Moreover, phytoconstituents isolated Recently, some medicinal plants have been reported from different plants which have shown insulinomimetic to be useful in diabetes worldwide and have been used activty are also represented in the Table 3. empirically in antidiabetic and antihyperlipidemic remedies. 3.1. Acacia arabica (Leguminosae) Antihyperglycemic activity of the plants is mainly due to their ability to restore the function of pancreatic tissues by Acacia arabica causing an increase in insulin output or inhibit the intestinal About 94% seed diet of showed hypoglycemic absorption of glucose or to the facilitation of metabolites in effect in ratsAcacia through arabica release of insulin. However, powdered insulin dependent processes. More than 400 plant species seeds of at 2, 3 and 4 g/kg, p.o. exerted a having hypoglycemic activity have been available in significant hypoglycemic effect in normal rabbits by literature, however, searching for new antidiabetic drugs initiating the release of insulin from pancreatic beta cells[12]. from natural plants is still attractive because they contain 3.2. Aegle marmelos (Rutaceae) substances which demonstrate alternative and safe effects on diabetes mellitus. Most of plants contain etc. glycosides, Aegle marmelos , terpenoids, flavonoids, carotenoids, , that are Aqueous leaf extract of showed frequently implicated as having antidiabetic effect[9]. antihyperglycemic activity in streptozotocin induced diabetic rats after 14 days treatment either by increasing 2. Medicinal plants used to treat diabetes utilization of glucose or by direct stimulation of glucose uptake through increased insulin secretion[13]. 3.3. Agrimony eupatoria (Rosaceae) Plants have always been a very good source of drugs and many of the currently available drugs have been derived Agrimony eupatoria directly or indirectly from them. The ethnobotanical Aqueous extract of evoked stimulation 800 11 information suggests that about plants mayMomordica possess of insulinin vitro secretion from the BRIN-BD pancreatic beta cell anti-diabetic potential, among all of them line . The effect of extract was found to be glucose- charantia Pterocarpus marsupium Trigonella foenum [11] greacum , , and independent . have been reported to be beneficial for treatment 3.4. Alangium salvifolium (Alangiaceae) of type 2 diabetes[3,8]. Several such herbs have shown anti- diabetic activity when evaluated using different type of Alangium salvifolium experimental techniques. Wide arrays of plant derived active Methanolic extract of leaves principles representing different type of biological activity, possesses antihyperglycemic and antihyperlipidemic effects among these alkaloids, glycosides, galactomannan gun, in dexamethasone induced insulin resistance in rats, which polysaccharides, peptidoglycans, hypoglycans, guanidine, may be due to the antioxidant and insulinotropic effect of steroids, carbohydrates, glycopeptides, terpenoids, amino extract[14]. acids and inorganic ions have demonstrated activity 3.5. Allium sativum (Alliaceae) including treatment of diabetes[10]. List of the medicinal plants having antidiabetic potential acording to the different part used and mode of action were presented in Table 1 and Antihyperglycemic activity of ethyl ether extract at 2 0 25 Table . . mg/kg, p.o. wasAllium reported sativum to be the most potent and active principle of (garlic) which was due [13] 3. Pharmacologically screened insulinomimetic or insulin to increased insulin like activity . OralAllium administration sativum secretagogues plant material and phytoconstituents of the ethanol extract, juice and oil of has remarkably blood sugar lowering effect in normal and alloxan-induced diabetic rats or a rabbit mediated The aim of this review is to collect the data available through stimulation of insulin secretion from parital cells on plants material having hypoglycaemic activity through of pancreas[15]. Allicin, a sulfur-containing compound either increased secretion of the insuline from pancrease showed to have significant hypoglycemic activity due to or similar action to the insulin reported in different source increased hepatic metabolism, increased insulin release ( ) of literature. According to the search several plants Opuntia species from pancreatic beta cells. S-allyl cystein sulfoxide inSACS vitro, havestreptacantha, been described Trigonella as hypoglycaemic foenum graecum, such Momordicaa the precursor of allicin and garlic oil, stimulated charantia, Ficus bengalensis, Polygala senega, Gymnema insulin secretion from beta cells isolated from normal rats. The beneficial effects of SACS could be due to its antioxidant sylvestre, Allium sativum, Citrullus colocynthis Aloe [11,16] vera and and secretagogues activity . Daily oral feeding of garlic [11]. The main focus of the present review is concerned extracts at 100 mg/kg increased plasma insulin level with Patel DK et al./Asian Pacific Journal of Tropical Biomedicine (2012)320-330 322 Table 1 List of plants having antidiabetic activity[53]. S. No. Plant part Name of plants Artemisia pallens, Bidens pilosa, Bixa orellana, Teramnus labialis 1 Aerial parts Cinnamomum zeylanicum, Croton cajucara 2 Bark Allium cepa, Allium sativum 3 Bulb Cassia auriculata, Gentiana olivier, Musa sapientum 4 Flower Carum carvi, Coriandrum sativum, Embellica officinalis, Juniperus communis, Momordica charantia, Xanthium strumarium 5 Fruit Aloe barbadensis, Annona squamosa, Averrhoa bilimbi, Azadirachta indica, Beta vulgaris, Camellia sinensis, Cassia 6 Leaves alata, Eclipta alba, Eucalyptus globulus , Euphrasia officinale, Ficus carica, Gymnema sylvestre, Gynura procumbens, Ipomoea aquatica, Mangifera indica, Myrtus communis, Memecylon umbellatum, Morus indica, Ocimum sanctum Nelumbo nucifera 7 Rhizome Clausena anisata, Glycerrhiza glabra, Helicteres isora, Pandanus odorus 8 Roots Acacia arabica, Agrimony eupatoria, Lupinus albus, Luffa aegyptiaca, Lepidium sativum, Mucuna pruriens, Punica 9 Seed granatum Amaranthus spinosus, Coscinium fenestratum 10 Stem Ipomoea batata 11 Tubers Abies pindrow, Achyranthus aspera, Ajauga iva, Aloe vera, Anacardium occidentale, Andrographis paniculata, Capsicum 12 Whole plant frutescens, Cryptolepis sanguinolenta, Enicostemma littorale, Ficus religiosa

Table 2 List of plants having insulin mimetic or insulin secreatory activity[53]. S. No. Plant botanical name Common name Family Mechanism of action Abies pindrow 1 Morinda Pinaceae Insulin secretagogue activity Acacia arabica 2 Babool Leguminosae Release of insulin from pancrease Agrimony eupatoria 3 Rosaceae Leaves Insulin releasing and insulin like activity Aloe barbadensis 4 Gheequar Liliaceae Stimulating synthesis and release of insulin Annona squamosa 5 Sharifa Annonaceae Increased plasma insulin level Averrhoa bilimbi 6 Bilimbi Oxalidaceae Increase serum insulin level Bixa orellana 7 Annotta Bixaceae Increase plasma insulin concentration and increase insulin binding on insulin receptor Boerhaavia diffusa 8 Punamava Nyctaginaceae Increase plasma insulin concentration Camellia sinensis 9 Green tea Theaceae Increase insulin secretion Capsicum frutescens 10 Mirch Solanaceae Increase insulin secretion and reduction of insulin binding on the insulin receptor Cinnamomum zeylanicum 11 Dalchini Lauraceae Elevation in plasma insulin level Clausena anisata 12 - Rutaceae Stimulate secretion of insulin Eucalyptus globulus 13 Eucalyptus Myrtaceae Increase insulin secretion from clonal pancreatic beta line (BRIN-BD 11) Ficus religiosa 14 Peepal Moraceae Initiating release of insulin Hibiscus rosa 15 Gudhal Malvaceae Stimulate insulin secretion from beta cells Helicteres isora 16 Indian screw Sterculiaceae Decrease plasma triglyceride level and insulin sensitizing activity tree Ipomoea batata 17 Shakarkand Convolvulaceae Reduce insulin resistance and blood glucose level Juniperus communis 18 Hauber Pinaceae Increase peripheral glucose consumption and induce insulin secretion Olea europia 19 Olive Oleaceae Increase insulin release and increase peripheral uptake of glucose Swertia chirayata 20 Chirayata Gentianaceae Stimulates insulin release from islets Scoparia dulcis 21 Mithi patti Scrophulariaceae Insulin-secretagogue activity Tinospora crispa 22 Giloe Menispermaceae Anti-hyperglycemic, stimulates insulin release from islets Urtifca dioica 23 Bichhu booti Urticaceae Increase insulin secretion Vinca rosea 24 Sadabahar Apocynaceae Beta cell rejuvenation, regeneration and stimulation Zingiber officinale 25 Adrak Zingiberaceae Increase insulin level and decrease fasting glucose level concomitant decrease in plasma glucose levels[10]. Effect of release of insulin from the beta-cells of Langerhans[12]. aqueous garlic (10% v/v) extracts on isolated pancreas were Effect of pseudoprototinosaponin AIII and prototinosaponins shown to potentiate glucose-induced insulin secretion[17]. AIII on glucose uptake and insulin release suggested Effect of garlic on high-fat diet feed rats for 2 weeks suggests their hypoglycaemic effects are due to actions on hepatic [18] [11] that garlic is insulinotropic rather than hypoglycemic . gluconeogenesis or glycogenolysis . SAloeingle vera as well as 3.6. Aloe vera (Liliaceae) repeated doses of bitter principle of the showed hypoglycemic effect in diabetic rats, which was through Aloe vera stimulation of synthesis or release of insulin from pancreatic Hypoglycemic effect by bitter principle of in beta cells[16]. the rats is mediated through stimulation of synthesis or Patel DK et al./Asian Pacific Journal of Tropical Biomedicine (2012)320-330 323 Table 3 List of plants phytoconstituents having insulin secretagogues or insulin mimetic activity. S. No. Plant botanical name Family Active constituents References Aloe vera 1 Liliaceae Pseudoprototinosaponin AIII and prototinosaponins AIII [11] Anemarrhena asphodeloides 2 Liliaceae Mangiferin and mangiferin-7-O- -dglucoside [8] Bauhinia variegata 毬 3 Caesalpiniaceae Roseoside [20] Camellia sinensis 4 Theaceae Epigallocatechin gallate [13] Citrullus colocynthis 5 Cucurbitaceae Beta-pyrazol-1-ylalanine [11] distachya 6 Ephedraceae L-ephedrine [15] Eriobotrya japonica 7 Rosaceae Cinchonain ib [33] Eugenia jambolana 8 Myrtaceae Pandanus odorus (Toei-hom) a 4- hydroxybenzoic acid [12] Ficus bengalensis 9 Moraceae Leucocyandin 3-O-beta-d-galactosyl cellobioside, leucopelargonidin-3- [11,13] O-alpha-L rhamnoside Glycyrrhizae radix 10 Fabaceae Glycyrrhetinic acid, dihydroxy gymnemic triacetate [36] Momordica charantia 11 Cucurbitaceae Momordicin, charantin, and galactose-binding lectin [6] Panax ginseng 12 Araliaceae Polypeptides [11] Prunella vulgaris 13 Labiatae Jiangtangsu [15] Psidium guajava 14 Myrtaceae Strictinin, isostrictinin and pedunculagin [15] Pterocarpus marsupium 15 Fabaceae Epicatechin [6,16] Semen coicis 16 Gramineae Coixans [15] Stevia rebaudiana 17 Asteraceae Stevioside, steviol [41,42] Swertia chirayita 18 Gentianaceae Swerchirin [10,11] Teucrium polium 19 Lamiaceae Apigenin [45] Trigonella foenum- 20 graecum Leguminosae 4-hydroxyleucine and hydroxyisoleucine [10,16,48,49] Zizyphus spina-christi 21 Rhamnaceae Christinin-A [50] 3.7. Annona muricata (Annonaceae) 3.11. Berberine

Annona muricata played an important role in reduction Berberine promoted glucose-stimulated insulin secretion of oxidative stress of pancreatic 毬-cells of streptozotocin rather than basal’ insulin secretion in dose-dependent induced diabetic rats, which was confirmed by the increased manner in rat s pancreatic islets. Berberine can enhance area of insulin immunoreactive 毬-cells and protection glucose-stimulated insulin secretion in ratvia islets, and against degeneration of 毬-cells[9]. probably exerts the insulinotropic effect a pathway 4 ( 4) 3.8. Annona squamosa (Annonaceae) involving hepatic nuclear factor alpha HNF alpha and glucokinase, which is distinct from sulphonylureas[21]. Annona squamosa Significant insulin sensitizing activity was observed in commonly called custard apple plant 3T3-L1 adipocytes which were given 50 毺M berberine plus possesses antidiabetic activity. It acts by promoting insulin 0.2 nM insulin to reach a glucose uptake level increased by release from the pancreatic islets, increasing utilization of 10 nM of insulin alone. This was associated with increased 4 glucose in muscle and inhibiting the glucose output from glucose transporter- via translocation into the plasma liver[9]. membrane enhancing insulin signalling pathways and 1 3 3.9. Asparagus racemosus (Liliaceae) the insulin receptor substrate- -phosphoinositide Kinase- Akt. Berberine also increased glucose-stimulatedvia insulin secretion and proliferation in Min6 cells an enhanced 1 The ethanolAsparagus extract, hexane,racemosus chloroform and ethyl acetate insulin/insulin-like growth factor- signalling cascade. fractions of root were shown to have Data suggested that berberine can act as an effective insulin dose-dependent insulin secretion in isolated perfused rat sensitizing and insulinotropic agent[22]. pancreas, isolated rat islet cells and clonal betaAsparagus -cells. 3.12. Biophytum sensitivum (Oxalidaceae) These findings reveal that constituents of racemosus [19] root extracts have insulinotropic activity . Biophytum sensitivum 3.10. Bauhinia variegata (Caesalpiniaceae) Leaf extract of the stimulates pancreatic beta cells to release insulin in diabetic male [13] Bauhinia variegata rabbits Biophytumand exerts hypoglycemicsensitivum activity . Administration Crude ethanolic extract of leaves of of the extract in 16-h fasted non- and its major metabolite (6S,7E,9R)-9-hydroxymegastigma- diabetic rabbits showed a significant rise in the serum 4 7 3 9 ( ) , -dien- -one- -beta-glycopyraroside roseoside have insulinBiophytum levels, whichsensitivum suggested a pancreatic mode of action 1 insulinotropic activity in insulin-secreting cell line INS- ofBiophytum sensitivum . The hypoglycaemic response of and it was found to be dose-dependent[20]. may be mediated through stimulating the synthesis/release of insulin from the beta cells of Patel DK et al./Asian Pacific Journal of Tropical Biomedicine (2012)320-330 324 3.20. Capsicum frutescens (Solanaceae) Langerhans[23]. 3.13. Boerhaavia diffusa (Nyctaginaceae) Capsicum frutescens increased serum insulin concentration ( ) 2 Boerhaavia diffusa in a high-fat HF diet-fed streptozotocin induced type 4 Chloroform extracts of leaves of diabetes rats after weeksCapsicum treatment. frutescens The data of this study showed antidiabetic activity in streptozotocin induced suggest that 2% dietary is insulinotropic diabetic rats which mainly act by reducing blood glucose rather than hypoglycemic in the experimental methods[18]. [9] level and increasing insulin sensitivity . Hypoglycemic and 3.21. Catharanthus roseus (Apocyaceae) antihyperglycemic activity of aqueous leaf extract at 200 mg/ kg p.o. for 4 weeks in normal and alloxan induced diabetic rats showed to increase plasma insulin levels and improve Catharanthus Dichloromethane-methanol roseus extract of leaves and twigs of glucose tolerance[13]. in carbohydrate metabolism, showed to 3.14. Bougainvillea spectabilis (Nyctaginaceae) enhance secretion of insulin. The extract was also found to be helpful in prevention of damage caused by oxygen free radicals[9]. The bloodBougainvillea glucose lowering spectabilis potential of ethanolic leaf 3.22. Citrullus colocynthis (Cucurbitaceae) extract of in streptozotocin- induced type I diabetic albino rats was probably due to Citrullus colocynthis increased glucose uptake by enhanced glycogenesis in the pulp extract at 300 mg/kg, p.o. liver and also due to increased insulin sensitivity[9]. was found to significantly increase insulin and decrease 3.15. Brassica nigra (Cruciferae) plasma glucose levels in alloxan induced diabetic rats. Immunohistochemistry procedure showed that the amount of Brassica nigra Citrullusinsulin in colocynthis beta-cells of the islets of Langerhans is greater in Oral administration of aqueous extract of treated-diabetic rats in comparison to [28] for two months decreased serum glucose level, which was the control group . AdministrationCitrullus colocynthis of the ethanol extract of due to the release of insulin from pancreas[24]. the dried seedless pulp of at 300 mg/kg, 3.16. Cinnamon zeylaniucm (Lauraceae) p.o had insulinotropic actionsCitrullus in alloxan-induced colocynthis diabetic rats[29]. Aqueous extract of showed dose-dependent increase in insulin release from isolated In vitro [12] incubation of pancreaticCinnamon isletszeylaniucm with islets . Different extracts such as crude extract, aqueous, cinnamaldehyde isolated from alcoholic, purified extract and beta-pyrazol-1-ylalanine, resulted in enhanced insulin release. The insulinotropic the major free amino acid derivative inpresent vitro in the seeds effect of cinnamaldehyde was due to increase in the glucose significantly induced insulin secretion in the isolated uptake through glucose transporter (GLUT4) translocation in rat pancreas and isolated rat islets[11]. [25] peripheral tissues . 3.23. Coccinia indica (Cucurbitaceae) 3.17. Caesalpinia bonducella (Cesalpinaceae) Coccinia indica Oral administration of dried extract of at 500 6 CaesalpiniaHypoglycemic bonducella activity of aqueous and ethanolic extracts mg/kg, p.o. for weeks significantly increased insulin of in chronic type II diabetic model, concentration in a clinical study. The plant extract showed showed an increase secretion of insulin in isolated islets[13]. to exert beneficial hypoglycemic effect in experimental 3.18. Caffeine animals and human diabetic subject possibly through an insulin secreting effect or through influence of enzymes involved in glucose metabolism[12]. 0 01% 90% Treatment with . caffeine solution in 3.24. Cornus officinalis (Cornaceae) pancreatectomized diabetic rats for 12-week reduced body weight, fats, and decreased insulin resistance. At Cornus officinalis the same time caffeine also enhanced glucose-stimulated Alcoholic extract of can increase first- and second-phase insulin secretion and beta-cell GLUT4 mRNA and its protein expression in NIDDM rats by hyperplasia[26]. promoting proliferation of pancreatic islets and by increasing 3.19. Camellia sinensis (Theaceae) postprandial secretion of insulin and therefore accelerating the glucose transport[15]. Methanol extract and its fractions Camellia sinensis had potent insulin mimic activity on phosphoenolpyruvate Epigallocatechin gallate, present in carboxykinase expression. The ability of fractions to protect increases insulin activity and prevents oxidative damages beta-cell against toxic challenge, and to enhance insulin [13] Cornus officinalis Camelliain streptozotocin sinensis induced diabetic rats . Lower dose of secretion strengthens the role of in on SD rats fed with high fat diet for 2 weeks diabetes therapy[30]. [27] showed insulinotropic effect in experimental condition . 3.25. Elephantopus scaber (Asteraceae) Patel DK et al./Asian Pacific Journal of Tropical Biomedicine (2012)320-330 325

3 Elephantopus scaber leucopelargonidin- - O-alpha-L rhamnoside at a dose The acetone extract of showed a of 100 mg/kg, p.o. showed significant hypoglycaemic and significant decrease in blood glucose level by improving insulinomimetic activity in healthy and alloxan induced- insulin sensitivity, augmenting glucose dependent insulin diabetic dogs during a period of 2 hour[11]. secretion and stimulating the regeneration of islets of 3.32. Fermented unsalted soybeans Langerhans in pancreas of STZ-induced diabetic rats[31]. 3.26. Enicostemma littorale (Gentianaceae) Effect of fermented unsalted soybeans in 90% 8 Enicostemma littorale pancreatectomized diabetic Px rats for -week enhanced Aqueous extract of induced serum insulin secretion. In addition, Cviahungkookjang potentiated insulin levels in alloxan-induced diabetic rats at 8 h was insulin/IGF-1 signaling in islets the induction of insulin associated with potentiation+ of glucose-induced insulin receptor substrate-2 expression, leading to increased release through K -ATP channel dependent pathway[32]. pancreatic duodenal homeobox-1, insulin promoter 3.27. (Ephedraceae) transcription factor. In parallel with the enhancement of the signaling, Chungkookjang elevated pancreatic beta-cell Ephedra distachya hyperplasia by increasing its proliferation and decreasing The alkaloids of herbs and l-ephedrine apoptosis[34]. have shown antihyperglycemic effect in diabetic mice due 3.33. Genistein to regeneration and restoration of atrophied pancreatic islets that induces the secretion of insulin[15]. 3.28. Eriobotrya japonica (Rosaceae) Genistein increases insulin secretion in both insulin- secreting cell lines (INS-1 and MIN6) and mouse pancreatic Eriobotrya japonica islets. It was found that genistein directly acts on pancreatic Aqueous extract of and the compounds beta-cells, leading to activation of the cAMP/PKA signalling cinchonain Ib, procyanidin B-2, chlorogenic acid and cascade to exert an insulinotropic effect[35]. epicatechin, were tested for insulin secretory activity in 3.34. Ginkgo biloba (Ginkgoaceae) INS-1 cells, showed significantl increase of insulin secretion 1 [33] from INS- cells in dose-dependent manner . Ginkgo biloba 3.29. Euccalyptus globulus (Myrtaceae) Effect of Ginkgo biloba extract in humans and healthy rats shows that significantly increased the insulin [11] Euccalyptus globulus concentration . (0 5 Aqueous extract of . g/L of 3.35. Radix glycyrrhizae (Fabaceae) solution) increased peripheral glucose utilization in the mouse abdominal muscle and increased insulin secretion Radix glycyrrhizae from the clonal pancreatic beta cell line[12]. and glycyrrhetinic acid enhanced 3.30. Eugenia jambolana (Myrtaceae) glucose-stimulated insulin secretion in isolated islets. In addition, they induced mRNA levels of insulin receptor 2 1 Eugenia jambolana substrate- , pancreas duodenum homeobox- , and Effect of seeds extract in isolated glucokinase in the islets, which contributed to improve pancreatic islet cells of normal and diabetic animals was beta-cell viability[36]. investigated Eanduge foundnia jambolana that it enhances insulin secretion 3.36. Gymnema sylvestre (Asclepiadaceae) from cells. extract also inhibited [11,12,16] insulinase activity from liver and kidney . Gymnema sylvestre 3.31. Ficus bengalensis (Moraceae) Alcoholic extract of stimulated insulin secretion from the rat islets of Langerhans and Ficus several pancreatic beta cell lines. In another study, bengalensis The oral administration of the extract of oralGym neadministrationma sylvestre of a water-soluble leaves extract of caused enhanced serum insulin levels in at 400 mg/day, p.o. to 27 IDDM patients normoglycaemic and diabetic rats. The increased insulin on insulin therapy lowered fasting blood glucose and insulin [10] secretion is mainly due to inhibited insulinase activity requirements . Pancreatic beta cells mayGymnema be regenerated sylvestre from liver and kidney[11,12]. Blood sugar lowering activity or repaired in type II diabetic patients on of a dimethoxy derivative of leucocyandin 3-O-beta- supplementation; this is supported by the raised insulin 250 [11] d-galactosyl cellobioside Ficus at a dosagebengalensis of mg/kg, p.o. levels in the serum of patients after supplementation . isolated from the bark of in normal and Gymnemic acid molecules dihydroxy gymnemic triacetate moderately diabetic rats was mainly due to insulinomimetic had the ability to release the insulin by the stimulation of [13] activity . GFicuslycoside bengalensis of leucopelargonidin isolated from a regeneration process and revitalizationGymnema of sylvestre the remaining the bark of demonstrated significant beta cells. Aqueous extract of leaves hypoglycaemic, hypolipidemic and serum insulin raising stimulated insulinin vitro secretion from mouse cells and isolated effects in moderately diabetic rats. Dimethoxy ether of human islets , without compromising cell viability[31]. Patel DK et al./Asian Pacific Journal of Tropical Biomedicine (2012)320-330 326 Gymnema sylvestre charantia Oral administration of to diabetic rats increases the renewal of partial cells in the increased the number of pancreatic islet and beta cells, pancreas or may permit the recovery of partially destroyed as well as insulin levels, suggesting a possible repair or cells and stimulates pancreatic insulin secretion[15]. [37] regeneration Gymnemaof the endocrine sylvestre pancreas . Water-soluble 3.43. Mucuna pruriens (Leguminosae) extracts of leaves release insulin probably by causing regeneration of pancreatic beta cells in vivo in vitro[6] both and . Mucuna Blood pruriensglucose lowering activity of powdered seeds of 0 5 1 2 3.37. Helicteres isora (Sterculiaceae) was observed at . , and g/kg, p.o. in normal rabbits as well as 1 and 2 g/kg, p.o. in alloxan- diabetic rabbits. It possibly acts through stimulation of the Helicteres Antihyperglycemic isora activity of butanol extracts of root of release of insulin or by a direct insulin-like action due 250 at mg/kg, p.o. in glucose loaded rats acts etcto the presence of trace elements like manganese, zinc, through insulin-sensitizing activity[13]. [10,13]. 3.38. Hibiscus rosa sinensis (Malvaceae) 3.44. Nigella sativa oil (Ranunculaceae)

Hibiscus rosa sinesis Oral administration of ethanol extract of Significant decreases in blood glucose level, and increase 250 at mg/kg, p.o. showed mild but significant inNigella serum sativa insulin level were observed on treatment with 4 hypoglycemia which was mainly due to insulin release by oil forNigella weeks. sativa Immunohistochemical staining stimulation of pancreatic beta cells[10]. of pancreas from oil-treated group showed 3.39. Hordeum vulgare (Gramineae) large areas with positive immunoreactivity for the presence of insulin[38]. Hordeum vulgare 3.45. Panax ginseng (Araliaceae) The germinant fruits of showed hypoglycemic and hyperinsulinemic effects in NIDDM Panax subjects, due to mobilization of insulin in NIDDM, which ginseng Ginseng polypeptides isolated from the root of makes it a suitable cereal for diabetes mellitus[15]. , when injected subcutaneously at daily doses of 50 100 7 3.40. Lepechinia caulescens (Lamiaceae) and mg/kg for successive days in mice resulted in decreased blood glucose, increased liver glycogen level [11] Lepechinia caulescens and stimulated insulin secretion . The aqueous ethanolic significantlyLepechinia decreased caulescens glucose extract of Korean red ginseng significantly evoked a insulin tolerance suggesting that has release in a glucose-independent manner[39]. [11] insulinomimetic activity . 3.46. Pandanus odorus (Pandanaceae) 3.41. Medicago sativa (Fabaceae) Pandanus odorus 4 5 Medicago sativa -Hydroxybenzoic acid from at mg/kg Aqueous extract of evoked stimulation increased serum insulin levels and liver glycogen content in 11 [11] of insulinin secretion vitro from the BRIN-BD pancreatic beta healthy rats . cell line . In another study it was found that insulin 3.47. Parinari excelsa (Chrysobalanaceae) releasing activity of the methanol and water fractions is mainly due to the cumulative effect of its constituent present Parinari excelsa in it[11]. Flavonoid of showed hypoglycemic effect due to the ability of insulin secretory activity in the diabetic 3.42. Momordica charantia (Cucurbitaceae) [31] animal models . 3.48. Prunella vulgaris (Labiatae) Significant reduction of blood glucose level and increased concentration of plasma insulin have been observedMomordica in Prunella vulgaris diabeticcharantia rats that were treated with fruit juice of Jiangtangsu had been isolated from and . The observed effect was due to an increase in confirmed to have a remarkable blood sugar lowering effect the number of beta cells in treated animals compared to in diabetic mice. The possible mechanism of Jiangtangsu is untreated one. The phytochemical momordicin, charantin, to repair cells of pancreatic islet to release insulin[15]. and a few compounds such as galactose-binding lectin 3.49. Psidium guajava (Myrtaceae) and insulin-like protein isolated from various parts of this [6,37] plant have been shown to have insulinMomordica mimetic activity charantia. Aqueous extract of unripe fruits of Flavonoid glycosides such as strictinin, isostrictininPsidium and has also been shown to partially stimulate insulin release pedunculaginguajava are the effective constituents of from isolated beta-cell of obese-hyperglycemic mice , which have been used in clinical treatment of [15] suggesting that the insulin-releasing action isMomordica the result diabetes due to improved sensitivity of insulin . of perturbations of membrane functions[10]. Patel DK et al./Asian Pacific Journal of Tropical Biomedicine (2012)320-330 327 3.50. Pterocarpus marsupium (Fabaceae) 3.57. Selaginella tamariscina (Selaginellaceae) Pterocarpus marsupium Flavonoid fraction from has Selaginella tamariscina been shown to cause pancreatic beta cell regranulation. Intraperitoneal administration of Epicatechin, its active principle, has been found to be at 25 g/kg for 12 days produced a decrease in blood glucose insulinogenic thus enhancing insulin release and conversion and serum lipid peroxide, as well as an increase in the in vitro[16] of proinsulin to insulin .Pterocarpus An active principle-marsupium concentration of serum insulin. Histological observations epicatechin isolated from the bark of showed that this plant could repair the structure of has been found to have protective and restorative effects on pancreatic islet beta cells injured by alloxan[11]. beta cells in diabetic subjects. Possibly, epicatechin acts by 3.58. Semen coicis (Gramineae) regenerating the beta cells and may produce actions similar [6] to that of insulin . coicis 3.51. Radix rehmanniae (Scrophulariaceae) seeds Coixans isolated and purified from the dried Semen , decreased blood glucose in normal rats with increased serum insulin level. The anti-diabetic mechanism of coixans The pectin Radix type rehmanniae polysaccharide, obtained from the may be due to prevention of pancreatic beta-cells injury, rhizome of exhibited hypoglycemic induced by alloxan[15]. activity in normal and streptozotocins induced diabetic mice 3.59. Smallanthus sonchifolius (Asteraceae) by stimulating the secretion of insulin and reducing the [15] glycogen content in the mice . Smallanthus sonchifolius 2% 3.52. Rehmania glutinosa (Scrophulariacea) Administration of to diabetic rats for 30-day increased levels of circulating insulin, which may be due to increased synthesis and secretion of Intraperitoneal administration of the ethanol precipitate insulin[40]. fractionRehm obtainedania glutinosa from the hot water extract from the rhizome 3.60. Stevia rebaudiana (Asteraceae) of stimulated the secretion of insulin and reduced the glycogen content in the livers of healthy mice[11]. Effect of stevioside in isolated mouse islets and the 1 3.53. Ricinus communis (Euphorbiaceae) clonal beta cell line INS- was investigated and found that glycoside stevioside exerts antihyperglycaemic, insulinotropic, and glucagonostatic actions in the type 2 Ricinus communis [41] Administration of ethanolic extract of to diabetic GK rat . In another study it was concludedvia that the diabetic rats at 500 mg/kg, p.o. for 20 days, significantly stevioside and steviol stimulate insulin secretion a direct increased the insulin levels and caused improvement in action on beta cells[42]. The natural sweetener stevioside, [31] Stevia rebaudiana lipid profile and body weight of the diabetic animals . which is found in the plant via acts through 3.54. Syzygium cumini (Rutaceae) stimulating insulin secretion direct action on the 毬-cells of pancreatic islets[8]. Syzygium 3.61. Swertia chirayita (Gentianaceae) c umini Oral administration of pulp extract of the fruit of to normoglycemic and STZ induced diabetic rats Swertia chirayita showed hypoglycemic activity in 30 min possibly mediated Hexane fraction of at 250 mg/kg, p.o. to by insulin secretion and inhibited insulinase activity[10]. normal rats significantly reduced blood sugar and increased 3.55. Salvia lavandifolia (Lamiacea) plasma insulin without influencing hepatic glycogen content. However, when administered for 28 days, it significantly Salvia lavandifolia increased hepatic glycogen content in conjunction with Hypoglycaemic effect of may be due other effects probably by releasing insulin[11]. Single oral to potentiation of insulin release induced by glucose and administration of swerchirin (50 mg/ kg) to rats caused hyperplasia of the pancreatic islet beta cells along with some fall in blood glucose with marked depletion of aldehyde- [11] otherSalvia mechanisms lavandifolia. The antidiabetic activity of the extract fuchsin stained beta-granules and immunostained insulin of at 10 mg/kg induced an increase in in the pancreatic islets. Swerchirin at 100, 10 and 1 mM the size and number of cells in the islets of Langerhans with concentration greatly enhanced glucose stimulated insulin increase in pancreatic insulin content[11]. release from isolated islets[10]. 3.56. Sarcopoterium spinosum (Rosaceae) 3.62. Swertia punicea (Gentianaceae)

Sarcopoterium spinosum The aqueous extract of exhibited Swertia Ethanol punicea extracts and ethyl acetate soluble fraction of an insulin-like effect on glucose uptake in hepatocytes showed hypoglycemic effects in STZ- 2 by inducing increasein vitro in glucose uptake. It also increased induced type- diabetic mice and may be beneficial to insulin secretion [31]. improve insulin resistance[31]. Patel DK et al./Asian Pacific Journal of Tropical Biomedicine (2012)320-330 328

3.63. Tabernanthe iboga (Apocynaceae) leaves and its major saponin glycoside, christinin-A, on the serum glucose and insulin levels showed that christinin-A Tabernanthe iboga potentiated glucose-induced insulin release in non-diabetic The effect of an aqueous extract of control rats[50]. Serum insulin and pancreatic cAMP levels augmented glucose-stimulatedTabernanthe insulin iboga secretion in a dose- showed significant increase in diabetic ratsZizyphus treated spina- for a dependent manner. contains water period of 4 weeks with the butanol extract of christi[11] soluble insulinotropicTabernanthe ibogacompounds. The insulin secretary . effect+ of might involve the closure of K -ATP and the intensification of calcium influx through 2+ 4. Discussion voltage-sensitive Ca channels[43]. 3.64. Teucrium polium (Lamiaceae) Diabetes is a disorder of carbohydrate, fat and protein Teucrium polium metabolism caused due to insufficient production of insulin Aqueous extract of crude extract is able or due to its inhibitory action, which can be considered as a to enhance insulin secretion through enhancing insulin major cause of high economic loss which can in turn impede [44] [51] Teucriumsecretion bypolium the pancreas . The insulinotropic properties of the development of nations . Before there were drugs extracts can be attributed to the presence from drug companies, natural cures were used and they can of apigenin existing only in methanol fractionTeucrium but polium not in still be used today. There are many herbs with strong anti- aqueoue fractions[45]. Crude extract of diabetic properties. Herbal treatments for diabetes have is capable of enhancing insulin secretion at high glucose been used in patients with insulin dependent and non- concentration and plant extract seems to be capable of insulin dependentetc diabetes, diabetic retinopathy, diabetic regenerating the islets of Langerhans in the treated diabetic neuropathy . The families of plants with the most potent rats compared to the untreated diabetic rats[46]. hypoglycaemic effects include Leguminoseae, Lamiaceae, 3.65. Tinospora crispa (Menispermaceae) Liliaceae, Cucurbitaceae, Asteraceae, Moraceae, Rosaceae, Euphorbiaceae and OpuntiaAraliaceae. streptacantha The most commonlyTrigonella Tinospora crispa studiedfoenum graecumspecies are:Momordica charantia Ficus , bengalensis Antihyperglycaemic effect of extractvia Polygala senega , Gymnema sylvestre , , is probably due to the stimulation2+ of insulin release and . In the experiments, modulation of beta-cell Ca concentration[11,47]. oral glucose tolerance test, streptozotocin and alloxan- 3.66. Tribuluks terrestris (Zygophyllaceae) induced diabetic mouse or rat were most commonly used model for the screening of antidiabetic drugs. Numerous Tribuluks terrestris mechanisms of actions have been proposed for plant The extract of significantly decreases extracts. Some hypothesis relates to their effects on the blood glucose level in normal and alloxan-induced diabetic activity of pancreatic beta cells, increase in the inhibitory mice, mainly due to the increased serum insulin level[15]. effect against insulinase enzyme, increase of the insulin 3.67. Trigonella foenum-graecum (Leguminosae) sensitivity or the insulin-like activity of the plant extracts. Other mechanisms may also be involved such as increase of peripheral utilization of glucose, increase of synthesis of 4-Hydroxyleucine, a novel amino acid from fenugreek hepatic glycogen or decrease of glycogenolysis, inhibition of seeds increased glucose stimulated insulin release by intestinal glucose absorption, reduction of glycaemic index [10,16,48,49] [11] Trigonellaisolated islet foenum-graecum cells in rats, mice and humans . of carbohydrates and reduction of the effect of glutathione . has inbeen vitro observedin vivoto cause In this review, natural products classified into terpenoids, glucose-induced insulin release and [6]. A alkaloids, flavonoids, phenolics, and some other specific amino acid, hydroxyisoleucine, Trigonella whichfoenum-graecum represents categories have shown antidiabetic potential through the 80% of the free amino acids in insulinomimetic activity of the plant extract. Roseoside, [37] 1 Trigonellaseeds, may foenum-graecumpossess insulin-stimulating properties . The epigallocatechin gallate, beta-pyrazol- -ylalanine, seeds may help to improve cinchonain Ib, leucocyandin 3-O-beta-d-galactosyl insulin sensitivity, which is presumed to be due to the effects cellobioside, leucopelargonidin-3-O-alpha-L rhamnoside, of fiber, which slows carbohydrate metabolism resulting in glycyrrhetinic acid, dehydrotrametenolic acid, strictinin, reduced insulin levels and lowered blood glucose[37]. Anti- isostrictinin and pedunculagin, epicatechin and christinin-A hyperglycemicTrigonella foenum-graecum effect of the extracts, powder and gum of isolated from the plant material have shown significant seeds and leaves have been insulinomimetic activity along with significant antidiabetic linked to delayed gastric emptying caused by the high fiber potential. Additionally, some flavonoids and polyphenols, content, inhibition of carbohydrate digestive enzymes and as well as sugar derivatives, are found to be effective due stimulation of insulin secretion[15]. to some other extrapancreatic mechanisms. In this review 3.68. Zizyphus spina-christi (Rhamnaceae) so many number of plants are included which have shown antidiabetic action through relese of insulin and some extra [8] Allium cepa Zizyphus spina-christi Clerodendronpancreatic mechanisms phlomoides Cinnamomum. Plants such tamalaas Coccinia, The effect of the butanol extract of , , Patel DK et al./Asian Pacific Journal of Tropical Biomedicine (2012)320-330 329 indica Enicostemma littorale Ficus bengalensis Gymnema J Ethnopharmacol 92 mellitus. 2004; (1): 1-21. sylvestre, Momordica, charantia Pterocarpus, é [5] S y GY, Ciss A, Nongonierma RB, Sarr M, Mbodj NA, Faye B. marsupium leaves,Syzygium cumini , Hypoglycaemic and antidiabetic activity of acetonic extract and have a great antidiabetic Vernonia colorata of leaves in normoglycaemic and alloxan- potential, which have already been subjected to the clinical J Ethnopharmacol 98 trial are included in the list, whereas some marketed herbal induced diabetic rats. 2005; (1-2): 171-175. ( 180 [6] S axena A, Vikram NK. Role of selected Indian plants in formulations diasulin, pancreatic tonic cp, chakrapani, J Altern Complement management of type 2 diabetes: a review. diabecon, bitter gourd powder, dia-car, diabetes-daily Med 10 2004; (2): 369-378. care, gurmar powder, epinsulin, diabecure, syndrex, Coptis ) [7] L ee HS. Rat lens aldose reductase inhibitory activities of diabetawhich which have been proved for its antidiabetic japonica J Agric Food Chem [16,52] root-derived isoquinoline alkaloids. activity are also listed in the database . Although all 50 these plants have shown varying degree of hypoglycemic 2002; (24): 7013-7026. [8] J ung M, Park M, Lee HC, Kang YH, Kang ES, Kim SK. and anti-hyperglycemic activity not all were effective in Curr Med Chem Antidiabetic agents from medicinal plants. 2006; severe experimental diabetes and its related complications. 13 A novel anti-hyperglycemic amino acid has been extracted (10): 1203-1218. (4 ) [9] M alviya N, Jain S, Malviya S. Antidiabetic potential of medicinal and purified from fenugreek seeds -hydroxyleucine which Acta Pol Pharm 67 reportedly increases glucose-induced insulin release[10]. plants. 2010; (2): 113-118. [10] G rover JK, Yadav S, Vats V. Medicinal plants of India with anti- In conclusion, this paper has presented a list of anti- J Ethnopharmacol 81 diabetic plants used in the treatment of diabetes mellitus. diabetic potential. 2002; (1): 81-100. It showed that these plants have hypoglycaemic effects and [11] B nouham M, Ziyyat A, Mekhfi H, Tahri A, Legssyer A. Medicinal plants with potential antidiabetic activity-a review of ten years of can be used to treat various type of secondary complications Int J Diabetes Metab herbal medicine research (1990-2000). 2006; of diabetes mellitus. Plants have been a good source of 14 medicine for the treatment of various type of disease, still : 1-25. [12] S ingh LW. Traditional medicinal plants of Manipur as anti- many plants and active compounds obtained from plants J Med Plant Res 5 have not been well characterized. More investigations must diabetics. 2011; (5): 677-687. [13] A yodhya S, Kusum S, Anjali S. Hypoglycaemic activity of different be carried out to evaluate the exact mechanism of action Int J Ayurveda Res Pharm extracts of various herbal plants Singh. of medicinal plants with antidiabetic and insulino mimetic 1 2010; (1): 212-224. activity. It is always believed that plant is safe, but so’ many Alangium [14] K shirsagar RP, Darade SS, Takale V. Effect of plant materials are not safe for the human being, that s why salvifolium (Alangiaceae) on dexamethasone induced insulin toxicity study of these plants should also be elucidated J Pharm Res 3 before consumption of these plant materials. resistance in rats. 2010; (11): 2714-2716. [15] C hauhan A, Sharma PK, Srivastava P, Kumar N, Duehe R. Plants Der Pharm Lett having potential antidiabetic activity: a review. Conflict of interest statement 2 2010; (3): 369-387. [16] M odak M, Dixit P, Londhe J, Ghaskadbi S, Paul A, Devasagayam T. Indian herbs and herbal drugs used for the treatment of We declare that we have no conflict of interest. J Clin Biochem Nutr 40 diabetes. 2007; (3): 163-173. [17] M ustafa SSS, Eid NI, Jafri SA, El-Latif HAA, Ahmed HMS. Acknowledgements Insulinotropic effect of aqueous ginger extract and aqueous garlic extract on the isolated perfused pancreas of streptozotocin Pak J Zool 39 induced diabetic rats. 2007; (5): 279-284. The financial assistance from University Grants Capsicum frutescens Commission, New Delhi, for Dinesh Kumar Patel (Senior [18] I slam MS, Choi H. Dietary red chilli ( L.) is ) insulinotropic rather than hypoglycemic in type 2 diabetes model Research Fellowship is greatly acknowledged. Phytother Res 22 of rats. 2008; (8): 1025-1029. 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