Antidiabetic Medicinal Plants with Insulinomimetic Material and Phytoconstituents

Antidiabetic agents of plant origin

Medicinal plants used to treat diabetes

Plants have always been very good sources of drugs and many of the currently available drugs have been derived directly or indirectly from them. The ethnobotanical information suggests that about 800 plants may possess anti-diabetic potential, among all of them Momordica charantia, Pterocarpus marsupium, and Trigonella foenum greacum have been reported to be beneficial for the treatment of type 2 diabetes. (Jung M et al, 2006) Several such herbs have shown anti-diabetic activities when evaluated using different types of experimental techniques. A wide array of plant active principles represents different types of biological activity, among these alkaloids, glycosides, galactomannan gun, polysaccharides, peptidoglycans, hypoglycin, guanidine, steroids, carbohydrates, glycopeptides, terpenoids, amino acids, and inorganic ions have demonstrated activities including treatment of diabetes. A list of the medicinal plants having antidiabetic potential according to the different parts used and modes of action is presented in the Table below.

List of plants having antidiabetic activities

List of plants having insulinomimetic or insulin secretory activities

Pharmacologically screened insulin-mimetic or insulin secretagogues plant material and phytoconstituents

The aim of this review is to collect the data available on plant material having hypoglycemic activity through either increased secretion of insulin from the pancreas or similar action as reported in different sources of literature. According to the search, several plant species have been described as ‘hypoglycemic’ such as Opuntia streptacantha, Trigonella foenum graecum, Momordica charantia, Ficus bengalensis, Polygala senega, Gymnema sylvestre, Allium sativum, Citrullus colocynthis and Aloe vera. The focus of the present review is concentrated on the experimental studies performed on the hypoglycemic activities of the plant material and the bioactive components related to the secretion of insulin or its action. Here all the plant materials which are listed were tested for their insulinomimetic or secretagogue activities in the different in vivo or in vitro model systems. Moreover, phytoconstituents isolated from different plants which have shown insulinomimetic activity are also represented in the table below

List of plants phytoconstituents having insulin secretagogue or insulin-mimetic activity.

Pharmacologically screened insulinomimetic or insulin secretagogues plant material and phytoconstituents (Asian Pacific Journal of Tropical Biomedicine)

Acacia arabica (Leguminosae)

About 94% seed diet of Acacia arabica showed a hypoglycemic effect in rats through the release of insulin. However, powdered seeds of Acacia arabica at 2, 3, and 4 g/kg, p.o. exerted a significant hypoglycemic effect in normal rabbits by initiating the release of insulin from pancreatic beta cells. (Modak M et al, 2007)

Aegle marmelos (Rutaceae)

Aqueous leaf extract of Aegle marmelos showed antihyperglycemic activity in streptozotocin-induced diabetic rats after 14 days of treatment either by increasing utilization of glucose or by direct stimulation of glucose uptake through increased insulin secretion.

Agrimony eupatoria (Rosaceae)

Aqueous extract of Agrimony eupatoria evoked stimulation of insulin secretion from the BRIN-BD11 pancreatic beta cell line in vitro. The effect of the extract was found to be glucose-independent. (DK Patel, 2012)

Alangium salvifolium (Alangiaceae)

Methanolic extract of Alangium salvifolium leaves possesses antihyperglycemic and antihyperlipidemic effects in dexamethasone-induced insulin resistance in rats, which may be due to the antioxidant and insulinotropic effect of the extract.

Allium sativum (Alliaceae)

Antihyperglycemic activity of ethyl ether extract at 0.25 mg/kg, p.o. was reported to be the most potent and active principle of Allium sativum (garlic) which was due to increased insulin-like activity. Oral administration of the ethanol extract, juice, and oil of Allium sativum has remarkably blood sugar lowering effects in normal and alloxan-induced diabetic rats or a rabbit mediated through stimulation of insulin secretion from parietal cells of the pancreas. Allicin, a sulfur-containing compound showed to have significant hypoglycemic activity due to increased hepatic metabolism and increased insulin release from pancreatic beta cells. S-allyl cysteine sulfoxide (SACS), the precursor of allicin and garlic oil, stimulated in vitro insulin secretion from beta cells isolated from normal rats. (Modak M et al, 2007) The beneficial effects of SACS could be due to its antioxidant and secretagogues activity. Daily oral feeding of garlic extracts at 100 mg/kg increased plasma insulin level with a concomitant decrease in plasma glucose levels. The effect of aqueous garlic (10% v/v) extracts on isolated pancreas was shown to potentiate glucose-induced insulin secretion. The effect of garlic on high-fat diet feed rats for 2 weeks suggests that garlic is insulinotropic rather than hypoglycemic. (DK Patel, 2012)

Aloe vera (Liliaceae)

The hypoglycemic effect of the bitter principle of Aloe vera in rats is mediated through stimulation of synthesis or release of insulin from the beta-cells of Langerhans. (Modak M et al, 2007) The effect of pseudoprototinosaponin AIII and prototinosaponins AIII on glucose uptake and insulin release suggested their hypoglycaemic effects are due to actions on hepatic gluconeogenesis or glycogenolysis. Single as well as repeated doses of the bitter principle of Aloe vera showed a hypoglycemic effect in diabetic rats, which was through stimulation of synthesis or release of insulin from pancreatic beta cells.

Annona muricata (Annonaceae)

Annona muricata played an important role in the reduction of oxidative stress of pancreatic β-cells of streptozotocin-induced diabetic rats, which was confirmed by the increased area of insulin immunoreactive β-cells and protection against degeneration of β-cells.

Annona squamosa (Annonaceae)

Annona squamosa commonly called the custard apple plant possesses antidiabetic activity. It acts by promoting insulin release from the pancreatic islets, increasing the utilization of glucose in muscle and inhibiting the glucose output from the liver.

Asparagus racemosus (Liliaceae)

The ethanol extract, hexane, chloroform, and ethyl acetate fractions of Asparagus racemosus root were shown to have dose-dependent insulin secretion in isolated perfused rat pancreas, isolated rat islet cells, and clonal beta-cells. These findings reveal that constituents of Asparagus racemosus root extracts have insulinotropic activity. (Hannan JM et al, 2007)

Bauhinia variegata (Caesalpiniaceae)

Crude ethanolic extract of leaves of Bauhinia variegata and its major metabolite (6S,7,9R)-9-hydroxymegastigma-4,7-dien-3-one-9-beta-glycopyraroside (roseoside) have insulinotropic activity in insulin-secreting cell line INS-1 and it was found to be dose-dependent. (Frankish N et al, 2010)

Berberine

Berberine promoted glucose-stimulated insulin secretion rather than basal insulin secretion in a dose-dependent manner in rat’s pancreatic islets. Berberine can enhance glucose-stimulated insulin secretion in rat islets and probably exerts the insulinotropic effect via a pathway involving hepatic nuclear factor 4 alpha (HNF4) alpha and glucokinase, which is distinct from sulphonylureas. The significant insulin-sensitizing activity was observed in 3T3-L1 adipocytes which were given 50 µM berberine plus 0.2 nM insulin to reach a glucose uptake level increased by 10 nM of insulin alone. This was associated with increased glucose transporter-4 translocation into the plasma membrane via enhancing insulin signaling pathways and the insulin receptor substrate-1-phosphoinositide 3 Kinase-Akt. Berberine also increased glucose-stimulated insulin secretion and proliferation in Min6 cells via an enhanced insulin/insulin-like growth factor-1 signaling cascade. Data suggested that berberine can act as an effective insulin-sensitizing and insulinotropic agent. (Wang ZQ et al, 2008)

Biophytum sensitivum (Oxalidaceae)

Leaf extract of the Biophytum sensitivum stimulates pancreatic beta cells to release insulin in diabetic male rabbits and exerts hypoglycemic activity. Administration of the Biophytum sensitivum extract in 16-h fasted non-diabetic rabbits showed a significant rise in the serum insulin levels, which suggested a pancreatic mode of action of Biophytum sensitivum. The hypoglycaemic response of Biophytum sensitivum may be mediated by stimulating the synthesis/release of insulin from the beta cells of Langerhans. (Puri D, 2001)

Boerhaavia diffusa (Nyctaginaceae)

Chloroform extracts of leaves of Boerhaavia diffusa showed antidiabetic activity in streptozotocin-induced diabetic rats which mainly act by reducing blood glucose levels and increasing insulin sensitivity. Hypoglycemic and 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 glucose tolerance. (DK Patel, 2012)

Bougainvillea spectabilis (Nyctaginaceae)

The blood glucose lowering potential of ethanolic leaf extract of Bougainvillea spectabilis in streptozotocin-induced type I diabetic albino rats was probably due to increased glucose uptake by enhanced glycogenesis in the liver and also due to increased insulin sensitivity.

Brassica nigra (Cruciferae)

Oral administration of an aqueous extract of Brassica nigra for two months decreased serum glucose level, which was due to the release of insulin from the pancreas. (Anand P et al, 2009)

Cinnamon zeylaniucm (Lauraceae)

In vitro incubation of pancreatic islets with cinnamaldehyde isolated from Cinnamon zeylaniucm resulted in enhanced insulin release. The insulinotropic effect of cinnamaldehyde was due to an increase in the glucose uptake through glucose transporter (GLUT4) translocation in peripheral tissues. (Anand P et al, 2010)

Caesalpinia bonducella (Cesalpinaceae)

Hypoglycemic activity of aqueous and ethanolic extracts of Caesalpinia bonducella in chronic type II diabetic model showed increased secretion of insulin in isolated islets.

Caffeine

Treatment with 0.01% caffeine solution in 90% pancreatectomized diabetic rats for 12 weeks reduced body weight, fats, and decreased insulin resistance. At the same time caffeine also enhanced glucose-stimulated first- and second-phase insulin secretion and beta-cell hyperplasia. (Park S et al, 2007)

Camellia sinensis (Theaceae)

Epigallocatechin gallate, present in Camellia sinensis increases insulin activity and prevents oxidative damage in streptozotocin-induced diabetic rats. A lower dose of Camellia sinensis on SD rats fed with a high-fat diet for 2 weeks showed an insulinotropic effect in the experimental conditions.

Capsicum frutescens (Solanaceae)

Capsicum frutescens increased serum insulin concentration in a high-fat (HF) diet-fed streptozotocin-induced type 2 diabetes rats after 4 weeks of treatment. The data of this study suggest that 2% dietary Capsicum frutescens is insulinotropic rather than hypoglycemic in the experimental methods. (DK Patel, 2012)

Catharanthus roseus (Apocyaceae)

Dichloromethane-methanol extract of leaves and twigs of Catharanthus roseus in carbohydrate metabolism showed to enhance the secretion of insulin. The extract was also found to be helpful in the prevention of damage caused by oxygen-free radicals.

Citrullus colocynthis (Cucurbitaceae)

Citrullus colocynthis pulp extract at 300 mg/kg, p.o. was found to significantly increase insulin and decrease plasma glucose levels in alloxan-induced diabetic rats. The immunohistochemistry procedure showed that the amount of insulin in beta-cells of the islets of Langerhans is greater in Citrullus colocynthis treated-diabetic rats in comparison to the control group. Administration of the ethanol extract of the dried seedless pulp of Citrullus colocynthis at 300 mg/kg, p.o had insulinotropic actions in alloxan-induced diabetic rats. Aqueous extract of Citrullus colocynthis showed a dose-dependent increase in insulin release from isolated islets. Different extracts such as crude extract, aqueous, alcoholic, purified extract, and beta-pyrazol-1-ylalanine, the major free amino acid derivative present in the seeds significantly induced insulin secretion in vitro in the isolated rat pancreas and isolated rat islets.

Coccinia indica (Cucurbitaceae)

Oral administration of dried extract of Coccinia indica at 500 mg/kg, p.o. for 6 weeks significantly increased insulin concentration in a clinical study. The plant extract showed to exert a beneficial hypoglycemic effect in experimental animals and human diabetic subjects possibly through an insulin-secreting effect or through the influence of enzymes involved in glucose metabolism. (Modak M et al, 2007)

Cornus officinalis (Cornaceae)

Alcoholic extract of Cornus officinalis can increase GLUT4 mRNA and its protein expression in NIDDM rats by promoting the proliferation of pancreatic islets and by increasing postprandial secretion of insulin and therefore accelerating glucose transport. Methanol extract and its fractions had potent insulin mimic activity on phosphoenolpyruvate carboxykinase expression. The ability of fractions to protect beta-cells against toxic challenges, and to enhance insulin secretion strengthens the role of Cornus officinalis in diabetes therapy. (DK Patel, 2012)

Elephantopus scaber (Asteraceae)

The acetone extract of Elephantopus scaber showed a significant decrease in blood glucose levels by improving insulin sensitivity, augmenting glucose-dependent insulin secretion, and stimulating the regeneration of islets of Langerhans in the pancreas of STZ-induced diabetic rats.

Enicostemma littorale (Gentianaceae)

Aqueous extract of Enicostemma littorale-induced serum insulin levels in alloxan-induced diabetic rats at 8 h was associated with potentiation of glucose-induced insulin release through the K⁺-ATP channel-dependent pathway.

Ephedra distachya (Ephedraceae)

The alkaloids of Ephedra distachya herbs and l-ephedrine have shown antihyperglycemic effect in diabetic mice due to regeneration and restoration of atrophied pancreatic islets that induces the secretion of insulin. (DK Patel, 2012)

Eriobotrya japonica (Rosaceae)

Aqueous extract of Eriobotrya japonica and the compounds cinchonain Ib, procyanidin B-2, chlorogenic acid, and epicatechin, were tested for insulin secretory activity in INS-1 cells, showed significantl increase of insulin secretion from INS-1 cells in a dose-dependent manner.

Euccalyptus globulus (Myrtaceae)

Aqueous extract of Euccalyptus globulus (0.5 g/L of solution) increased peripheral glucose utilization in the mouse abdominal muscle and increased insulin secretion from the clonal pancreatic beta cell line.

Eugenia jambolana (Myrtaceae)

The effect of Eugenia jambolana seeds extract in isolated pancreatic islet cells of normal and diabetic animals was investigated and found that it enhances insulin secretion from cells. Eugenia jambolana extract also inhibited insulinase activity from the liver and kidney. (Modak M et al, 2007)

Ficus bengalensis (Moraceae)

The oral administration of the extract of Ficus bengalensis caused enhanced serum insulin levels in normoglycaemic and diabetic rats. The increased insulin secretion is mainly due to inhibited insulinase activity from the liver and kidney. Blood sugar lowering activity of a dimethoxy derivative of leucocyandin 3-O-beta-d-galactosyl cellobioside at a dosage of 250 mg/kg, p.o. isolated from the bark of Ficus bengalensis in normal and moderately diabetic rats were mainly due to insulinomimetic activity. Glycoside of leucopelargonidin isolated from the bark of Ficus bengalensis demonstrated significant hypoglycaemic, hypolipidemic, and serum insulin-raising effects in moderately diabetic rats. Dimethoxy ether of leucopelargonidin-3- O-alpha-L rhamnoside at a dose of 100 mg/kg, p.o. showed significant hypoglycaemic and insulinomimetic activity in healthy and alloxan-induced-diabetic dogs during a period of 2 hours. (DK Patel, 2012)

Fermented unsalted soybeans

Effect of fermented unsalted soybeans in 90% pancreatectomized diabetic Px rats for 8-week enhanced insulin secretion. In addition, Chungkookjang potentiated insulin/IGF-1 signaling in islets via the induction of insulin receptor substrate-2 expression, leading to increased pancreatic duodenal homeobox-1, insulin promoter transcription factor. In parallel with the enhancement of the signaling, Chungkookjang elevated pancreatic beta-cell hyperplasia by increasing its proliferation and decreasing apoptosis. (DK Patel, 2012)

Genistein

Genistein increases insulin secretion in both insulin-secreting cell lines (INS-1 and MIN6) and mouse pancreatic islets. It was found that genistein directly acts on pancreatic beta-cells, leading to activation of the cAMP/PKA signaling cascade to exert an insulinotropic effect.

Ginkgo biloba (Ginkgoaceae)

The effect of Ginkgo biloba extract in humans and healthy rats shows that Ginkgo biloba significantly increased insulin concentration.

Radix glycyrrhizae (Fabaceae)

Radix glycyrrhizae and glycyrrhetinic acid enhanced glucose-stimulated insulin secretion in isolated islets. In addition, they induced mRNA levels of insulin receptor substrate-2, pancreas duodenum homeobox-1, and glucokinase in the islets, which contributed to improving beta-cell viability.

Gymnema sylvestre (Asclepiadaceae)

Alcoholic extract of Gymnema sylvestre stimulated insulin secretion from the rat islets of Langerhans and several pancreatic beta cell lines. In another study, oral administration of a water-soluble leaves extract of Gymnema sylvestre at 400 mg/day, p.o. to 27 IDDM patients on insulin therapy lowered fasting blood glucose and insulin requirements. Pancreatic beta cells may be regenerated or repaired in type II diabetic patients on Gymnema sylvestre supplementation; this is supported by the raised insulin levels in the serum of patients after supplementation. Gymnemic acid molecules dihydroxy gymnemic triacetate had the ability to release insulin by the stimulation of a regeneration process and revitalization of the remaining beta cells. Aqueous extract of Gymnema sylvestre leaves stimulated insulin secretion from mouse cells and isolated human islets in vitro, without compromising cell viability. Oral administration of Gymnema sylvestre to diabetic rats increased the number of pancreatic islet and beta cells, as well as insulin levels, suggesting a possible repair or regeneration of the endocrine pancreas. Water-soluble extracts of Gymnema sylvestre leaves release insulin probably by causing regeneration of pancreatic beta cells both in vivo and in vitro. (DK Patel, 2012)

Helicteres isora (Sterculiaceae)

Antihyperglycemic activity of butanol extracts of the root of Helicteres isora at 250 mg/kg, p.o. in glucose-loaded rats acts through insulin-sensitizing activity.

Hibiscus rosa sinensis (Malvaceae)

Oral administration of ethanol extract of Hibiscus rosa sinesis at 250 mg/kg, p.o. showed mild but significant hypoglycemia which was mainly due to insulin release by stimulation of pancreatic beta cells. (DK Patel, 2012)

Hordeum vulgare (Gramineae)

The germinant fruits of Hordeum vulgare showed hypoglycemic and hyperinsulinemic effects in NIDDM subjects, due to the mobilization of insulin in NIDDM, which makes it a suitable cereal for diabetes mellitus.

Lepechinia caulescens (Lamiaceae)

Lepechinia caulescens significantly decreased glucose tolerance suggesting that Lepechinia caulescens has insulinomimetic activity. (DK Patel, 2012)

Medicago sativa (Fabaceae)

Aqueous extract of Medicago sativa evoked stimulation of insulin secretion from the BRIN-BD11 pancreatic beta cell line in vitro. In another study, it was found that the insulin-releasing activity of the methanol and water fractions is mainly due to the cumulative effect of its constituent present in it.

Momordica charantia (Cucurbitaceae)

Significant reduction of blood glucose levels and increased concentration of plasma insulin have been observed in diabetic rats that were treated with fruit juice of Momordica charantia. The observed effect was due to an increase in the number of beta cells in treated animals compared to the untreated ones. The phytochemical momordicin, charantin, and a few compounds such as galactose-binding lectin and insulin-like protein isolated from various parts of this plant have been shown to have insulin-mimetic activity. Aqueous extract of unripe fruits of Momordica charantia has also been shown to partially stimulate insulin release from isolated beta-cell of obese-hyperglycemic mice suggesting that the insulin-releasing action is the result of perturbations of membrane functions. Momordica charantia increases the renewal of partial cells in the pancreas or may permit the recovery of partially destroyed cells and stimulates pancreatic insulin secretion. (DK Patel, 2012)

Mucuna pruriens (Leguminosae)

Blood glucose lowering activity of powdered seeds of Mucuna pruriens was observed at 0.5, 1, and 2 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 release of insulin or by a direct insulin-like action due to the presence of trace elements like manganese, zinc, etc.

Nigella sativa oil (Ranunculaceae)

Significant decreases in blood glucose level and increase in serum insulin level were observed on treatment with Nigella sativa oil for 4 weeks. Immunohistochemical staining of the pancreas from Nigella sativa oil-treated group showed large areas with positive immunoreactivity for the presence of insulin. (DK Patel, 2012)

Panax ginseng (Araliaceae)

Ginseng polypeptides isolated from the root of Panax ginseng, when injected subcutaneously at daily doses of 50 and 100 mg/kg for 7 successive days in mice resulted in decreased blood glucose, increased liver glycogen level, and stimulated insulin secretion. The aqueous ethanolic extract of Korean red ginseng significantly evoked an insulin release in a glucose-independent manner.

Pandanus odorus (Pandanaceae)

4-Hydroxybenzoic acid from Pandanus odorus at 5 mg/kg increased serum insulin levels and liver glycogen content in healthy rats.

Parinari excelsa (Chrysobalanaceae)

Flavonoid of Parinari excelsa showed hypoglycemic effect due to the ability of insulin secretory activity in the diabetic animal models.

Prunella vulgaris (Labiatae)

Jiangtangsu had been isolated from Prunella vulgaris and confirmed to have a remarkable blood sugar-lowering effect in diabetic mice. The possible mechanism of action of Jiangtangsu is to repair cells of the pancreatic islets to release insulin. (DK Patel, 2012)

Psidium guajava (Myrtaceae)

Flavonoid glycosides such as strictinin, isostrictinin, and pedunculagin are the effective constituents of Psidium guajava, which have been used in the clinical treatment of diabetes because it improves insulin sensitivity.

Pterocarpus marsupium (Fabaceae)

Flavonoid fraction from Pterocarpus marsupium has been shown to cause pancreatic beta cell regranulation. Epicatechin, its active principle, has been found to be insulinogenic thus enhancing insulin release and conversion of proinsulin to insulin in vitro. Epicatechin isolated from the bark of Pterocarpus marsupium has been found to have protective and restorative effects on beta cells in diabetic subjects. Possibly, epicatechin acts by regenerating the beta cells and may produce actions similar to that of insulin. (Modak M et al, 2007)