INTRODUCTION:

Diabetes mellitus is an endocrinological metabolic disorder characterized by hyperglycemia, glycosuria, hyperlipemia, negative nitrogen balance and sometimes ketonemia. A wide-spread pathological change is thickening of capillary basement membrane, increase in vessel wall matrix and cellular proliferation resulting in vascular complications like lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency^{1, 2}.

Two major types of diabetes mellitus are:

Type I: Insulin dependent diabetes mellitus (IDDM), juvenile onset diabetes mellitus is caused due to insulin insufficiency because of lack of functional b-cells. Patients suffering are totally dependent on exogenous source of insulin³. This type is less common and has a low degree of genetic predisposition².

Type II: Non Insulin dependent diabetes mellitus (NIDDM), maturity onset diabetes mellitus is unable to respond to insulin and can be treated with dietary changes, exercise and medication. Type II diabetes is the more common form of diabetes constituting 90% of the diabetic population³.

The therapeutic measurements include use of insulin and other agents like amylin analogues, α-glycosidase inhibitors (Table-1) for the treatment of hyperglycemia. These drugs also have certain adverse effects like causing hypoglycaemia at higher doses, liver problems, lactic acidosis and diarrhea (Table-2) and drug interaction (Table-3). Apart from currently available therapeutic options, many herbal medicines have been recommended for the treatment of diabetes. Traditional plant medicines are used throughout the world for a range of diabetic population. Herbal drugs are prescribed widely because of their effectiveness, less side effects and relatively low cost⁴.

Therefore, investigation on such agents from traditional medicinal plants has become more important⁵. Thus there is still need to develop new drugs with greater clinical efficacy, minimal side effect, devoid of unfavorable drug interactions properties.

Natural products-

Diabetes mellitus (DM) is a chronic disease caused by inherited or acquired deficiency in insulin secretion and by decreased responsiveness of the organs to secreted insulin⁸. Diabetes is in the top 10, perhaps in the top 5, of the most significant diseases in the developed world and is still gaining significance⁹. According to the W.H.O. (2005) there were 150 million people over 20 years of age living with diabetes in 2000 and they project that by 2025 there will be 300 million people living with this condition. The increase is expected to be 42% in developed countries and 70% in developing countries (W.H.O. 2005). India is estimated to have 19.5 million diabetics¹. Reasons for this rise include increase in sedentary lifestyle, consumption of energy rich diet, obesity, higher life span, etc¹⁰. Different types of oral hypoglycaemic agents are available along with insulin for the treatment of diabetes mellitus¹¹. The oral hypoglycaemic agents currently used in clinical practice have characteristic profiles of serious side effects, high cost and drug-drug interactions prompting the patients to stop taking the medication and DM progresses with further acute and chronic complications and even death¹². Hence, there is a need to search for newer anti-diabetic agents that retain therapeutic efficacy and are devoid of side effects that could be important sources of such agents¹³. Plant-based drugs have been used against various diseases since long time. The primitive man used herbs as therapeutic agents and medicament, which they were able to procure easily. The nature has provided abundant plant wealth for all living creatures, which possess medicinal virtues⁹. Many herbal medicines have been recommended for the treatment of diabetes¹⁰. Phytomedicine capable of treating the disease , but with fewer side effects and less expensive, will be of great help to the diabetic patients specially due to the extended belief that natural treatments cause less harm to the organism than synthetic ones^10,12. Herbal preparations are preferred therapeutic agents to manage the glycemic control in diabetics because of their lesser side effects¹. Various formulated herbal drugs with antidiabetic properties are described (Table 4), and detailed of various plants are also described (Table 5). With this regards herbal antidiabetics that are successfully exploited are reviewed as under.

MECHANISM THROUGH WHICH PLANTS ACT AS ANTIDIABETIC AGENTS:

Aerva lanata:

Aerva lanata. (Amaranthaceae) is an erect, hoary-tomentose herb available throughout India, Ceylon, tropical Africa, Java and Philippines. A. lanata (L.), commonly known as ‘Sunny khur’ is widely used in Indian folk medicine for the treatment of Diabetes mellitus. A. lanata was found to reduce the increase of blood sugar in alloxan-induced diabetic rats (42% at 375 mg/kg and 48% at 500 mg/kg body weight). Chronic administration of A. lanata significantly (P<0.001) reduced the blood sugar of alloxan induced diabetic rats for 2 weeks. Also the extract prevented a decrease in body weight and reduced the increased lipid peroxides in alloxan induced diabetic rats. Treatment with A. lanata reduces the level of serum peroxides and confirmed the function of the extract on the protection of vital tissues including the pancreas, thereby reducing the causation of diabetes in rats. Since the flavonoids and terpenes present in the A. lanata are reported to be hepatoprotective agents. Improvement of liver function and subsequent increase in uptake of blood glucose and its utilization may be another mechanism of action of A. lanata¹³.

Allium sativum:

Allium sativum (Liliaceae), Garlic, is a common spicy flavouring agent used since ancient times. Hypoglycaemic effect of garlic, attributed mainly to allicin-type compounds or sulphur compounds [di (2-propenyl) disulphide and 2-propenyl propyl disulphide, respectively]. The mechanism of hypoglycaemic action probably involves direct or indirect stimulation of insulin secretion. These disulphide compounds have the effect of sparing insulin from –SH inactivation by reacting with endogenous thiol containing molecule such as cysteine, glutathione, and serum albumins. The garlic extract might enhance glucose utilization because it significantly decreased the blood glucose level in glucose-loaded rats. It may be due to restoration of delayed insulin response or due to inhibition of intestinal absorption of glucose. This could be due to potentiation of the insulin effect of plasma by increasing the pancreatic secretion of insulin from existing b-cells or its release from bound insulin. Oral administrations of the garlic extract significantly decreased serum glucose, total cholesterol, triglycerides, urea, uric acid, creatinine, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, while increased serum insulin in diabetic rats but not in normal rats (p<0:05)^10,45.

Aporosa lindleyana:

Aporosa lindleyana (Euphorbiaceae), grows as small middle sized tree upto 15 m height, found throughout India and is commonly called Kotili in Tamil. The aqueous and alcoholic extracts of A. lindleyana (100 mg/kg) produced a significant fall in the blood glucose level in both normal and diabetic rats after 1h administration of the extracts. The aqueous and alcoholic extracts of A. lindleyana produced the maximum glucose lowering activity in diabetic rats after 3 h and both extracts produced significant hypoglycaemic activity in normal rats. The aqueous and alcoholic extracts of A. lindleyana (100 mg/kg) reduced the blood glucose of normal rat from 80.±9/2.7 to 69.8±/2.0 mg% and 82.69±1.9 to 70.8±/3.2 mg%, respectively 3 h after oral administration of the extract (P</0.001) and also significantly lowered blood glucose level in alloxan induced diabetic rat from 306±/3.37 to 160±/2.46 and 328±/4.15 to 152±/3.86 mg%, respectively 3 h after oral administration of the extract (P</0.001)¹⁹.

Ajuga iva:

Ajuga iva act by enhancing glucose utilisation in the peripheral tissues. Flavonoids are the major constituents of the aqueous extract. These natural compounds could be responsible for the hypoglycaemic effect of A. iva. Single and repeated oral administration of the extract of A.iva at a dose of 10 mg/kg produced a slight and significant decrease in plasma glucose levels in normal rats 6 h after administration and after 3 weeks of treatment. A.iva reduced plasma glucose levels of streptozotocin diabetic rats from 337±9.3 to 102.2±17.7 mg/dl after 6 h of oral administration (P<0.001). Repeated oral administration of A. iva to streptozotocin diabetic rats significantly decreased the plasma glucose levels after 1 week of treatment (112±14.4 mg/dl at 1 week vs 337±9.3 mg/dl at the baseline values, (P<0.001). It continuously decreased thereafter and showed a rapid normalisation after 1 week of A. iva treatment¹⁷.

Beta vulgaris:

Beta vulgaris , Chard is a widespread plant in Turkey and is used as an antidiabetic agent in folk medicine. Blood glucose lowering compounds saponins and flavonoids have been isolated from B. Vulgaris. Chard may decrease blood sugar by increasing insulin secretion from b cells of the pancreas²⁴.

Bauhinia forficate:

Bauhinia forficata (Leguminosae) is a small tree that grows to a height of 5-9 m. It is commonly known as ‘‘Pata de vaca’’ due to its large, divided leaves resembling a cow’s hoof, a feature that is distinctive to the genus Bauhinia. The hypoglycemic effect in normal rats may be due to the potentiation of insulin release from b-cells, to action on insulin receptors or inhibition of glucose reabsorption in the proximal tubules of the kidney. The hypoglycemic effect of this fraction in alloxan-diabetic rats was more powerful when compared to normal rats. It could be caused by an increase in peripheral glucose consumption²³.

Caesalpinia bonducella:

Caesalpinia bonducella commonly known as Nata Karanja, a prickly shrub found throughout the hotter parts of India, Myanmar and Sri Lanka, has grey, hard, globular shaped seeds with a smooth shining surface. Significant blood sugar lowering effect (P</0.05) of C. bonducella was observed in type 2 diabetic model. The ethanolic (80%) extract of C. bonducella is potentially active with sub-chronic treatment schedule (nine dose, 5 days) at a dose of 250 mg/kg b.w. in type 2 Long Evans rats. In type 1 diabetic model (IDDM), there were reduction of serum glucose levels on day 7 in both aqueous (22.34 mmol/l) and ethanolic extracts (20.22 mmol/l) treated groups but were not so significant with respect to their values of day 1 (26.90 and 25.15 mmol/l, respectively). This indicates that the aqueous and ethanolic extracts of the seed shell of C. bonducella potentially control the hyperglycemic state of type 2 diabetes. Therefore, it may be ascertained that the hypoglycemic activity of C. bonducella (aqueous and ethanolic extract) in both type 1 and 2 models is due to increase uptake of glucose for the formation of glycogen by enhanced glycogenesis. This may be the probable mechanism for the hypoglycemic action, as the drug has no role on the gut sugar absorption^{27, 28}.

Camellia sinensis:

Camellia sinensis is Green tea produced by enzymatic inactivation of leaves followed by rolling or comminution and drying. Administration of GTP (500 mg/kg b.wt.) to normal rats increased glucose tolerance significantly (P</0.005) at 60 min. GTP was also found to reduce serum glucose level in alloxan diabetic rats significantly at a dose level of 100 mg/kg b.wt. Continued daily administration (15 days) of the extract 50, 100 mg/kg b.wt. Produced 29 and 44% reduction in the elevated serum glucose level produced by alloxan administration²⁹.

Canarium schweinfurthii:

Canarium schweinfurthii is a big tree with deciduous leaves attaining 45m of height and 150 cm stem diameter. Extracts may possess insulin like effect on peripheral tissues by either promoting glucose uptake and metabolism, by inhibiting hepatic gluconeogenesis or absorption of glucose into the muscles and adipose tissues, by the stimulation of a regeneration process and revitalisation of the remaining b-cells. At 300 mg/kg, the extracts C. schweinfurthii, significantly showed at least 69.9% reduction in blood glucose level³⁰.

Carum carvi:

Carum carvi (Apiaceae), locally known as “Karwiya” is native shrubs. The hypoglycaemic activity of these plants may therefore be due to inhibition of hepatic glucose production or stimulation of glucose utilisation by peripheral tissues, especially muscle and adipose tissue. The plant extracts could also act as inhibitors of tubular renal glucose reabsorption. The known main constituents of C. carvi have been demonstrated to be carvone (40–60%), limonene, carveol, dihydrocarveol, thymol in addition to glucosides and flavonoids. After a single dose or 14 daily doses, oral administration of the aqueous C. carvi (20 mg/kg) produced a significant decrease on blood glucose levels in STZ diabetic rats (P< 0.001)³¹.

Capparis spinosa: Capparis spinosa (Capparidaceae), locally known as “Kebbar”, are native. The hypoglycaemic activity of these plants may therefore be due to inhibition of hepatic glucose production and/or stimulation of glucose utilisation by peripheral tissues, especially muscle and adipose tissue. The plant extracts could also act as inhibitors of tubular renal glucose reabsorption. The main constituents of C. spinosa have been demonstrated to be flavonoids, alkaloids, lipids and glucosinolates. After a single dose or 14 daily doses, oral administration of the aqueous C. carvi extracts (20 mg/kg) produced a significant decrease on blood glucose levels in STZ diabetic rats (P< 0.001)³¹.

Cassia auriculata:

Cassia auriculata (Leguminosae) is a fast growing branched tall, evergreen shrub with reddish brown branches. Maximum reduction in serum glucose level was observed after 4 h at a dose levels of 100, 200, 400 mg/kg body weight of the extract. In normal rats the serum glucose level reduction at 4th h was 23% by 100 mg/kg body weight and 31% by 200 mg/kg body weight. The extract of C. auriculata leaves produced significant hypoglycemic effect at 200 mg/kg dose, both in normal and alloxan-induced diabetic animals. In alloxan induced diabetic rats, chronic administration of the extract significantly reduced the serum glucose level from third day to till the end of the experiment³².

Fraxinus excelsior:

Fraxinus excelsior, locally known as “l’ssanel’ousfour”, is a native shrub widely distributed throughout the south-eastern region of Morocco. The known main isolated constituents of F. excelsior have been demonstrated to be phenols and fraxin. The hypoglycaemic activity of these plants may therefore be due to inhibition of hepatic glucose production and/or stimulation of glucose utilization by peripheral tissues, especially muscle and adipose tissue. After a single dose or 15 daily doses, oral administration of the aqueous extracts (20 mg/kg) produced a significant decrease of blood glucose levels in both normal and STZ diabetic rats (P < 0.001). From the first week, the body weight was increased in normal rats (P < 0.05) and decreased in STZ rats (P < 0.01) after F. excelsior administration⁵².

Ganoderma lucidum:

Ganoderma lucidum (Lingzhi) is a dried fruit-body of a large, dark mushroom with various therapeutic values with no documented toxicity. G. lucidum (0.03 and 0.3 g/kg) lowered the serum glucose level in +db/+db mice after the first week of treatment whereas a reduction was observed in +db/+m mice only fed with 0.3 g/kg at the fourth week. The phosphoenolpyruvate carboxykinase expression was markedly reduced in +db/+db mice (0.3 g/kg). G. lucidum consumption can provide beneficial effects in treating type 2 diabetes mellitus by lowering the serum glucose levels through the suppression of the hepatic phosphoenolpyruvate carboxykinase gene expression⁵³.

Globularia alypum:

Globularia alypum (Globulariaceae), locally named as ‘Ain Larneb’ is a wild plant. Mechanism by which these plants decreased blood glucose levels seems to be, at least for the doses used in study, independent of elevation of insulin secretion. Other extra-pancreatic actions influencing glucose metabolism may be involved in this pharmacological effect such as stimulation of glucose uptake by peripheral tissues, correction of insulin resistance and/or inhibition of the endogenous glucose production or activation of the glycogenesis pathway by stimulating glycogen synthase activity. In STZ rats, single and repeated oral administration of G. alypum produced significant decrease of blood glucose levels. LD₅₀ value was over 8.1g/kg⁵⁴.

Helicteres isora:

Helicteres isora is a shrub or small tree available in forests throughout the Central and Western India. Blood glucose lowering effect of the aqueous bark extract of H. isora was observed in STZ diabetic rats as well as in fasted normal rats, this effect could, possibly be due to inhibition of the proximal tubular reabsorption mechanism for glucose in the kidney. From the roots and barks of H. isora, betulic acid, daucosterol, sitosterol, isorin were isolated. In many plants, sitosterols have been reported to exhibit hypoglycemic effects. The LD₅₀value of the aqueous extract of bark of H.isora (5 g/kg) was higher than the therapeutic effective dose⁵⁶.

Hemionitis arifolia (Burm.):

Hemionitis arifolia is a commonly occurring fern in most of the moist forest areas in the Western Ghats. The ethanol extract showed optimum activity at 200 mg/kg. The extract exhibited only marginal hypoglycaemic activity in overnight fasted normal rats and it was devoid of conspicuous toxic symptoms in sub-acute toxicity evaluation in mice. When the alcohol extract was fractionated by sequential solvent extraction, the activity was found in ethyl acetate fraction (50 mg/kg). This fraction containing steroids and coumarins showed anti-diabetes activity in alloxan diabetic rats as judged from serum glucose levels, liver glycogen content and body weight⁵⁷.

Hibiscus rosasinensis:

Hibiscus rosasinensis, (Solonaceae) is an evergreen woody, glabrous, showy shrub, known as shoe flower plant or Chinese hibiscus. A single dose (500 mg/kg) of extract showed a significant reduction in the blood sugar level after 1 h, where 250 mg/kg showed a significant (P<0.05) after 3 h. the regeneration of β cells following destruction by alloxan might be the primary cause for the antidiabetic activity of the extracts⁵⁸.

Inula viscose:

Inula viscosa (Asteraceae), vernacularly known as “Trehla”. Hypoglycaemic activity of I. viscosa may involve an extra pancreatic effect. Plants extract may reduce blood glucose with an insulin independent pathways such as inhibition of hepatic glucose production, inhibition of intestinal glucose absorption or correction of insulin resistance. In normal rats, a significant reduction in blood glucose levels 2h was observed after a single oral administration (p<0.001). Repeated daily oral administration significantly reduced blood glucose levels after 4 days of treatment (p<0.01). In diabetic rats, a significant reduction in blood glucose levels was observed 1 h after a single oral administration (p<0.001). Repeated oral administration reduced blood glucose levels at the 4^th day (p<0.001)⁶⁷.

Juniperus chinensis:

Juniperus chinensis (Chinese juniper) is an ornamental tree with scaly, partly needle and year-round foliages. The blood glucose levels of alloxan-induced diabetic rats treated with the ethanolic extract were reduced to 94, 81%, 66%, 45% and 40% at 1, 3, 5, 7 and 9 h, respectively (p<0.05), while the aqueous extract had no effect at all⁶⁰.

Lagerstroemia speciosa:

Lagerstroemia speciosa (Lythraceae), commonly known as Crepe Myrtle, grows widely in tropical countries, including the Philippines, India, Malaysia, China, and Australia. Researchers in Japan isolated corosolic acid (2-hydroxyursoloic acid, C₃₀H₄₈O₄) from the methanol extract of L. speciosa leaf, which showed a significant glucose transport-stimulating activity at 1µM. This extracts of the plant leaves were standardized to corosolic acid, and one such extract is Glucosol^TM, which contain 1% corosolic acid. Glucosol^TM shows a significant dose–response relationship over the range of 16–48 mg/day. Subjects received Glucosol^TM in the soft gel form showed a 30% decrease in their blood glucose, while those received Glucosol^TM in the hard gel form had 20% reduction in the blood glucose level. The difference in blood glucose reduction at 32 and 48 mg/day dose of Glucosol^TM between the soft gel and hard gel formulations (P<0.001), and thus, the soft gel is more effective compared to the hard gel dry-powder formulation. Oral formulations of an extract from the leaves of L. speciosa standardized to 1% corosolic acid (Glucosol^TM) exert a marked lowering of blood sugar in Type II diabetics. The active triterpene ingredient in Glucosol^TMis lipophilic and better absorbed in an oil-based soft gelatin capsule formulation⁶².

Lepidium sativum:

Lepidium sativum (Brassicaceae) locally known as “hab arrachad” is a native shrub. Phytochemical analysis of L. sativum reported the presence of imidazole alkaloids. These compounds isolated from other plants were demonstrated to possess a hypoglycaemic activity. Hypoglycaemic action of L. sativum seems to be extra-pancreatic. The aqueous L. sativum extract may act in the key organs of glucose homeostasis such as liver by the inhibition of endogenous glucose production, the kidney by the inhibition of renal glucose reabsorption probably by the alteration of renal glucose transporters (SLGT1) expression in the kidney, muscle and adipose tissues by increasing both glucose uptake and glucose intracellular metabolism. Inhibition of intestinal glucose absorption could be involved in this observed hypoglycaemic activity of L. sativum. After a acute (single dose) or chronic (15 daily repeated administration) oral treatments, the aqueous L. sativum extract (20 mg/kg) produced a significant decrease on blood glucose levels in STZ diabetic rats (p < 0.001); the blood glucose levels were normalised 2 weeks after daily repeated oral administration of aqueous L. sativum extract (20 mg/kg) (p < 0.001). Significant reduction on blood glucose levels were noticed in normal rats after both acute (p < 0.01) and chronic treatment (p < 0.001). In addition, no changes were observed in basal plasma insulin concentrations after treatment either in normal or STZ diabetic rats indicating that the underlying mechanism of this pharmacological activity seems to be independent of insulin secretion⁶¹.

Mucuna pruriens:

Mucuna pruriens is commonly known as Cowitch in English and Poonaikalli in Tamil.In normal rats, the aqueous extract of the seeds of M. pririens (100 and 200 mg/kg body weight) significantly (P<0.001) reduced the blood glucose levels after an oral glucose load from 127.5±3.2 to 75.6±4.8 mg% 2 h after oral administration of seed extract. It also significantly lowered the blood glucose in STZ diabetic rats from 240.5±7.2 to 90.6±5.6 mg% after 21 days of daily oral administration of the extract (P<0.001). A number of essential minerals viz., Na, K, Ca, Zn, Mg, P, Fe, Cu, Mn and Cr are found to be present in M. pruriens. These mineral elements may be associated with the mechanism of insulin release and its activity or glucose tolerance factor as described in different laboratory animals and in human beings⁶⁷.

Momordica cymbalaria:

Aqueous extract of Momordica cymbalaria at a dosage of 0.5 g/kg b.w. is showing maximal blood glucose lowering effect in diabetic rats. The blood glucose lowering effect of the aqueous extract of M. cymbalaria fruit in diabetic rats is 26% higher after 3 h of drug administration than that of the oral hypoglycemic agent, glibenclamide. M. cymbalaria fruits consists of alkaloids, tannins, amino acids, proteins and phenols. Maximum lowering effect of blood glucose of 41.8% by using 0.5 g/kg b.w. of aqueous extract of M. cymbalaria fruit, compared to the other solvent extracts of the M. cymbalaria in the diabetic rats. An aqueous extract from the M. charantia was a potent stimulator of insulin release of b-cell rich pancreatic islets isolated from obese-hyperglycemic mice. The antihyperglycemic activity of M. Cymbalaria may be due to its stimulating effect on the remnant b-cells or improvement in insulin action at cellular level or it could also be due to the insulin like effect of the active principle(s) present in the extract^{69, 70}.

Nymphaea stellata:

Ethanolic extract of leaves of Nymphaea stellata given by oral route to diabetic rats at dose of 100 and 200 mg/kg/day for seven days reduced significantly by 31.6 and 42.6 % the plasma glucose level increased by intraperitoneal injection of 120 mg/day of alloxan treatment⁷².

Panax ginseng:

Panax ginseng (ginseng) has been widely used to treat diabetes in traditional Chinese medicine. A significant antihyperglycemic action on the fasting serum glucose was observed after a two-week treatment of diabetic rats with 20 mg/kg ginsenoside-Re. Ginsenoside-Re treatment of the diabetic rats has resulted in a significant reduction in the C-reactive protein level. This result demonstrated that the intake of ginsenoside Re could reduce the elevation of C-reactive protein in diabetes, implying ginsenoside Re may improve diabetes and its complications by reducing Inflammation^100.

Ocimum sanctum:

Ocimum sanctum is found throughout India and is commonly called Tulsi in Hindi and Holy Basil in English. Administration of O. sanctum extract produced a dose dependent reduction in blood sugar at 60 and 120 min treated rats (100, 200 and 400 mg/kg) was 7.64, 17.18 and 19.78%, respectively (P<0.001). O. sanctum may be acting through affect glucose absorption from the gut⁷⁴.

Origanum vulgare:

Origanum vulgare (Lamiaceae), locally known as “Zaatar” is a native plant widely distributed throughout the south-eastern region of Morocco (Tafilalet). The known main constituents of O. vulgare have been demonstrated to be volatile compounds such as linalool, alcohols, phenols and terpens. The hypoglycaemic activity of the O. vulgare extract may, therefore, be due to inhibition of hepatic glucose production and/or stimulation of glucose utilisation by peripheral tissues, especially muscle and adipose tissue. In normal rats, the blood glucose levels were slightly decreased 6 h after a single oral administration (P<0.05) as well as 15 days after once daily repeated oral administration of aqueous O. vulgare extract (P<0.05) (20 mg/kg). After a single dose or 15 daily doses, oral administration of the aqueous extract (20 mg/kg) produced a significant decrease on blood glucose levels in STZ diabetic rats (P<0.001). In STZ rats, the blood glucose levels were normalised from the fourth day after daily repeated oral administration of aqueous O. vulgare extract (20 mg/kg) (P<0.001). However, this effect was less pronounced 2 weeks after daily repeated oral administration of O. vulgare extract⁷³.

Parinari excels:

Parinari excelsa is a big tree that grows to a height of 25 m. Phytochemical screening shows the presence of flavonoids and tannins in the bark of P. excelsa. Studies reported the hypoglycaemic effect and the ability to induce insulin secretion of flavonoids in diabetic animal models. As well as glibenclamide, the P. excelsa aqueous extract at 100 and 300 mg/kg/day for 7 days reverse the permanent hyperglycaemia induced by alloxan. The blood glucose decreased from 3.11±0.24 to 0.91±0.02 g/l and 3.60±0.12 to 0.85±0.04 g/l, respectively (in alloxan-induced diabetic).the oral treatment with P. excelsa barks aq. extract at the dose of 100 and 300 mg/kg reduced significantly (P<0.05) the blood glucose level at 1/2 h, after glucose administration and in a similar extent to that of the reference drug glibenclamide (200 μg/kg). This effect persists until 6 h⁷⁶.

Pterocarpus santalinus:

Pterocarpus santalinus (Fabaceae) is restricted to part of Andhra Pradesh and neighbouring areas of Madras and Mysore state. The antihyperglycemic activity of P. santalinus may be due to its stimulating effect on the remnant beta cells or improvement in insulin action at cellular level or it could also be due to its insulin like effect. Phytochemical studies have revealed that P. santalinus bark consists of b-sitosterol, lupeol and (-)-epicatechin with hypoglycemic and antihyperglycemic activity. The hypoglycemic activity of active principle (-)-epicatechin isolated from the bark and wood of P. santalinus is well established and is due to beta cell regeneration insulin like activity and also by converting proinsulin to insulin. Compared with the diabetic rats treated with glibenclamide and the antihyperglycemic activity of ethanolic extract of P. santalinus bark at the dose of 0.25 g/kg b.w. was found to be more effective than that of glibenclamide⁷⁸.

Rosa damascene:

Rosa damascena, (Rosaceae) Known as Persian rose, is an erect shrub of 1–2min height. Flowers of this plant are large, showy and colourful. R. damascena to day is cultivated extensively all over the world. R. damascena might exert an anti-diabetic effect by suppressing carbohydrate absorption from the intestine and can reduce the postprandial glucose level. The petals of R.damascena are a rich source of polyphenols, flavonoids, phenolic compounds and essential oils R. damascena extract had intensive inhibitory effect on α-glucosidase and its inhibition mode was non-competitive.synthetic α-glucosidase inhibitors have undesirable side-effects such as abdominal cramping and diarrhea and some of these may increase the chance of hepatic syndrome and renal tumors. The R. damascena can be used to suppress postprandial hyperglycemia in diabetic patients. Given the common, side-effect-free uses of this plant in diets of Persians as flavouring agent in yogurt and as a laxative, this plant would be a good candidate for alternative and/or complementary medicine inthe management of diabetic patients and for decreasing diabetes complication such as retinopathy⁸².

Retama raetam:

Retama raetam, (Fabaceae) locally named as “R’tm”, is a spontaneous plant. It is common to North and East Mediterranean region and the Sinai Peninsula. The mechanism involved in this pharmacological effect is extra-pancreatic. In some advanced studies, we have demonstrated that the probable mechanism of R. raetam action seems to be the inhibition of renal glucose reabsorption as indicated by increment of urinary glucose loss. R. raetam extract may exert its hypoglycaemic effect by other mechanisms such as stimulation of glucose uptake by peripheral tissues such as muscles and adipose tissues, correction of insulin resistance inhibition of endogenous glucose production or activation of glycogenogenesis in liver and muscles. The main constituents of R. raetam are flavonoids, exhibits hypoglycaemic activities in both normal and STZ diabetic rats. The aqueous extract of R. raetam at a dose of 20 mg/kg significantly reduced the blood glucose in normal rats 6 h after a single oral administration (P<0.005) and two weeks after repeated oral administration (P < 0.05). This hypoglycaemic effect is more pronounced in streptozotocin diabetic rats (P < 0.001)⁸¹.

Rubus fructicosis:

Rubus fructicosis, (Rosaceae) (Blackberry) locally named as ‘Toute chaouki’. It is a deciduous tree which is widely distributed in Morocco. Oral administration of R. fructicosis lowered significantly the blood glucose levels, The mechanism by which these plants decreased blood glucose levels independent of elevation of insulin secretion. Other extra-pancreatic actions influencing glucose metabolism may be involved in this pharmacological effect such as stimulation of glucose uptake by peripheral tissues, correction of insulin resistance or inhibition of the endogenous glucose production or activation of the glycogenesis pathway by stimulating glycogen synthase activity. The presence of essential oils, flavonoids and tannins as the main constituents of the aqueous extract used. These natural compounds could act separately or synergistically to cause the hypoglycaemic effect. 20% dried leaf infusion of R. fructicosis produced a significant decrease of blood glucose levels in STZ rats because counter-regulatory mechanisms cannot normalize rapidly blood glucose levels. LD₅₀ value was over 8.1 g/kg for R. fructicosis⁵⁴.

Salvia officinalis (Sage):

Salvia officinalis (sage) have been used as traditional herbal medicine against a variety of diseases. Oral administration of 0.2 and 0.4 g/kg body wt. of the sage extract for 14 days exhibited a significant reduction in serum glucose, triglycerides, total cholesterol, urea, uric acid, creatinine, AST, ALT and increased plasma insulin in streptozotocin-induced diabetic rats but not in normal rats. The elevation in plasma insulin levels in the sage extract treated STZ diabetic rats could be due to substances present in the plant extract which stimulate insulin secretion or which protect the intact functional b-cells from further deterioration so that they remain active and continue to produce insulin. Protection of the b-cells could be at least, in part, a result of the reduction in blood glucose, eliminating glucotoxicity to the b-cells. Sage extract contains rosmarinic acid, phenolic acids, carnosic compounds and flavonoids or their derivatives⁸.

Sclerocarya birrea:

Sclerocarya birrea (Anacardiaceae), popularly known in South Africa as ‘marula tree’, is a medium-sized, single-stemmed tree of up to 15 metres in height. Coumarins, flavonoids, terpenoids, and a host of other secondary plant metabolites, including arginine and glutamic acid, possess hypoglycaemic effects in various experimental animal models. Hypoglycemic effect of terpenoids appears to involve stimulation of pancreatic b-cells and subsequent secretion of preformed insulin, the mechanism of the hypoglycemic action of coumarins probably involves hepatotoxicity. For instance, possibilities exist that arginine could have increased the ability of the plant extract to stimulate and increase preformed insulin secretion from pancreatic b-cells by depolarizing pancreatic b-cells. Moreover, insulin secretion by the pancreatic b-cells could also have been increased by glutamic acid metabolism. One or more of the other chemical constituents of the plant, especially flavonoids, arginine, glutamic acid, and so on, is/are also likely to have played a crucial role in the hypoglycemic action of the plant extract. Administrations of the single dose of S. birrea stem-bark aqueous extract (800 mg/kg p.o.) significantly reduced (P<0.001) the blood glucose levels of both fasted normal (normoglycemic) and fasted STZ-treated, diabetic rats⁸⁵.

Smallantus sonchifolius (yacon):

Smallantus sonchifolius (Polymnia sonchifolia, Asteraceae) or yacon is a perennial herb 1.5–3 m tall with a root system composed of 4–20 edible fleshy tuberous storage roots. Ten-percent yacon decoction produced a significant decrease in plasma glucose levels in normal rats when administered by intraperitoneal injection or gastric tube 30 day administration of 2% yacon tea increased circulating insulin levels. This increase may be a consequence of the stimulation of insulin synthesis and secretion, of the inhibition of insulin degradation or of both, since many compounds present in plants have been demonstrated to produce these effects. For instance, benzoic acid related molecules inhibited insulinase and enhanced insulin effects⁸⁶.

Suaeda fruticosa:

The English common name for Suaeda fruticosa (Chenopodiaceae) is ‘Alkali seepweed’. It is an annual herbaceous plant, growing in saline soil. Its tiny leaves are part of the natural diet of sand rats (Psammomys obesus Cretzschmar, Muridae). The aqueous extract of S. fruticosa according to the Paris and Nothis (1969) method revealed the presence of flavonoids. Earlier investigations on the antidiabetic effect in sand rats of Atriplex halimus L. (Chenopodiaceae) suggested that mineral salts, specifically of chromium, magnesium and manganese, may be the most active constituents. However, the active principle responsible for the hypoglycemic activity remain to be identified. The hypoglycemic effect of our extract may involve an extra-pancreatic action. The aqueous extract may act at a peripheral level. This could be done by facilitating glucose metabolism via the increase of its cellular uptake (increase of the number of receptors and/or the glucose receptor affinity), and also possibly at the hepatic level by increasing glycogenesis via the activation of glycogen synthetase. The aqueous extract at a dose of 192 mg/kg produced a significant decrease in blood glucose levels in normalrats (P<0.05), and even more in diabetic rats (P<0.001)⁸⁷.

Silybum Marianum:

Silybum marianum, locally known as “Chouk J’mal” or “Guandoule”, is a native shrub (less than one meter high) widely distributed throughout the south-eastern region of Morocco (Tafilalet). The hypoglycaemic activity of these plants may therefore be due to inhibition of hepatic glucose production and/or stimulation of glucose utilization by peripheral tissues, especially muscle and adipose tissue. Phytochemical investigations of S. marianum have demonstrated that flavonolignan represent the main compounds⁵².

Teucrium polium:

STZ diabetic rats fed with a single dose of Teucrium polium extract (equivalent to 0.5 g plant powder per kg body weight) per day for six consecutive weeks exhibited significant blood glucose reduction (by 64%) and increase of blood insulin level by 160%. T. polium crude extract is able to enhance insulin secretion by almost 135% after a single dose of plant extract (equivalent to 0.1 mg plant leaf powder per ml of the culture medium) at high glucose concentration (16mmol/l). T. polium crude extract is able to produce a dose-dependent stimulation of basal insulin release and also to potentiate glucose-stimulated release of insulin in rat islets with no significant and detectable effects on the time pattern of insulin secretion. Plant extract, probably without metabolic transformation, is capable of reducing high blood glucose mainly through enhancing insulin secretion⁹⁰.

Table 5: Hypoglycaemic properties of selected plant-products-

S. No.	Name of plants	Parts used	Solvent used	Method	Ref.
1-	Aegle marmelos (L.) Correa ex Roxb. (Rutaceae) ,,	Leaf extract Fruit extract	Aqueous Aqueous	Alloxanized rats Streptozotocin induced female albino Wistar diabetic rats	14 15,16,71
2-	Ajuga iva (L.) Schreber (Labiatae)	Whole plant	Lyophilised aqueous extract	Normal and streptozotocin-induced diabetic rats	17
3-	Allium sativum L. ( Liliaceae)	Fresh bulbs	Ethanolic extract	Normal and Streptozotocin-induced diabetic rats	10
4-	Aerva lanata (L.) Juss. ex Schultes (Amaranthaceae)	Shoots	Alcoholic extract	Alloxan-induced diabetic rats	13
5-	Annona squamosa L. (Annonaceae)	Leaf extracts	Aqueous	Streptozotocin-nicotinamide induced diabetic rats	18
6-	Aporosa lindleyana (Euphorbiaceae)	Root	Aqueous and alcoholic extracts	Normal and alloxan induced diabetic rats	19
7-	Artemisia pallens Wall. ex DC. (Compositae)	Aerial parts	-	Alloxan-induced diabetic rats.	20
8-	Azadirachta indica A.Juss. (Meliaceae)	Plant extract	Hydro alcoholic	Streptozotocin induced diabetic rats	21,22
9-	Bauhinia forficata Link (Leguminosae)	Leaves	n-butanol fraction	Normal and alloxan-induced diabetic rats	23
10-	Beta vulgaris L. var. cicla	Leaves	Aqueous	Streptozotocin-induced hyperglycemic animals	24
11-	Biophytum sensitivum (L.) DC. (Oxalidaceae)	Leaf extract	-	Alloxan diabetic male rabbits	25
12-	Boerhavia diffusa L. (Nyctaginaceae)	Leaf extract	Aqueous	Alloxan induced diabetic rats	26
13-	Caesalpinia bonducella F. (Leguminosae)	Seeds	Aqueous and ethanolic extracts	Long-Evans rats	27,28
14-	Camellia sinensis	Leaves	Water and water soluble fraction	Alloxan-induced oxidative damage and diabetes in rats	29
15-	Canarium schweinfurthii (Burseraceae)	Stem bark	Methanol/methylene chloride	Streptozotocin-induced diabetic rats	30
16-	Carum carvi (Apiaceae)	Fruit	Aqueous extracts	Normal and streptozotocin diabetic rats	31
17-	Capparis spinosa (Capparidaceae)	Fruit	Aqueous extracts	Normal and streptozotocin diabetic rats	31
18-	Cassia auriculata Linn. (Leguminosae) ,,	Leaf extract Flower extract	Aqueous Aqueous	Normal and Alloxan induced fasted diabetic rats Streptozotocin-induced diabetic rats	32 33,34
19-	Caesalpinia bonducella (L.) Roxb.( Caesalpiniaceae )	Seed extracts	Aqueous and 50% ethanolic	Normal and streptozotocin-diabetic rats	35
20-	Catharanthus roseus (L.) G.( Apocynaceae) ,,	Leaf extract Leaves	Ethanolic Dichloromethane: methanol extract	Streptozotocin rats Streptozotocin (STZ) induced diabetic rat	36 37
21-	Cecropia obtusifolia Bertol (Cecropiaceae)	Leaves	Aqueous extracts	Diabetic patients, women and men,	12
22-	Citrullus colocynthis (Cucurbitaciae)	Fruit	Aqueous extract	Normal and alloxan diabetic rabbits	38
23-	Cichorium intybus (Compositae)	Whole plant	Ethanolic extract	Streptozotocin-induced diabetic rats	39
24-	Capparis spinosa (Capparidaceae)	Fruits	Aqueous extract	Normal and streptozotocin-induced diabetic rats	40
25-	Chamaemelum nobile (Asteraceae)	Aerial part	Aqueous extract	Normal and streptozotocin-induced diabetic rats	41
26-	Clausena anisata (Willd) Hook (Rutaceae)	Root extract	Methanolic	Normal (normoglycaemic) and in streptozotocin-treated diabetic rats	42
27-	Clemeo feline L. (Comperatacea)	Whole plant	Petroleum ether and benzene extracts	Alloxan diabetic rats	43
28-	Coccinia indicaWight & Arn. ( Cucurbitaceae )	Leaves	-	Alloxanized dogs	44
29-	Elephantopus scaber L.	-	Acetone extract	Reduced the blood glucose levels in streptozotocin- induced diabetic rats	46
30-	Enicostemma littorale Blume	Whole dried plant	Aqueous extract	Alloxan induced diabetic rats	1
31-	Equisetum myriochaetum (Equisetaceae)	Aerial parts	Water as well as butanolic extracts	Streptozotocin diabetic rats	47
32-	Eugenia jambolana (Myrtaceae) ,, ,,	Seeds Seeds Kernels	Ethanol Ethanol Aqueous and alcoholic extracts	Streptozotocin induced diabetic rats Streptozotocin-induced diabetic mice Alloxan and streptozotocin-induced diabetic mice	48 49 50
33-	Ficus bengalensis L. (Moraceae)	Bark extract	Ethanol	Normal and alloxan diabetic rabbits	51
34-	Fraxinus excelsior (Oleaceae)	Seed	Aqueous extracts	Normal and streptozotocin diabetic rats	52
35-	Ganoderma lucidum	Capsules	Water-extract	Obese/diabetic mice	53
36-	Globularia alypum L. ( Globulariaceae)	Leaves	Aqueous extract	Normal and streptozotocin diabetic rats	54
37-	Helicteres isora (Sterculiaceae) ,,	Root Bark	Ethanolic extract Aqueous extract	Normoglycemic and mildly hypertriglyceridemic Swiss albino mice. Normal, glucose load conditions and streptozotocin-induced diabetic rats.	55 56
38-	Hemionitis arifolia (Hemionitidaceae)	Whole plants	Ethanol and water extracts	Normal rats and alloxan diabetic rats	57
39-	Hibiscus rosasinensis L. (Malvaceae) ,,	Flowers Leaf extract	Ethanol extract Alcoholic	Alloxan-induced diabetic rats Glucose induced hyperglycemia model in rats	58 59
40-	Juniperus chinensis L.	Berries	Ethanolic and aqueous extracts	Alloxan-induced diabetic rats.	60
41-	Lepidium sativum L. (Brassicaceae)	Seeds	Aqueous extract	Normal and streptozotocin induced diabetic rats	61
42-	Lagerstroemia speciosa (Lythraceae)	Leaves	Aqueous ethanol	-	62
43-	Inula viscose L. (Asteraceae)	Aerial parts	Aqueous extract	Normal and diabetic rats	63
44-	Ipomoea aquatic (Convolvulaceae)	Edible portion	Aqueous extract	Normoglycaemic wistar rats	64
45-	Mangifera indica L. (Anacardiaceae)	Leaf extract	Aqueous	Streptozotocin-induced diabetic rats	65
46-	Memecylon umbellatum (Melastomaceae)	Leaves	Alcoholic extract	Normal and alloxan diabetic mice	66
47-	Mucuna pruriens (Fabaceae)	Seeds	Aqueous extract	Normal, glucose load conditions and streptozotocin-induced diabetic rats	67
48-	Momordica charantia Momordica cymbalaria Momordica cymbalaria	- Fruits Fruits	Freeze-dried powder Aqueous, ethanolic and Hexane fractions aqueous extract	Normal and diabetic rats Alloxan diabetic rats Alloxan-induced diabetic rats.	68 69 70
49-	Nymphaea stellata Willd. (Nymphaeceae)	leaves	Ethanolic extract	Alloxan induced diabetic rats	72
50-	Origanum vulgare (Lamiaceae)	Leaves	Aqueous extract	Normal and streptozotocin diabetic rats	73
51-	Ocimum sanctum Linn, Ocimum canum Sim (Lamiaceae)	Leaves Fresh leaves	Alcoholic extract Aqueous extract	Normal and alloxan-induced diabetic rats Diabetic and normoglycemic mice	74 75
52-	Parinari excelsa (Chrysobalanaceae)	Barks	Aqueous	Alloxan-induced diabetic rats	76
53-	Pandanus odorus (Pandanaceae)	Root	Aqueous extract	Normal rats	77
54-	Pterocarpus santalinus L. ( Fabaceae) ,,	Bark Bark	Aqueous, ethanol and Hexane aqueous extract	Normal and diabetic rats Normal and alloxan-induced diabetic rats.	78 74
55-	Punica granatum L. ( Punicaceae) ,,	Flower extract seed extract	Ethanolic methanoli	Glucose fed and alloxanized hyperglycemic rats strepotozotocin diabetic rats	79 80
56-	Retama raetam (Fabaceae)	Fresh leaves	Aqueous extract	Normal and streptozotocin induced diabetic rats	81
57-	Rosa damascena Mill. ( Rosaceae)	Flowers	Methanol extract	Normal and streptozotocin-induced diabetic rats.	82
58-	Rubus fructicosis L. ( Rosaceae)	Leaves	Aqueous extract	Normal and streptozotocin-diabetic rats	54
59-	Salacia Oblonga Wall. (Celastaceae)	Root bark	Petroleum ether	Streptozotocin diabetic rats	83
60-	Salvia officinalis L.	Leaves	Ethanolic extract	Normal and streptozotocin-induced diabetic rats	8
61-	Scoparia dulcis L. ( Scrophulariaceae)	Leaf extract	Aqueous	Diabetic rats	84
62-	Silybum marianum (Asteraceae)	Aerial part	Aqueous extracts	Normal and streptozotocin induced diabetic rats	52
63-	Sclerocarya birrea (Anacardiaceae)	Stem-bark	Aqueous extract	Normal (normoglycemic) and in streptozotocin-treated, diabetic wistar rats	85
64-	Smallantus sonchifolius (Asteraceae)	Leaves	Water extract	Normal, transiently hyperglycemic and streptozotocin-induced diabetic rats	86
65-	Suaeda fruticosa (Chenopodiaceae)	Aerial part	Aqueous extract	Normal and streptozotocin-induced diabetic rats	87
66-	Syzygium cumini (Myrtaceae)	Leaves and seeds	-	Non-diabetic rats and with streptozotocin induced diabetic rats	88
67-	Terminalia pallida (Combretaceae ) Terminalia superba (Combretaceae)	Fruits Stem bark	Ethanol Methanol/meth-ylene chloride	Alloxan induced diabetic rats streptozotocin induced diabetic Rats	11 30
68-	Theobroma cacao	Fermented and roasted beans	80% Ethanol	Streptozotocin-diabetic rats	89
69-	Teucrium polium (Labiatae)	Aerial parts	Aqueous extract	Streptozotocin-induced diabetic rats	90
70-	Tinospora cordifolia (Menispermaceae)	Kernels	Aqueous and alcoholic	Streptozotocin diabetic micea	50
71-	Trema micrantha (Ulmaceae)	Leaves	Ethanolic crude extract	Normal rats, rats with alloxan-induced diabetes and hyperglycemic normal rats	91
72-	Tridax procumbens (Compositae)	leaf extract	aqueous, alcoholic, and petroleum ether	alloxan-induced diabetes in rats	9
73-	Triticum repens P. Beauv. (Graminae)	Rhizome	Aqueous extract	Normal and streptozotocin diabetic rats	92
74-	Trigonella foenum-graecum (Leguminosae) ,, ,, ,,	Leaves Seeds Seeds Seeds	Aqueous and alcohol extract Ethanolic extract Alcoholic extract aqueous extract	Normal and alloxan diabetic rats Normal and streptozotocin-induced diabetic rats normal and Alloxan-induced diabetic rats normal mice	93 94 74 95
75-	Vernonia Colorata (Composeae)	Leaves	Aqueous extract	Normoglycaemic and alloxan-induced diabetic rats	96
76-	Varthemia iphionoides (Compositae)	Complete herbs	Aqueous extract	Normal rats and rats with streptozocin-induced diabetes mellitus	97
77-	Vitex megapotamica (Verbenaceae)	Leaves	Ethyl acetate and n-butanol fractions	Alloxan-diabetic rats	98
78-	Zizyphus spina-christi (L.) (Rhamnaceae)	Leaves	Butanol extract	Diabetic rats	99

Theobroma cacao:

Theobroma cacao, translated from the Greek means “food of the gods”, and it was first discovered in the ancient civilization of the Mayas and Aztecs in South America. In Malaysia, the first cocoa tree was planted in Malacca in 1778. Cocoa is one of the polyphenol-rich foods along with tea and wine. They are rich in polyphenol substances, such as (−)-epicatechin, (+)-catechin, quercetin (including its glucoside), clovamide, deoxyclovamide, and procyanidin. (−)-epicatechin is a major component of the polyphenols in cocoa beans, and it is also a monomer of procyanidins. To reduce hyperglycaemia and hypercholesterolemia effect can be attributed to the compound present in cocoa extract such as (−)-epicatechin and other polymers. The extract of three dosages (1, 2, and 3%) was fed to normal and diabetic rats for a period of 4 weeks. In hyperglycaemic group, cocoa extract (1 and 3%) diets were found to significantly lower (p < 0.05) the serum glucose levels compared to the control⁸⁹.

Tinospora cordifolia:

Tinospora cordifolia (Menispermaceae) is commonly known as Glunchanb or Tinospora in English and Giloe or Ambervel in Hindi. T. cordifolia increased the G-6-P content in the liver, indicating an overall increase in glucose influx; In the pilot study (mild diabetes), maximum reduction of 70.37% in glucose levels was seen in animals receiving 200 mg/kg /day of lyophilized powder of 400 mg/kg /day of aqueous extract of T. cordifolia after 3 and 15 weeks of treatment, respectively. There percent reduction in glucose decreased significantly in the moderate and severe diabetes were 48.81 and 45.23% for T. cordifolia ⁵⁰.

Terminalia pallid:

Terminalia pallida (Combretaceae) is a small evergreen endemic tree. T. pallida fruit has been in use for the treatment of diabetes by tribal people. Ethanolic extract of fruits of T. pallida at a dose of 0.5 g/kg b.w. could produce a significant fall in blood glucose levels by about 24% in diabetic rats, after 5 h of treatment. The phytochemical screening of T. pallida fruit revealed the presence of flavonoids, phenolic acids, sterols/triterpenoids, alkaloids, tannins and anthocyanins. Flavonoids are known to regenerate the damaged beta cells in the alloxan diabetic rats. Flavonoids, sterols/triterpenoids, alkaloids and phenolics are known to be bioactive antidiabetic principles.Phenolics are found to be effective antihyperglycemic agents.In the present study, 7.83mg% of flavonoids and 12.26 mg% of phenolic acids were found to be present in the T. pallida fruits¹¹.

Terminalia superb:

Terminalia superb is a big tree with deciduous leaves, attaining 50m of height and 120 cm stem diameter. It is widely distributed in the dense humid forests, semi-deciduous forests and also in easily flooded and secondary forests. At 300 mg/kg, the extracts significantly showed at least 67.1% reduction in blood glucose level. Extracts may possess an insulin like effect on peripheral tissues by either promoting glucose uptake and metabolism, by inhibiting hepatic gluconeogenesis or absorption of glucose into the muscles and adipose tissues, by the stimulation of a regeneration process and revitalisation of the remaining b-cells³⁰.

Trema micrantha:

Trema micrantha (Ulmaceae) is a small tree growing in South America, Central America and Mexico, known by the popular name grandi´uva. The acute treatment with T. micrantha Ethanolic crude extract( ECE) (250 and 1000 mg/kg) caused a significant decrease in the blood glucose levels in diabetic rats, but no effect was observed among the normal treated rats nor the hyperglycemic normal rats. ECE may produce its antidiabetic effect in diabetic rats by an extrapancreatic mechanism, such as enhancement of the peripheral utilization of glucose or potentiation of the biological effect of insulin⁹¹.

Trigonella foenum-graecum:

Trigonella foenum-graecum is cultivated throughout India and its leaves are used as a vegetable while seeds are used as a spice. Reduction was seen with Alc extract of T. foenum-graecum (74.33±4.77 to 60.56±1.9 in normal rats and 201.25±7.69 to 121.25±6.25 in diabetic rats) (P<0.001). In T. foenum-graecum treated group (1, 2 and 4 g/kg) was 15.28, 16.4 and 18.5%, respectively. The maximal hypoglycemic effect (18.52% at 2 h) seen with T. foenum-graecum. T. foenum-graecum on the other hand has been shown to work like guargum, inhibition of intestinal glucosidase and insulin release⁷⁴.

Triticum repens:

Triticum repens (Graminae) locally named as “N’jm L’bouri or outara” is a spontaneous plant. The mechanism involved in this pharmacological effect, therefore is extra-pancreatic. e Aqueous extract of T. repens exert its hypoglycaemic action by stimulating of glucose uptake by peripheral tissues, inhibition of endogenous glucose production or inhibition of renal glucose reabsorption. After a single oral administration of the aqueous extract (20 mg/kg) a significant decrease on blood glucose levels in STZ diabetic rats (p<0.001) was observed; the blood glucose levels were normalized after 2 weeks of daily oral administration of T. repens aqueous extract (20 mg/kg) (p<0.001). Significant reduction on blood glucose levels were noticed in normal rats after both acute (p < 0.001) and chronic treatment (p<0.001)⁹².

Vernonia colorata:

Vernonia colorata (Composeae) is a shrub that grows to a height of 3–4 m. Its leaves are used in culinary art in Benin, Cameroon and Togo the acetonic extract of the leaves of V. colorata could have a sulfonylurea-like mechanism since it decreased blood glucose in normoglycaemic rats such as glibenclamide. The acetonic extract of the leaves of V. colorata (100 mg/kg, per os) induced a significant decrease of blood glucose in normoglycaemic rats. The glycaemia varied from 4.72±0.11 to 3.72±0.22 mmol/l (p < 0.05, n = 5) 3 h after acetonic extract of the leaves of V. colorata administration per os. In contrast, the hexanic extract of the leaves of V. colorata increased significantly the glycaemia in normoglycaemic rats. acetonic extract and hexanic extract of the leaves of V.colorata have an opposite effect on basal blood glucose in normoglycaemic rats, suggesting that the mechanisms of action of both above-mentioned extracts are different; (ii) acetonic extract of the leaves of V. colorata has also an antidiabetic activity in hyperglycaemic rat models. The acetonic extract of the leaves of V. colorata possesses both hypoglycaemic and antidiabetic activities in normoglycaemic and alloxan-induced diabetic rats, respectively⁹⁶.

Vitex megapotamica:

Vitex megapotamica is a tree that grows to a height of 20m. Oral administration of crude extract significantly reduced serum glucose levels in both normal and diabetic animals. In normal rats, serum glucose lowering was observed with 400 and 800 mg/kg at 2 and 2–3 h, respectively after oral crude extract treatment. Nevertheless, the hypoglycemic effect of V. megapotamica in diabetic rats was evident at 1 and 2 h and from 1 to 3 h after treatment with 400 and 800 mg/kg, respectively. The ethyl acetate as well as n-butanol fractions were able to diminish glycemia in diabetic animals. The ethyl acetate fraction (400 and 800 mg/kg) produced the maximum hypoglycemic effect (28 and 20%, respectively) in diabetic rats and the same dose of the n-butanol fraction reduced the hyperglycemia only by 11% at 1 h after treatment. Additionally, in hyperglycemic normal rats neither crude extract nor ethyl acetate fraction modified the glucose tolerance and the known tolbutamide effect on insulin release was clearly observed in this group⁹⁸.

Zizyphus spina-christi:

Zizyphus spinachristi (Rhamnaceae) leaves decrease the serum glucose level in control and type-II diabetic rats. This effect is mediated by releasing insulin. The insulinotropic effect of Z. spinachristi leaves may be due to blockade of KATP channels in pancreatic b-cell membranes. Z. spinachristi leaves may potentially be safe for use as an antidiabetic agent. Butanol extract of Z. spinachristi leaves is safe, having a relatively high LD₅₀ value in mice. Four triterpenoidal saponin glycosides from the butanol extract of the leaves of Z. spinachristi were isolated and named christinin-A, B, C and D, respectively. Christinin-A was the major saponin. Pretreatment either with 100 mg/kg butanol extract or christinin-A potentiated glucose-induced insulin release in non-diabetic control rats. In type-II but not in type-I diabetic rats pretreatment with the butanol extract or christinin-A improved the oral glucose tolerance and potentiated glucose-induced insulin release. Treatment either with 100 mg/kg butanol extract or christinin-A reduced the serum glucose level and increased the serum insulin level of non-diabetic control and type-II diabetic rats but not of type-I diabetic rats. Z. spinachristi leaves appears to be a safe alternative to lower blood glucose. The safe insulinotropic and subsequent hypoglycemic effects of Z. spinachristi leaves may be due to a sulfonylurea-like activity⁹⁹.

Natural Lead compounds with hypoglycemic activity:

Compounds with different structure isolated from different plant species act as active moieties for the treatment of various diseases. Some of these active principles originate from edible plants and their inclusion in the diet would undoubtedly be of some value because of their hypoglycemic potential. Several phytomolecules including alkaloids, amino acids, carbohydrates, dietary fibres, flavonoids, glycosides, glycolipids, polysaccharides, peptidoglycans, saponins and others obtained from various plant sources have been reported as potent hypoglycemic agent.

Berberine (Alkaloid) is known to have potent hypoglycemic activity. It is obtained from Tinospora cordifolia. The mode of its antihyperglycemic activity was investigated in the Caco-2 cell line. Berberine effectively inhibited the activity of disaccharidases in Caco-2 cells, decreased sucrase activity after preincubation with Caco-2 cells for 72 h but failed to produce any significant effect on gluconeogenesis and glucose consumption of Caco-2 cells, antihyperglycaemic activity of berberine is at least partly due to its ability to inhibit α-glucosidase and decrease glucose transport through the intestinal epithelium. Alkaloids like catharanthine, vindoline and vindolinine obtained from C. roseus also lower blood sugar level.

Certain imidazoline compounds are known to have a stimulatory action on insulin secretion by activation of imidazoline binding sites in the pancreatic beta cell. Harmane, norharmane and pinoline, the b-carbolines were found to increase insulin secretion two- to three-fold from isolated human islets of Langerhans. Harmane and norharmane obtained from Tribulus terrestris L. may account for the hypoglycemic property of the plant. Harmane stimulates insulin secretion in a glucose-dependent manner.

A protein-bound polysaccharide, isolated from water-soluble substances of pumpkin has hypoglycemic activity at various doses (500 and 1000 mg/kg body weight) in alloxan diabetic rats. Polysaccharides increased the levels of serum insulin, reduce the blood glucose levels and improve tolerance of glucose.

Some flavonoids have hypoglycemic properties because they improve altered glucose and oxidative metabolisms of diabetic states. Quercetinis an important flavonoid known to possess a vast array of pharmacological activities. Intraperitoneal administration of quercetin to normal as well as streptozocin-induced diabetic rats resulted in marked reduction in plasma glucose level of diabetic animals while the glucose level of the normoglycemic rats remained unalterd. Quecrcetin also suppressed the glucose level in diabetic rats in a glucose tolerance tests, reduced plasma cholesterol and triglycerides significantly and increased their hepatic glucokinase activity probably by enhancing the insulin release from pancreatic islets of the diabetic rats. Some flavonoid molecules like quercetin, naringenin, chrysin significantly enhanced the insulin release from isolated rat islets of langerhans. Quercetin exerted its stimulatory effect on insulin release partly by changing Ca²⁺ metabolism.

Supplementation of the citrus flavonoids (0.2 g/kg diet) in the diet significantly reduced the blood glucose level as well as increased hepatic glucokinase activity and glycogen concentration in diabetic rats. Naringin also markedly lowered the activity of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase and the plasma insulin, C-peptide, and leptin levels in the diabetic mice were significantly increased as a result of supplementation. Hesperidin and naringin both play important roles in preventing the progression of hyperglycemia, partly by increasing hepatic glycolysis and glycogen concentration or by lowering hepatic gluconeogenesis.

The soy isoflavones genistein or daidzein have hypoglycemic activity in male and female obese Zucker rats, a model of Type II diabetes. Isoflavones significantly improved lipid and glucose metabolism by acting as hypoglycaemic peroxisome-proliferator activated receptors agonist.

Proanthocyanidins, the flavonoids with an oligomeric structure, are found to improve the pathological oxidative state of a diabetic situation. An extract of grape seed procyanidins administered orally to streptozotocin-induced diabetic rats produced significant antihyperglycemic activity possibly by its insulinomimetic activity. It also stimulated glucose uptake in insulin sensitive cells in vitro. Flavonoid glycoside Kaempferitrin (Kaempferol-3,7-O-(α)-l-dirhamnoside) was found to have an acute lowering effect on blood glucose in diabetic rats and stimulated the glucose uptake, as efficiently as insulin in muscle from normal rats in vitro. Blood glucose lowering activity of the compound attributed to altered intrinsic activity of the glucose transporter.

Green tea flavonoid, epigallocatechin gallate have glucose lowering effects in animals. It was found to decrease hepatic glucose production and increased tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1) like insulin. It also reduces phosphoenolpyruvate carboxykinase gene expression in a phosphoinositide 3-kinase-dependent manner and mimics insulin by increasing phosphoinositide 3-kinase, mitogen-activated protein kinase, and p70 (s6k) activity.

Epigallocatechin gallate is an important hypoglycemic agent. Flavonoid molecule, (−)-epicatechin, has been reported to possess insulin-like activity. The molecule protected the experimental albino rats against the diabetogenic actions of alloxan. This flavonoid molecule mimics insulin in its effect on erythrocyte membrane acetylcholinesterase (AChE) and has a pronounced insulin-like effect on erythrocyte membrane-bound acetylcholinesterase in Type II diabetic patients.

Triterpenoid and steroidal glycosides, referred to collectively as saponins, are bioactive compounds present naturally in many plants and known to possess potent hypoglycemic activity. Charantin, a steroidal saponin, obtained from Momordica charantia is known to have an insulin-like activity, responsible for its hypoglycemic effect. Charantin stimulates the release of insulin and blocks the formation of glucose in the bloodstream, which may be helpful in the treatment of diabetes, particularly in noninsulin-dependent diabetes. Lactucain and furofuran lignan, lactucaside, obtained from Lactuca indica found to produce significant hypoglycemic activity. b-Sitosterol, a steroid obtained from Azadirachta indica, may be responsible for its hypoglycemic property. Andrographolide, diterpenoid lactone, obtained from Andrographis paniculata was found to possess significant hypoglycemic activity. Gymnemic acid, obtained from leaves of Gymnema sylvestre exhibits potent hypoglycemic activity in experimental animals models of diabetes.

Ferulic acid is 4-hydroxy-3-methoxycinnamic acid found in the leaves and seeds of many plants like Curcuma longa L. Oral administration of ferulic acid at low dose produced significant hypoglycemic activity in both types of diabetes as streptozotocin-induced diabetic mice and KK-Ay mice.

The phenolic compound, elaeocyanidin as well as the gallotannins and ouratea proanthocyanidin A from Elaeodendron transvaalense are responsible for the hypoglycaemic activity. Some neryl geraniol derivates, clerodane and three diterpenes form Pteronia divaricata. The triterpenes Betulin and lupeol were isolated from Euclea natalensis. Lupeol and its derivative normalized the lipid profile in Wistar rats that were fed a high cholesterol diet. Lupeol inhibited α-amylase enzyme.

Kaempferol 3-O-galactoside and Kaempferol 3-rhamno glucoside from Bahuina variegata, Kaempferol 3-O-rhamnoside from Zizhyphus rugosa, Kaempferol 3-O-b-glucopyranoside from Morus insignis, and Kaempferol-3-O-(2gal-rhamnosilobonoside) from Sterculia rupestris. Kaempferol-3-Osophoroside-4%-O-b-D-glucoside is one of the responsible factors for the hypoglycemic effect of E. Myriochaetum.

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Received on 10.11.2009 Modified on 13.01.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page300-318

Classes of hypoglycaemic drugs	First generation drugs	Second generation drugs
Sulfonylureas	Tolbutamide,Chlorpropamide Tolazamide and Acetohexamide	Gilbenclamide,Glipizide, Gliclazide and Glimepiride
Biguanides	Phenformin	Metformin
Meglitinide analogues	Repaglinide	Nateglinide
Thiazolidinediones(or Glitazones)	Rosiglitazone	Pioglitazone
α-Glucosidase inhibitors	Acarbose	Miglitol

Classes of hypoglycaemic drugs	Contraindication	Adverse effects/Side effects
Sulfonylureas	-	Hypersensitivity, nausea, vomiting, diarrhoea or constipation, headache and weight gain
Biguanides	Hypotensive state, cardiovascular, respirator, hepatic and renal disease and alcoholics	Abdominal pain, anorexia, nausea,mild diarrhoea and metallic taste
Thiazolidinediones	Liver disease	Edema,weight gain, headache, myalgia and mild anaemia
Meglitinide analogues	Liver disease	Mild headache, dyspepsia, arthralgia, weight gain, dizziness, nausea, flu like symptoms and joint pain

Classes of hypoglycaemic drugs	Other drugs	Interactions
Sulfonylureas	Phenobarbitone,phenytoin,rifampicin,chronic alcoholism	Decrease sulfonylurea action through induce metabolism
Sulfonylureas	Corticosteroids,diazoxide,thiazides furosemide and oral contraceptive	Decrease sulfonylurea action through opposite action/suppress insulin release
Pioglitazone	Oral contraceptive	Failure of oral contraception
Pioglitazone	Ketoconazole	Inhibits metabolism of pioglitazone
Metformin	Cimetidine	Competitive inhibition of renal excretion of metformin,which lead to increased metformin blood levels

Drug	Company	Ingredients
Bitter gourd Powder	Garry and Sun natural Remedies	Bitter gourd (Momordica charantia)
Diabeta	Ayurvedic cure Ayurvedic Herbal Health Products	Gymnema sylvestre, Vinca rosea (Periwinkle), Curcuma longa (Turmeric), Azadirachta indica (Neem), Pterocarpus marsupium (Kino Tree), Momordica charantia (Bitter Gourd), Syzygiumcumini (Black Plum), Acacia arabica (Black Babhul), Tinospora cordifolia , Zingiber officinale (Ginger)
Dia-care	Admark Herbals Limited	Sanjeevan Mool; Himej, Jambu beej, Kadu, Namejav, Neem chal.
Diabecon	Himalaya	Gymnema sylvestre, Pterocarpus marsupium, Glycyrrhiza glabra, Casearia esculenta, Syzygium cumini, Asparagus racemosus, Boerhavia diffusa, Sphaeranthus indicus, Tinospora cordifolia, Swertia chirata, Tribulus terrestris, Phyllanthus amarus, Gmelina arborea, Gossypium herbaceum, Berberis aristata, Aloe vera, Triphala, Commiphora wightii, shilajeet, Momordica charantia, Piper nigrum, Ocimum sanctum, Abutilon indicum, Curcuma longa, Rumex maritimus
Diabecure	Nature beaute sante	Juglans regia, Berberis vulgaris, Erytherea centaurium, Millefolium, Taraxacum
Epinsulin	Swastik Formulations	vijaysar (Pterocarpus marsupium)
Gurmar powder	Garry and Sun natural Remedies	Remedies Gummer (Gymnema sylvestre)
Pancreatic tonic 180 cp	Ayurvedic herbal supplement	Pterocarpus marsupium, Gymnema sylvestre, Momordica charantia, Syzygium cumini, Trigonella foenum graceum, Azadirachta indica, Ficus racemosa, Aegle marmelos, Cinnamomum tamala
Syndrex	Plethico Laboretaries	Germinated Fenugreek seed extract