Phytotherapy in diabetes: Review on potential mechanistic perspectives

Abstract

Diabetes mellitus (DM) is a widely spread epidemic disease that results from the absence of insulin, decreased secretion and/or impaired function. Since DM is a multi-factorial disease, the available pharmaceuticals, despite their sensible treatment, target mostly one pathway to control hyperglycemia and encounter several side effects. Therefore, new therapeutic paradigms aim to hit several pathways using only one agent. Traditionally, antidiabetic plants and/or their active constituents may fulfill this need. More than 200 species of plants possess antidiabetic properties which were evaluated mostly by screening tests without digging far for the exact mode of action. Searching among the different literature resources and various database and in view of the above aspects, the present article provides a comprehensive review on the available antidiabetic plants that have been approved by pharmacological and clinical evaluations, and which their mechanism(s) of action is assured. These plants are categorized according to their proved mode of action and are classified into those that act by inhibiting glucose absorption from intestine, increasing insulin secretion from the pancreas, inhibiting glucose production from hepatocytes, or enhancing glucose uptake by adipose and muscle tissues. The current review also highlights those that mimic in their action the new peptide analogs, such as exenatide, liraglutide and dipeptidylpeptidase-4 inhibitors that increase glucagon-like peptide-1 serum concentration and slow down the gastric emptying.

Key Words: Hypoglycaemic nutraceuticals, Antidiabetic phyto-constituents, Medicinal plants, Phytotherapy, Diabetes mellitus

Core tip: Diabetes is a serious metabolic disorder that is currently treated by different types of synthetic oral hypoglycemic agents, in addition to insulin. However, due to the unwanted side effects, the efficacies of these compounds are debatable and there is a demand for new compounds for the treatment of diabetes. Therefore, attention has been directed towards nutraceuticals originating from plants that are rich in antidiabetic phyto-constituents. Although the evidenced-based therapeutic usage of many plants is scarce, the plants cited in this review are those reputed traditionally for their antidiabetic effect and that were verified either experimentally or clinically.

INTRODUCTION

Diabetes mellitus (DM) is a common disorder of carbohydrate, fat and protein metabolism reflected by an inappropriate fasting and postprandial high blood glucose levels (hyperglycaemia). This ailment results from the absence or scantiness of insulin secretion with or without concurrent impairment of insulin action. Consequently, the disease was classified into two types known as type I (insulin dependent, IDDM) and II (non-insulin dependent, NIDDM) according to the degree of the pancreatic defect. This classification has been even recognized since the time of Ibn Sinaa who mentioned it in his book “The Canon of Medicine”.

DM is not confined to abnormal blood glucose level, but it progresses to affect other body systems. This fact was confirmed by several epidemiological studies and clinical trials that linked hyperglycemia to several complications at the macrovascular (coronary artery disease and cerebrovascular disease), as well as the microvascular levels (renal failure, blindness, limb amputation, neurological complications and pre-mature death)[1].

Based on the pathophysiology and severity of this disease, it can be controlled by dietary restriction, exercise, different types of synthetic oral hypoglycemic agents and/or insulin. Since DM is one of the multi-factorial based diseases, therefore, a balanced modulation of several targets can provide a superior therapeutic effect and a decrease in the side effects profile compared to the action of a single selective agent[2]. Hence, the current strategy used for the treatment of type II DM depends on combining an insulin secretagogue and an insulin sensitizer to provide a sensible therapeutic approach (Figure 1)[3]. Albeit reasonable management provided by these drugs, yet over time, some of the type II diabetic patients lose response towards conventional antidiabetics, leading to an inadequate control of their blood glucose level. Moreover, several side effects could hinder their capability in alleviating the symptoms of diabetes, such as severe hypoglycemia, lactic acidosis, idiosyncratic liver cell injury, permanent neurological deficit, digestive discomfort, headache, dizziness and even death. In addition, treatment of IDDM using insulin has also its complications, since continuous exposure to insulin causes a reduction in the number of receptors on the cell surface by promoting internalization, as well as degradation of hormone-occupied receptors[4].

Figure 1 Pathophysiological mechanisms of hyperglycemia matched with the suitable pharmacotherapeutics (Data adapted from Hui et al[3]).

In spite of the introduction and extensive utilization of hypoglycaemic agents, diabetes and its related complications continue to be a major health problem worldwide. Globally, around 150 millions of people are believed to be diabetic and the incidence rate is expected to double by 2025[5]. These expectations are “good to be true”, especially for NIDDM, since the slothful lifestyle along with the high consumption of westernized diet, are considered to be the cornerstone for the development of this type of DM. Hence, it is a requisite to have safer and more effective oral hypoglycemic agents which can hit many targets to fulfill the new paradigm in drug discovery[6]. To achieve this objective, one may either employ a single compound to strike multiple targets; this can be termed as a one compound-multiple-target strategy[2], or use a combination of active compounds in one drug[7]. Therefore, attention has been directed towards nutraceuticals, since they can fulfill these criteria.

Herbal products may contain several active constituents or compounds that can act by several modes of action to influence multiple biological pathways and to alleviate the diabetic symptoms, providing thereby multifaceted benefits[8]. Nevertheless, this vision is not totally new, since prior to and after the discovery of insulin, herbs with hypoglycaemic effect have been used in folk medicine and are still prevalent[9-11]. As a support for this concept, metformin, which is notable for its substantial favorable impact on diabetes prevention, was purified from the French lilac Galega officinalis L.[12]. Moreover, the low cost of these compounds and the minimal side effects are other reasons behind the hunt for effective natural agents to be used as complementary and/or alternative medicine.

Since restoring glucose homeostasis is influenced by several aspects, the current article classifies the hypoglycemic herbs that are available in literature resource from various database, into poroper categorization according to their potential mode of action to reduce blood glucose level. Different search engines were explored including Pubmed, Google, Asci database by using different keywords, as well as some of the traditional tertiary resources. Priority was given to research articles and information given by authentic organizations and federations. Plants cited in this review are those reputed traditionally for their antidiabetic effect and that were verified, either experimentally or clinically. The efficacy of hypoglycemic herbs is achieved by inhibiting glucose absorption from intestine, increasing insulin secretion from the pancreas, inhibiting glucose production from hepatocytes, or enhancing glucose uptake into the peripheral tissue via the glucose transporters (GLUT). Additionally, the plants that act by simulating the action of the new incretin peptide analogs were also mentioned in the present review.

INHIBITION OF GLUCOSE ABSORPTION

Postprandial hyperglycemia plays an important role in the incidence of type II DM, since recent studies suggest that it could induce the non-enzymatic glycosylation of various proteins, resulting in the development of chronic complications. Therefore, controlling its level, via inhibiting the activities of α-glucosidase enzymes, is believed to be an important strategy to manage this disease. Alfa-glucosidase enzyme is a member of the glucosidases located in the brush-border surface membrane of the intestinal cells and is a rate-limiting step in the conversion of oligosaccharides and disaccharides into monosaccharides, necessary for gastrointestinal absorption[13]. In addition, α-amylase, which is present in both salivary and pancreatic secretions[14], is responsible for cleaving large malto-oligosaccharides to maltose which is a substrate for the intestinal α-glucosidase. Hence, the inhibition of α-glucosidase and/or α-amylase enzymes is currently in vogue, especially if these inhibitors stem from natural bases. The following are some examples of plants or their constituents that are proven to possess anti-enzymatic properties.

Methanolic extract of Adhatoda vasica Nees (Acanthaceae) was shown to have the highest sucrase inhibitory activity among forty species tested in an experimentally screening study by Gao et al[15]. This effect was attributed to its active constituents, viz., vasicine and vasicinol, beside other constituents, offering thus, a possibility to develop successful α-glucosidase inhibitors. Previous studies by Gao et al[15] also reported the isolation of maltase inhibitory principles from the fruits of Terminalia chebula[16] and Tussilago farfarae[17].

Belonging to the same Acanthaceae family, in vitro studies on the ethanolic extract of Andrographis paniculata (Burm. f.) Nees and its principal active constituent, andrographolide (AG), seem to possess an antihyperglycemic activity[18]. They delay the quick digestion of starch, as well as sucrose, and prolong the absorption time of carbohydrates, pointing to an α-glucosidase inhibitory activity. Moreover, essential oils obtained from the woods of Cedrus libani A. Rich (Pinaceae), but not its leaves or cones, were able to inhibit the α-amylase activity[19].

Nigella sativa L. (Ranunculaceae), a plant commonly used in the Middle Eastern and North African traditional medicine was validated for its multi-factorial anti-diabetic actions. The crude aqueous extract tested in experimental rats was able to restore glucose homeostasis[20] and to improve glucose tolerance as efficiently as metformin. Apart from its effect to enhance insulin sensitivity in liver cells[21], and to possess an insulinotropic and insulin-like activities in cultured pancreatic β-cells, skeletal muscle cells and adipocytes[22], it is now documented[23] that the crude aqueous extract of Nigella sativa seeds directly inhibits the electrogenic intestinal absorption of glucose in vitro. This effect is mediated by reducing the intestinal sodium-dependent D-glucose cotransporter-1 (SGLT1) which is the major transporter of glucose in the intestine[24,25]. SGLT1 is also considered a key molecule in the sensing of glucose entry that is highly regulated by peptides and hormones[26].

Another plant that is widely used as an anti-diabetic in folk medicine in México is Tournefortia hartwegiana, where the decoction of its aerial parts controls the disease, when given orally for 10-14 d to alloxanized rats. The plant is thought to control the glucose level via several routes, including the inhibition of the intestinal α-glucosidase and other intestinal enzymes, as maltase and sucrase that are implicated in the digestion of polysaccharides and oligosaccharides[27,28]. The inhibitory effect of this decoction suppresses the absorption of carbohydrates from intestine and thereby reduces the post-prandial increase in the glucose level. On the other hand, Ortiz-Andrade et al[27] referred the anti-diabetic effect of the methanolic extract of the same plant to the enhancement of insulin secretion and/or action. Furthermore, other machineries , such as the modulation of the pancreatic and extrapancreatic effects[29-32], besides the enhancement of β-cell glucose metabolism or an activation of enzyme system generating cyclic adenosine mono phosphate (AMP) or phospholipid derived messenger[33], and/or blockage of glucose co-transporters from intestine to circulation[34], cannot be ruled out. These diverse mechanisms are attributed to the different components that were tested for their individual hypoglycemic action, where the “cocktail” of these constituents could trigger a synergic effect.

In 2004, Asano et al[34] in their search for an anti-glycosidase, succeeded to isolate new alkaloids from the bulbs of Scilla peruviana (Hyacinthaceae) that display an inhibitory action of bacterial β-glucosidase and bovine liver β-galactosidase to varying degrees. In addition, the methanolic extract of the rhizome of Rheum emodi, known as Himalayan rhubarb, inhibited the activity of both mild yeast and mammalian intestinal α-glucosidase as proven by Suresh Babu et al[35]. This action correlates with the active components isolated from this rhizome such as chrysophanol-8-O-β-D-glucopyranoside, desoxyrhaponticin and torachrysone-8-O-β-D-glucopyranoside which showed a potent to moderate mammalian α-glucosidase inhibitory activity.

In a recent study, Loizzo et al[36] examined the influence of nine extracts of plant species collected in Lebanon, viz., Calamintha origanifolia, Satureja thymbra, Prangos asperula, Sideritis perfoliata, Asperula glomerata, Hyssopus officinalis, Erythraea centaurium, Marrubium radiatum and Salvia acetabulosa. The authors prepared different extractions with methanol, n-hexane and chloroform, yet the methanolic extracts of Marrubium radiatum and Salvia acetabulosa exerted the strongest activity against α-amylase and α-glucosidase. The leaf extract of the Marrubium related species, viz., Marrubium vulgare, is used in Brazilian and Mexican traditional medicine for its anti-diabetic role, an effect that was documented clinically in patients with type II non-controlled diabetes mellitus[37]. Several Salvia species have been reported for their hypoglycaemic effect in Iranian folk medicine[38,39] where they act by different mechanisms. For example, Salvia lavandulaefolia extract acts by decreasing the intestinal absorption of glucose, increasing the peripheral uptake of glucose, potentiating glucose-induced insulin release, and causing pancreatic islet cells hyperplasia[40].

The hypoglycemic mechanisms of another anti-diabetic plant, Plantago ovata husk, has also been studied and it was found that its aqueous extract hinders markedly the intestinal glucose absorption in rats; however, the extract failed to affect insulin secretion nor glucose transport in adipocytes[41].

Salacia species (Celastraceae) are widely distributed in East Asian countries and many plants from this genus (e.g., S. oblonga, S. reticulata and S. prinoides) have been used for thousands of years in traditional medicines, particularly for the treatment of diabetes and obesity. Pharmacological studies have demonstrated that Salacia roots modulate multiple targets, including the inhibition of α-glucosidase, aldose reductase and pancreatic lipase, as well as the activation of peroxisome proliferator-activated receptor-alpha (PPAR-α)-mediated lipogenic gene transcription. All these mechanisms reinforce its usage in Ayurvedic medicine for diabetes and obesity. The methanolic extracts of S. reticulata and S. oblonga stems and roots reduced, dose-dependently, the postprandial hyperglycemia induced in rats by maltose, sucrose or starch, but not by glucose or lactose[42-44], pointing to their inhibitory effect on intestinal enzymes. Moreover, the aqueous extract of S. reticulata inhibited strongly the activities of α-glucosidase and α-amylase[42], while that of S. chinensis inhibited the α-glucosidase activity only[45]. These favorable effects are attributed to the identified components of the plant, viz., mangiferin, salacinol, kotalanol and kotalagenin 16-acetate. Mangiferin causes concentration-dependent α-glucosidase inhibition in vitro[46], while salacinol, kotalanol and kotalagenin 16-acetate inhibited the increased serum glucose levels in maltose and sucrose loaded rats more than acarbose[43,44]. Thus, these findings suggest that the anti-diabetic property of Salacia is partially attributed to its intestinal α-glucosidase inhibitory activity.

Mangifera indica Linn. (Anacardiaceae) is a plant that possesses several properties, one of which is hypoglycemia that favors it to control type II DM in some rural African communities[46]. Mangiferin is one of the active constituents of this plant, besides the polyphenolics, flavonoids, triterpenoids, and other chemical compounds. Therefore, the mangiferin-mediated inhibition of α-glucosidase activity[47], offers one mechanism for the hypoglycemic effect of this plant.

The potential antidiabetic activity of six pentacyclic triterpenes (oleanolic acid, arjunolic acid, asiatic acid, maslinic acid, corosolic acid and 23-hydroxyursolic acid) were isolated from the ethyl acetate extract of the leaves of Lagerstroemia speciosa (LSL) and were investigated by α-amylase and α-glucosidase inhibition assay[48]. However, the compounds showed week α-amylase inhibitory effect, while α-glucosidase was moderately inhibited, mainly by corosolic acid. In a search for an α-amylase inhibitory compound from plant origin, Ali et al[49] studied extracts of six selected Malaysian plants with a reputation of usefulness in treating diabetes using an in vitro model. Their work depicted that the hexane extract of Phyllanthus amarus had α-amylase inhibitory properties, an effect that was provoked by only three pure pentacyclic triterpenoids, namely, oleanolic acid, ursolic acid and lupeol.

The antidiabetic capacity of the standardized extract of maritime pine bark, derived from Pinus pinaster, Aiton. subs. Atlantica des Villar (Pycnogenol^®), was documented clinically by Liu et al[50]. In their study a double-blind, placebo-controlled, randomized, multicenter study was performed with 77 type II diabetic patients to investigate the potential antidiabetic effects of the French matitime pine bark extract, Pynogenol (100 mg) for 12 wk. Supplementation of Pycnogenol to conventional diabetes treatment loweres glucose levels and improves the endothelial functions, as evidenced by the significant reduction in HbA1c and endothelin-1. To characterize the possible mechanism of action, the authors attributed the effect of Pycnogenol to the suppression of α-glucosidase enzyme[50], rather than enhancing the insulin secretion, an effect that was more potent than green tea or acarbose[51]. The clinical antidiabetic effect was found also to be dose dependent and correlates positively with the procyanidins comprising of catechin and epicatechin subunits with varying chain lengths[52,53].

Another plant that is used extensively in folk medicine is the Fenugreek (Trigonella foenum-graecum L.), which is a member of the Leguminosae family, and is cultivated predominantly in Asia, the Mediterranean, and North African regions. Mainly the seeds are the part used for centuries for a wide range of diseases, as they were shown experimentally to possess significant hypoglycemic[54], antiathrosclerotic[55], anti-inflammatory[56], antinociceptive[57], antiulcerogenic[58], and antineoplastic effects[59]. Studies carried to elucidate its anti-diabetic mechanism(s) reveal that the plant works by inhibiting the intestinal glycosidase[60], in addition to its positive effect on glycolytic, gluconeogenic, and lipogenic enzymes to restore glucose homeostasis in various animal models[60,61].

The in vitroα-glucosidase inhibitory model has been used by several research teams to verify the potential antidiabetic properties of different plant parts/extracts. In this context the antidiabetic effect of the Corni fructus (Cornus officinalis Sieb. et Zucc.) extract is mediated partly by inhibiting the α-glucosidase activity, an effect that reached to over 80% by one of the extract tested fractions[62]. Likewise, the alcohol extract of Alismatis Rhizoma-related hypoglycemic effect is mediated via the same mechanism, owing to its protostane-type triterpenes, besides promoting the glucose uptake in vitro[63]. Similarly, chemical components isolated from the safflower seed (Carthamus tinctorius L.)[64] and from the leaves of Ficus deltoidea, viz., vitexin and isovitexin[65], as well as the methanolic extract of the aerial parts of Swertia corymbosa (used in Ayurveda herbal preparations in India)[66] exhibited in vitro/in vivoα-glucosidase inhibition.

Moreover, the same in vitro technique showed that the grape seed extract inhibits the intestinal α-glucosidases and α-pancreatic amylase that may delay carbohydrate digestion and absorption. Recently, this fact has been further documented, where grape seed extract has lowered the postprandial plasma glucose concentration in an acute, randomized, controlled crossover design study, in which healthy subjects received high carbohydrate meal with or without grape seed extract[67].

A prospective epidemiology links heavy coffee consumption to a substantial reduction in risk for type 2 diabetes, yet there is no evidence that coffee improves insulin sensitivity. Thus, it is reasonable to suspect that coffee influences the risk for beta cell “failure” that precipitates diabetes in subjects who are already insulin resistant. Indeed, coffee was proven to increase the production of the incretin hormone glucagon-like peptide-1 (GLP-1), possibly by its chlorogenic acid constituent (CGA-the chief polyphenol in coffee). The latter was also found to inhibit the intestinal glucose transport, as documented by the consumption of plants containing CGA, to be including coffee[68]. Further studies correlated the presence of CGA, the main polyphenolic compound in coffee, to the decreased diabetic risk where CGA slows carbohydrate absorption by its effect on the intestinal brush border membrane glucose transport, thus mimicking the effect of acarbose at the experimental level[69], as well as acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans[70]. CGA inhibits also the activity of glucose-6-phosphate translocase[71] which is now believed to play a role in glucose absorption[72,73]. In 2008, Andrade-Cetto et al[74] have tested the hypoglycemic effect of butanolic extracts of some Mexican plants and have found that Malmea depressa Baill R.E. and Acosmium panamense Benth. extracts resemble the effect of acarbose and decrease the plasma glucose level significantly by affecting the α-glucosidase enzyme. Nevertheless, the effect of the butanolic extract of Cecropia obtusifolia Bertol. was the most potent and it produced the highest reduction in the plasma glucose level that was even lower than the fasting level after 90 min, an effect that suggests an additive mechanism of action. This assumption could be true since this plant contains CGA which hits several targets in the diabetes metabolic pathways, besides its acarbose-like effect[75,76].

ENHANCEMENT OF GLUCOSE UPTAKE AND UPREGULATION OF GLUCOSE TRANSPORTERS

Stimulating the peripheral glucose uptake is one of the multiple mechanisms that control blood glucose level; hence, targeting this point is among the most promising goals for the treatment of type-II DM. Basically, several factors assimilate to facilitate the glucose uptake process, including the activation of the GLUT in liver (GLUT-2), adipocytes and skeletal muscles (GLUT-4), the induction of the nuclear receptors, viz., PPARs, especially the gamma subtype, as well as increasing the release of positive adipocytokines, such as adiponectin[77].

As illustrated in Figure 2, the cell membrane lipid bilayer is impermeable to carbohydrates, which necessitates the presence of specific transporters. These carriers are differentiated into two families, the first one is a sodium-linked GLUT that works actively and is limited to the intestine and kidney. The second family consists of eight homologous transmembrane proteins, GLUT-1-8, that are encoded by distinct genes, and they convey glucose by the facilitated diffusion down the glucose-concentration gradients[77]. However, the GLUT proteins have distinct substrate specificities, kinetic properties, and tissue distributions that dictate their functional roles. GLUT-1 is expressed in the brain, erythrocytes and endothelial cells, while GLUT-2 is found in the liver, kidney, small intestine, and pancreatic β-cells. This low-affinity GLUT (GLUT-2) has a role in sensing glucose concentrations in the islets of Langerhans. GLUT-3 is responsible for transporting glucose in neurons and placenta, while GLUT-4 is present in skeletal muscles, cardiac muscles and the adipose tissue. Of all the GLUT, only GLUT-4 is insulin-responsive. GLUT-5 has high affinity to transport fructose rather than glucose and it exists in the small intestine, sperm, kidney, brain, and adipose cells[77]. In 2003, Gorovits et al[78] found that GLUT-8, present in liver, plays a role in the regulation of glucose in case of diabetes. GLUT-4 is sequestered intracellularly and is translocated to the plasma membrane upon its stimulation by insulin. Thus, a decrease in the expression of GLUT-4 mRNA and protein reduced the insulin-mediated glucose uptake in diabetes[79]; in other words, imperfect GLUT-4 function could be a causative factor for insulin resistance[80].

Figure 2 Insulin signaling pathway and insulin insensitive. The inner part of insulin receptor (IR) reveals a tyrosine kinase activity and coupled with multifunctional docking proteins IRS-1 and IRS-2. The in turn signaling leads to an activation of the MAPK cascade involved in mitogenesis and the open status of a hexose transporter protein (GLUTs) which is located in the cell membrane and is the only channel for glucose entery into cells. The decreased serine/threonine phosphorylation of IR, inactivates hexokinase and glycogen synthase, as well as defects in the phosphorylation of glucose transporter protein (GLUT4) and genetic primary defect in mitochondrial fatty acid oxidation, leading to insulin resistance and an increase of triglyceride synthesis contribute to this insulin insensitivity. The action sites of hypoglycemia herbs are indicated with red arrows[3].

From this point of view, herbs or their active constituents that can up-regulate GLUT-4 expression or that increase the translocation of this transporter could aid in the treatment of insulin resistance and hyperglycemia.

Cecropia obtusifolia Bertol (Cecropiaceae) is a plant extensively used for the empirical treatment of type II diabetes in México[76]. The active hypoglycemic compounds found in this plant are CGA and isoorientin which are also found in other anti-diabetic plants as mentioned before[76]. In 2008, Alonso-Castro et al[76] studied the anti-diabetic mechanisms of Cecropia obtusifolia aqueous extract and its active compound CGA, and reported that the two preparations exert their anti-diabetic effects by stimulating glucose uptake in both insulin-sensitive and insulin-resistant adipocytes without appreciable pro-adipogenic effects. Thus, they could act by potentiating the insulin action or by activating a signaling pathway parallel to the insulin pathway.

Other anti-diabetic plants that act via increasing the glucose uptake in adipocytes, alone and in combination with insulin, include the ethanolic extract of Amomum xanthioides seeds[81], Lagerstroemia speciosa[82] and plants used by the Cree Nation in Canada, such as Abies balsamea, Pinus banksiana and Rhododendron groenlandicum[83]. Moreover, an aqueous extract from Cinnamomum zeylanicum[84], aqueous and ethanolic extracts of Momordica charantia[85], and aqueous extract of Guazuma ulmifolia[86], stimulated glucose uptake in 3T3-L1 adipocytes. However, none was evaluated on insulin-resistant adipocytes, except for Guazuma ulmifolia, which similar to Cecropia obtusifolia, mediated its action by stimulating glucose uptake in normal and diabetic adipocytes without inducing adipogenesis; nevertheless, its hypoglycemiant component(s) are not fully characterized.

Miura et al[87] validated the antidiabetic activity of Lyophyllum decastes (Tricholomataceae) in KK-Ay mice, an animal model of genetically type II diabetes with hyperinsulinemia. The results of their work reported that mice receiving the aqueous extract showed an increase in the muscle content of GLUT-4 protein, which is responsible, at least in part, for decreasing insulin resistance. In 2004, Miura et al[88] again used the same model to test the hypoglycemic effect of corosolic acid, and found that it increased GLUT-4 translocation in muscle, without affecting the insulin level. This acid is one of the active constituents of Lagerstroemia speciosa L., banaba leaf. The plant is used traditionally in Philippines to treat diabetes and was studied by Takagi et al[89] who referred the antidiabetic effect to the inhibition of sucrose hydrolysis. However, the effect of corosolic acid on GLUT-4 can not be ruled out, although this requires further verification

In another study[90], the 3T3-L1 adipocytes were used to prove that the methanolic extract of Liriope platyphylla Wang et Tang ( LPWT), Liliaceae, increased insulin-induced glucose uptake in adipocytes, by virtue of its homoisoflavone. This uptake was mediated through the translocation of GLUT-4 to the plasma membrane, via Insulin receptor Substrate - phosphatidyl inositol 3 kinase-Akt signaling mechanism. Aside from delaying the carbohydrate absorption via affecting α-glucosidase enzyme[19], Andrographis paniculata adopts another mechanism of action for its hypoglycemic effect through increasing the expression of GLUT-4. This was confirmed by the administration of its main constituent andrographolide in diabetic mice using streptozocin (STZ)[91].

Panax ginseng, also known as Korean red ginseng, appears to be a powerful anti-diabetic plant that has multi modes of action, due to its potent active constituents including ginsenoside Rh2. In a study by Lai et al[92], the authors reported that the ginsenoside Rh2 increases the gene expression of GLUT-4, at the mRNA and protein levels, in soleus muscle obtained from STZ-diabetic rats. They also suggest that the GLUT-4 expression is increased as a result of the increased β-endorphin secretion which will be detailed later in this review.

In an attempt to develop new substances for treating insulin resistance, obese Zucker rats were employed to screen the effect of myricetin, an active principle of Abelmoschus moschatus (Malvaceae), on insulin resistance[93]. The findings showed that myricetin increased insulin sensitivity by increasing the expression of GLUT-4 and by activating the phosphorylation of insulin receptor substrate-1. These results were also obtained from another study[94] using the methanolic extract of Aegles marmelos and Syzygium cumini that are anti-diabetic medicinal plants used in Indian traditional medicine. The latter study reported an additive mechanism for lowering glucose level via the elevation of PPAR-γ, a nuclear receptor that will be discussed in the following section. Azadirchata indica Neem is among the Indian herbs that possess an antidiabetic effect. The hydroalcoholic extract of this herb exerted its antihyperglycemic activity by increasing glucose uptake, as well as glycogen deposition[95]. Furthermore, the anti-diabetic action of Tinospora cordifolia is mediated by increasing the expression of GLUT-4 by about 5 folds, as well as PPARα and γ, as tested in differentiated myocytes, L6 cells[96].

ACTIVATION OF THE NUCLEAR RECEPTOR PPAR-γ

The PPAR family belongs to type II nuclear hormone receptors involved in the regulation of fatty acid, carbohydrate and glucose metabolism[97]. There are three isoforms of PPARs with specific tissue distribution and biological activity; they are identified as α, β or δ and γ with two subforms PPAR-γ₁ and PPAR-γ₂[98]. The receptors are ligand dependent, with the antidiabetic thiazolidinediones (TZDs) being the potent PPAR-γ agonist[97]. After their stimulation by their specific ligands, they regulate the transcriptional process via their heterodimerization with RXR, a retinoid X receptor, and then bind to peroxisome prolixferator-response element (PPRE)[97,98]. Clinical data demonstrated that the PPAR-γ agonists TZDs modulate glucose homeostasis by enhancing the peripheral glucose uptake through increasing GLUT-4 expression and translocation in adipocytes[99], as well as decreasing hepatic glucose output[100]. TZDs alleviate insulin sensitization by the redistribution of adipose deposits where these agents minimize visceral adipose content, responsible for the induction of insulin resistance, and redeposit it subcutaneously, in a phenomenon known as the “fatty acid steal” hypothesis[101]. In addition, activating PPAR-γ increased adipocyte fatty acid uptake, and decreased lipotoxic damage to insulin-sensitive tissues[102].

To date, the chief research interest in finding a nutraceutical compound(s) that mimics the PPAR-γ ligands constitute promising approaches for the treatment of diabetes, obesity and metabolic syndrome. Previously, multiple trials have shown conflicting results whether cinnamon lowers glucose or hemoglobin A1_C (HbA1_C). In 2009, Crawford[103] tested the cinnamon hypoglycemic activity in patients with type 2 diabetes through a randomized, controlled trial to evaluate whether daily cinnamon plus usual care versus usual care alone lowers HbA1c. Cinnamon lowered HbA1_C (0.83%) compared with usual care alone lowering HbA1_C (0.37%). Because one of the proposed mechanisms of cinnamon is increasing insulin sensitivity, hence, the treatment of patients with metabolic syndrome by adjunct cinnamon may yield weight loss, improved lipid profiles, and better glucose tolerance.

Park et al[104] used db/db mice, a typical non-insulin-dependent model, to study the anti-diabetic mechanism of Mulberry leaf water extract, Korean red ginseng and/or banaba leaf water extract. Herbs alone and their combination increased the expressions of liver PPAR-α mRNA and adipose tissue PPAR-γ mRNA in animals fed diets supplemented with the test herbs, in addition to restoring glucose and lipid homeostasis. Furthermore, the Labiate herbs rosemary and sage were documented in a recent study[105] as activators of the human PPAR-γ, possibly by their active constituents carnosol and carnosic acid.

What provides a potential validation for using traditional herbs as antidiabetics are the results of the screening study attained by Rau et al[106]. Among 52 ethanolic extracts, obtained from traditionally used herbs, the researchers found amazingly that nearly half the extracts activated PPAR-γ and 14 activated PPAR-α, while three of them were pan-PPAR activators, findings which were considered exceptionally high hit rate. The most active extracts were those of Alisma plantago aquatica (ze xie/European waterplantain), Catharanthus roseus (Madagascar periwinkle), Acorus calamus (sweet calamus), Euphorbia balsamifera (balsam spurge), Jatropha curcas (barbados nut), Origanum majorana (marjoram), Zea mays (corn silk), Capsicum frutescens (chilli) and Urtica dioica (stinging nettle).

The effect of the North American ginseng (Panax quinquefolius), a close relative to Panax ginseng, on glucose control was verified in a study by Banz et al[107], using male Zucker diabetic fatty rats. The findings showed that ginseng had marked effects on the expression of genes involved in PPAR actions and triglyceride metabolism. The authors encourage further research to determine the therapeutic value of this medicinal herb in treating human diabetes.

Green tea (Camellia sinensis L.) leaf extract on triglyceride and glucose homeostasis was evaluated in a fructose-fed insulin-resistant hamster model[108]. Supplementation of the green tea epigallocatechin gallate-enriched extract improves lipid and glucose homeostasis and increases the expression of PPAR-α and PPAR-γ proteins. These data suggest that intake of the green tea extract increases insulin-sensitivity, at least through boosting up PPAR.

Clematis species (Ranunculaceae) have been used continuously as anti-inflammatory agents by indigenous Australians. During examining the ethanol extract of C. pickeringii, C. glycinoides and C. microphylla, on COX-1, COX-2 and 5-lipoxygenase[109], the authors found that Clematis pickeringii has activated significantly the protein expression of both PPAR-α and PPAR-γ. These results merit the study of the potential antidiabetic mechanism(s) of these species. In a search for a natural PPAR-γ agonist, Atanasov et al[110] reported that the natural product honokiol from the traditional Chinese herbal drug Magnolia bark stimulates the basal glucose uptake in a comparable pattern to pioglitazone, but without inducing adipogenesis.

INCREASING ADIPONECTIN RELEASE

An additive role for PPAR-γ in the manipulation of glucose homeostasis is the modulation of adipocytokines. These bioactive substances are produced and secreted from adipose tissues which happened to be an endocrine organ[111]. Adipocytokines play central role in body insulin resistance, where the dysregulation of their production participates in the pathophysiology of the metabolic syndrome.

The plasma level of adiponectin is documented to be lower in patients with diabetes[112] and ischemic heart disease[113] than their age- and body mass index (BMI)-matched nondiabetic mates. This fact was further documented in a screening study on Japanese patients with type 2 diabetes and their age- and BMI-matched nondiabetic control subjects, and is attributed to the genetic mutation of the adiponectin gene associated with metabolic syndrome, including insulin resistant diabetes and atherosclerotic disease[114].

Consequently, adiponectin possesses antidiabetic and antiatherogenic properties[115]. The antidiabetic mechanism(s) involves enhancement of glucose uptake in skeletal muscles, activation of IRS-1-mediated phosphatidylinositol-3 kinase[115,116], acceleration of muscle β-oxidation via the activation of AMP-kinase[117], and suppression of hepatic glucose production[118,119]. These events are summarized in Figure 3.

Figure 3 Effects of adiponectin on carbohydrate and lipid metabolism in liver and skeletal muscle (c. f. http://www.jpp.krakow.pl/.../articles/08_article.html[119]). FAT: Fatty acid translocase.

Normal adiponectin plasma level is under the influence of PPAR-γ, where stimulation of this nuclear receptor potentiates its direct binding with the PPRE responsive element in the promoter region of the adiponectin gene, thus, enhancing the production and secretion of this cytokine.

Clinical studies now assure the beneficial effects of some plants in controlling glucose disorders. For instance, the extract of white-skinned sweet potato Ipomoea batatas (Caiapo) has been evaluated in type II diabetic patients, and was shown to control plasma glucose level through increasing insulin sensitivity along with the level of adiponectin[120]. Moreover, the mushroom Agaricus blazei Murill (ABM) extract was documented to improve insulin resistance and to elevate adiponectin level in subjects with type II diabetes receiving metformin and gliclazide; the latter cytokine provides at least one potential antidiabetic mechanism of this plant[121]. Concerning the antiatherogenic property of adiponectin, the extract of Aronia melanocarpa E. was administered to forty-four patients who survived myocardial infraction and have received statin therapy[121]. Compared to placebo, the chokeberry flavonoid extract increased adiponectin level, among other corrected parameters that nominate this extract as an adjunct therapy in patients with ischemic heart disease.

Momordica charantia owes its anti diabetic effect to its insulin-like action[122,123], antioxidant property[124,125], and glucose uptake enhancement[79]. The latter mechanism could be explained by the finding of Ryu et al[126], who stated that Momordica-induced glucose uptake is accompanied by, and may be the result of, increased adiponectin secretion, which is the communication between adipose tissue and skeletal muscle.

Adiponectin was also induced by the oral ingestion of Plum ekisu, tested on insulin- resistant obese Wistar fatty rats[127]. Dried plum is highly consumed in the West as a healthy food and is used in India as medicine to protect against geriatric related diseases, possibly by their phenolic compounds. Rats receiving plum concentrated juice showed better insulin sensitivity, increased PPAR-γ mRNA expression and marked elevation in adiponectin. These mechanisms are tightly correlated, where stimulation of PPAR-γ initiates the cycle, leading to increased production of adiponectin and alleviation of insulin sensitivity.

Apart from the multiple machineries by which Salacia reticulate extract mediates its antidiabetic effect[42], increasing the release of adiponectin adds also to these effects, which make it useful in the treatment of diabetes mellitus, insulin resistance and other metabolic diseases[128].

GLYCOGEM METABOLISM

Another cornerstone in controlling blood glucose level is the “hepatic output”, which correlates with liver metabolic functions, including lipogenesis and glycogenesis. The latter process is precisely adjusted by adequate levels of insulin[129], which stimulates glycogen synthase and inhibits glycogen phosphorylase, resulting in the proper glycogen deposition in various tissues, especially skeletal muscle. Since glycogen is the storable form of glucose, thus, insulin inadequacy initiates muscle protein breakdown to provide gluconeogenic precursors that could be the reason behind diabetes-induced weight loss. Consequently, compounds that enhance glycogen formation and/or increase its content in liver and muscles are considered beneficial anti-diabetic agents.

In an attempt to elucidate the anti-diabetic mechanism(s) of some plants used in the management of diabetes, it was found that Caralluma sinaica L. (Asclepiadaceae)[130] found in south Hejaz, west of Saudi Arabia, and Sinai region of Egypt, showed an anti-diabetic effect. This plant exerts its effect through opposing the STZ-induced glycogen depletion in liver and muscle, and by reversing weight loss in the diabetic rabbits, results that may be promoted by the realease of insulin.

Panax ginseng is suggested to induce glycemic control by sparing insulin and increasing glucose transport. Various preparations of Panax ginseng have been shown to upregulate insulin and non-insulin stimulated glucose transport in different animal models and cell lines[131-133]. Furthermore, Momordica charantia was able to renovate β-cells in the pancreas or partially destroyed ones[85] and to stimulate pancreatic insulin secretion[134]. These insulin-like properties[122,123] kindle glycogen storage by the liver and improve peripheral glucose uptake[126]. The anti-diabetic property of the aqueous extract of Tamarindus indica seed (T. indica) was also verified in a type I and II experimental models[135]. This action is mediated by restoring glycogen levels in liver and skeletal muscles, as well as inhibiting the glucose-6-P-ase activity. Increasing insulin level, however, was limited only to the type I model. Recently in 2012 the aqueous extract tested on STZ-induced diabetes showed that complex mechanisms stand behind its antidiabetic effect, such as β-cell neogenesis, calcium handling, as well as increasing GLUT-2 and GLUT-4. These findings show the scope for formulating a new herbal drug for diabetes therapy[136].

INSULINOMIMETIC AND INSULINOTROPIC EFFECT

In 2007, Eidi et al[137] studied again the hypoglycemic effect of the fenugreek seeds which was previously found to inhibit α-glucosidase, and they reported that the ethanolic extract significantly decreased serum glucose, triacylglycerol, cholesterol, urea, uric acid, AST, and ALT, whereas it increased serum insulin levels in treated STZ-induced diabetic rats. As a result, the authors concluded that fenugreek seeds extract encompasses antidiabetic activities similar to that observed for glibenclamide used as a standard drug. Eidi et al[138] have tested also the possible antidiabetic mechanism of Garlic (Allium sativum, Liliaceae) which is a common spice flavoring agent believed to lower plasma glucose level in diabetic patients. Therefore, using STZ-induced diabetic rats, they found that the alcoholic extract of garlic potentiates the insulin effect by increasing its pancreatic secretion from existing β-cells or its release from bound insulin. These effects are attributed mainly to the allicin-type compounds[139,140] which are disulphide compounds that can react with endogenous thiol containing molecules, such as cysteine, glutathione, and serum albumins to spare insulin from SH inactivation[141]. In another study, using STZ/high-fat diet Sprague Dawley rats, a comparison between the anti-diabetic effects of dietary freeze-dried ginger and garlic, was conducted. The experimental results revealed that ginger and garlic are insulinotropic rather than hypoglycemic, and that the anti-diabetic effects of ginger are better than those of garlic[142]. Using the same rat model, Islam et al^143] investigated the insulinotropic effect of dietary red chilli (Capsicum frutescens L.) in low and high concentrations and revealed that 2% dietary red chilli is insulinotropic rather than hypoglycemic at least in this experimental condition.

The effects of the ethanol extract and five partition fractions of the Asparagus racemosus root and Ocimum sanctum leaf were evaluated on insulin secretion together with exploration of their mechanisms of action. The ethanol extract and each of the hexane, chloroform and ethyl acetate partition fractions stimulated insulin secretion in isolated perfused rat pancreas, isolated rat islet cells and clonal β-cells. These findings reveal that constituents of both extracts have wide-ranging stimulatory effects on physiological insulinotropic pathways[144]. Similarly, the aqueous extract of Asparagus adscendens induced a significant increase in glucose-dependent insulinotropic actions in the clonal pancreatic β-cell line, enhanced glucose uptake in 3T3-L1 adipocytes and decreased starch digestion in vitro. These outcomes revealed that Asparagus adscendens possesses insulinotropic, insulin-enhancing activity and inhibitory effects on starch digestion[145].

The antihyperglycemic action of Stevia rebaudiana (Asteraceae) Bertoni leaves extracts were confirmed using type II diabetic Goto-Kakizaki rats[146]. The large quantities of the glycoside stevioside in the Stevia rebaudiana leaves are responsible for the anti-hyperglycaemic, insulinotropic, and glucagonostatic actions of the herb; results which support the traditional use of this herb in the treatment of diabetes in Paraguay and Brazil. Similar efficacy pattern was obtained by the crude extract of Viscum album (V. album) leaf which produced about 35.3% decrease in glucose concentration in STZ-induced diabetic rats and stimulated insulin secretion by about 81.5%. Although, only a subtle suppression in glucagon level was observed, yet it was significant. Thus, the V. album leaves extract may possess antihyperglycaemic, insulinotropic, and possibly, mild glucagonostatic agent(s) and may, therefore be a candidate for the anti-diabetic drugs[147].

Butanol extract of Zizyphus spina-christi L. (Rhamnaceae) leaves and its major saponin glycoside, christinin-A, were tested to evaluate their effect on serum glucose and insulin levels in non-diabetic control, type-I and type-II diabetic rats[148]. Both the extract and the saponin compound improved the oral glucose tolerance , potentiated glucose-induced insulin release, reduced the serum glucose level and increased the serum insulin level of non-diabetic control and type-II diabetic rats, but not those of type-I diabetic rats. They also enhanced the glucose lowering and insulinotropic effects of glibenclamide. The data pointed to the insulinotropic capacity of the tested plant.

Furthermore, in traditional Nepalese folk medicine the leaf extract of the annual herb Biophytum sensitivum is used for the treatment of hyperglycemic patients. This property was documented by Puri[149] who ascribed the leaf extract hypoglycemic response to its insulinotropic effect, where he found that the tested extract induces the release and/or synthesis of insulin.

Similar insulinotropic effect was presented by pterostilbene, a flavonoid constituent derived from the wood of Pterocarpus marsupium, a herb used in the Indian folk medicine; the active compound causes pancreatic β-cell regranulation[150]. Marsupin, pterosupin and liquiritigenin obtained from the plant showed also antihyperlipidemic activity. Moreover, epicatechin, an active principle, has been found to be insulinogenic, enhancing the insulin release and the conversion of proinsulin to insulin in vitro. Like insulin, epicatechin stimulates oxygen uptake in fat cells and increases glycogen content of rat diaphragm. Aloe vera (Liliaceae) exerts its hypoglycemic effect in rats by its bitter principle through stimulating the release of insulin from the β-cells of Langerhans as documented after the use of single, as well as repeated doses of the bitter principle of the Aloe vera in diabetic rats[150]. Other insulinptropic Indian herbs include Acacia Arabica (Babhul), Eugenia jambolana (Indian gooseberry), Annona squamosa (sugar apple), Caesalpinia bonducella (Fevernut), Hibiscus rosa-sinesis (Gudhal), Scoparia dulcis (sweet broomweed) and Tinospora crispa[96].

Patel et al[151] presented a thorough review on 65 species of plants with insulinomimetic or insulin secretagogue. Most of these belong to the family Leguminoseae, Lamiaceae, Liliaceae, Curcubitaceae, Asteraceae, Moraceae, Rosaceae and Araliaceae. The most active plants are Allium sativum, Gymnema sylvestre, Citrullus colocynthis, Trigonella foenum greacum, Momordica charantia and Ficus bengalensis. Citrullus colocynthis (Cucurbitaceae) pulp ethanolic extract at 300 mg/kg, p.o. was found to increase insulin and decrease plasma glucose levels significantly in alloxan-induced diabetic rats. Moreover, the aqueous extract also showed a dose-dependent increase in the insulin release from isolated islets, as well as other 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[151].

Trigonella foenum-graecum has been observed to cause glucose-induced insulin release in vitro and in vivo. 4-Hydroxyleucine, a novel amino acid from fenugreek seeds, increased glucose-stimulated insulin release from isolated islet cells in rats, mice and humans, and possibly hydroxyisoleucine which represents 80% of the free amino acids in Trigonella foenum-graecum seeds. The extracts, powder and gum of Trigonella foenum-graecum seeds may help to improve insulin sensitivity presumably due to the presence of fibers, which slow the metabolism of carbohydrates, resulting in reduced insulin levels and lowered blood glucose[151].

Alcoholic extract of Gymnema sylvestre (Asclepiadaceae) stimulated insulin secretion from the rat islets of Langerhans and several pancreatic β-cell lines. In another study, the oral administration of the water-soluble leaves extract (400 mg/d) to 27 IDDM patients on insulin therapy lowered their fasting blood glucose and their insulin requirements. In type II diabetic patients on Gymnema sylvestre supplementation the pancreatic β-cells is suggested to be regenerated or repaired as supported by the raised insulin levels in their serum. This assumption has been concluded also when the number of the pancreatic islet and β-cells, as well as insulin levels wre increase after oral administration of the aqueous extract to diabetic rats. Gymnemic acid molecules dihydroxy gymnemic triacetate had the ability to release the insulin by the stimulation of a regeneration process and revitalization of the remaining β-cells. The aqueous extract of Gymnema sylvestre leaves stimulated insulin secretion from mouse cells and isolated human islets in vitro, without compromising cell viability[151].

Among the glucagonostatic Indian herbs are Caesalpinia bonducell, Coccinia indica, Boerhavia diffusa, Enicostema littorale and Murraya koenigii. These herbal extracts increase glycogenesis, restore the activities of lipoprotein lipases and decrease the glucose-6-phosphatases, thereby inhibiting the glycogenolysis, and gluconeogenesis processes, as well as increasing the peripheral glucose utilization[150].

In a recent study, the ethanolic extract of ethanolic extract of Schizandra arisanensis and its isolated constituents provided some insulinotropic effects by ameliorating cytokine-mediated β-cell death and dysfunction via anti-apoptotic and insulinotropic actions[152].

ELEVATION OF D-CHIRO-INOSITOL

D-chiro-inositol (D-CI) is a rare inositol isomer present in inositol phosphoglycans (IPGs) which are putative insulin second messengers. These mediators are released from cell membranes, cells and human blood by insulin and other growth factors[153] and mediate some, but not all, of insulin actions[154]. D-CI acts as an insulin surrogate where it exhibited an anti-hyperglycaemic effect in vivo[155], and enhanced insulin-induced glucose incorporation into glycogen, in vitro[155]. Albeit, D-CI modulates favorably insulin’s effect on peripheral glucose utilization under physiological conditions, Kennington et al[156], reported abnormal low or immeasurable levels of D-chiro-inositol in urine and muscle from type II diabetic patients, suggesting that D-CI deficiency might be related to the insulin resistance. Accordingly, D-chiro-inositol when administered to STZ diabetic rats[157] and humans[158] decreased hyperglycemia and enhanced glucose disposal (Table 1).

Table 1 Following is a list of plants that are reported to have insulin mimetic or insulin secreatory action.

1 Abies pindrow (Pinaceae )	34 Momordica charantia (Cucurbitaceae)
2 Aegle marmelos (Rutaceae)	35 Mucuna pruriens (Leguminosae)
3 Agrimony eupatoria (Rosaceae)	36 Nigella sativa oil (Ranunculaceae)
4 Aloe barbadensis (Liliacea)	37 Olea europia (Oleacea)
5 Annona squamosa (Annonacea)	38 Panax ginseng (Araliaceae)
6 Averrhoa bilimbi(Oxalidacea)	39 Pandanus odorus (Pandanaceae)
7 Bixa orellana (Bixaceae)	40 Parinari excelsa (Chrysobalanaceae)
8 Boerhaavia diffusa (Nyctaginaceae)	41 Prunella vulgaris (Labiatae)
9 Bougainvillea spectabilis (Nyctaginaceae)	42 Psidium guajava (Myrtaceae)
10 Brassica nigra (Cruciferae)	43 Pterocarpus marsupium (Fabaceae)
11 Camellia sinensis (Theaceae)	44 Radix glycyrrhizae (Fabaceae)
12 Capsicum frutescens (Solanacea)	45 Radix rehmanniae (Scrophulariaceae)
13 Catharanthus roseus (Apocyaceae)	46 Rehmania glutinosa (Scrophulariacea)
14 Cinnamon zeylaniucm (Lauraceae)	47 Ricinus communis (Euphorbiaceae)
15 Coccinia indica (Cucurbitaceae)	48 Salvia lavandifolia (Lamiacea)
16 Cornus officinalis (Cornaceae)	49 Sarcopoterium spinosum (Rosaceae)
17 Elephantopus scaber (Asteraceae)	50 Scoparia dulcis (Scrophulariaceae)
18 Enicostemma littorale (Gentianaceae)	51 Selaginella tamariscina (Selaginellaceae)
19 Ephedra distachya (Ephedraceae)	52 Semen coicis (Ggramineae)
20 Eriobotrya japonica (Rosaceae)	53 Smallanthus sonchifolius (Asteraceae)
21 Euccalyptus globulus (Myrtaceae)	54 Stevia rebaudiana (Asteraceae)
22 Fermented unsalted soybeans	55 Swertia chirayita (Gentianaceae)
23 Ficus bengalensis (Moraceae)	56 Swertia punicea (Gentianaceae)
24 Genistein	57 Syzygium cumini (Rutaceae)
25 Ginkgo biloba (Ginkgoaceae)	58 Tabernanthe iboga (Apocynaceae)
26 Helicteres isora (Sterculiaceae)	59 Teucrium polium (Lamiaceae)
27 Hibiscus rosa (Malvacea)	60 Tinospora crispa (Menispermaceae)
28 Hordeum vulgare (Gramineae)	61 Tribuluks terrestris (Zygophyllaceae)
29 Ipomoea batata (Convolvulaceae)	62 Urtifca dioica (Urticaceae)
30 Juniperus communis (Pinacea)	63 Vinca rosea (Apocyanacea)
31 Lausena anisata (Rutacea)	64 Zingiber officinale (Zingiberaceae)
32 Lepechinia caulescens (Lamiaceae)	65 Zizyphus spina-christi (Rhamnaceae)
33 Medicago sativa (Fabaceae)

Cucurbita ficifolia is traditionally used in Asia for the management of diabetes; however, its mechanism of action was not clarified. In 2006, Xia et al^159] found that C. ficifolia may be a natural source of D-CI which is present in fairly high levels in this plant and may be the cause for its anti-diabetic character. Using STZ diabetic rats, the fruit extract of C. ficifolia lowered the blood glucose level and increased the hepatic glycogen content, and the plasma insulin. Furthermore, the same extract improved the blood glucose tolerance when an oral glucose tolerance test was performed in fasted diabetic and normal rats. The results of this experimental animal study lend a pharmacological credence to the suggested folkloric uses of the plant in the management and control of diabetes mellitus, owing to its high content of the insulin-mimetic, D-CI. This compound is also the active constituent of Fagopyrum tataricum L. Gaench that possesses an insulin-like bioactivity. Yao et al[160] illustrated that the D-CI-enriched extract of Fagopyrum tataricum lowered plasma glucose, C-peptide, improved glucose tolerance, and enhanced insulin immunoreactivity in KK-Ay mice.

INCRETIN MIMETICS AND INCRETIN ENHANCERS

A new target for the management of type II DM is the gut hormone, GLP-1 (incretin) which is secreted as a riposte to meal. This hormone maintains glucose balance by different routes where it stimulated glucose-dependent insulin secretion, delays gastric emptying, inhibits glucagon secretion, and protects or even exerts a trophic effect on β-cells, as illustrated in Figure 4. However, the hormone is rapidly degraded by dipeptidylpeptidase-4 (DPP-4), an enzyme that inactivates also glucose-dependent insulinotropic peptide (GIP)[161]. Thus, the aim in pharmaceutical research is either to inhibit DPP-4, to prolong GLP-1 duration of action, or to use compounds that can partially resist DPP-4. These compounds are either incretin-mimetic agents that simulate GLP-1 (exenatide) or a long-acting incretin analogue (liraglutide)[162]. Incretin, thus, challenged the pharmaceutical researchers to find a nutraceutical compound that could modulate this hormone.

Figure 4 Effects of active glucagon-like peptide-1 and dipeptidylpeptidase-4 on glucose homeostasis [(c. f. http://www.medscape.com) Am J Health Syst Pharm, 2007]. GLP-1: Glucagon-like peptide-1; DPP-4: Dipeptidylpeptidase-4.

In this regard, recent data reported that inulin-type fructans extracted from chicory roots regulated glucose and lipid homeostasis by enhancing colon production of GLP-1. Therefore, Urías-Silvas et al[163] evaluated the fructans extracted from Agave tequilana Gto. and Dasylirion spp. on glucose and lipid metabolism. The data showed a decrease in body weight of mice fed fructans-containing diet, besides the restoration of glucose and lipid levels. As a conclusion, the authors reported that fructans from any botanical origin initiates the production of GLP-1 from colon, and it is responsible for the amendment of glucose and lipid metabolism.

The potential antihyperglycemic activity of an ethanolic extract of Artemisia dracunculus L., called Tarralin, in diabetic mice was studied by Ribnicky et al[164]. This extract posed a positive antidiabetic action, via decreasing the mRNA expression of phospho-enolpyruvate carboxykinase (PEPCK), the main catalyzing enzyme in gluconeogenesis, and increasing the binding of incretin (GLP-1) to its receptor.

Impairment of β-cell function results from the improper insulin/IGF-1 signaling cascade through insulin receptor substrate-2 (IRS-2). Thus, induction of IRS-2 in β-cells can potentiate its function and mass, an effect that was attained by the GLP-1 receptor agonist, exendin-4, through elevation of intracellular cyclic Adenosine mono phosphate (cAMP)[165]. GLP-1/exendin-4 is known to enhance glucose-stimulated insulin secretion and to increase β-cell transcription factors, such as pancreas duodenum homeobox-1 (PDX-1), to promote β-cell growth and survival[165]. These promising actions of exendin-4 were associated with the induction of IRS-2, the pathways of which play an important role in β-cell expansion, and augmentation of insulin secretion.

In a recent study, Park et al[165] examined the potential antidiabetic mechanism(s) of six herbs used in Chinese medicine to treat diabetes. These herbs were Galla rhois, Rehmanniae radix (Rehmannia glutinosa Liboschitz var. purpurea Making), Machilus bark (Machilus thynbergii Siebold et Zuccarini), Polygonatum radix (Polygonatum odoratum Miller Druce), Ginseng radix (Panax ginseng C.A. Meyer), and Scutellariae radix (Scutellariae baicalensis Georgi). The authors reported that these herbs induced IRS-2 in rat islets, improved glucose-stimulating insulin secretion and increased β-cell survival. In addition, Rehmanniae radix, Ginseng radix and Scutellariae radix were found to mediate insulin secretion through cAMP/PKA-dependent and/or -independent pathways. These herbs also induced PDX-1 and glucokinase, besides the increased expression of IRS-2. Activation of glucokinase could vindicate the enhancement of glucose stimulated insulin secretion, while induction of PDX-1 was associated with β-cell proliferation[165]. The promising effects of Ginseng radix and Scutellariae radix could be ascribed to the active constituents, ginsenosides and the flavonoid baicalein, respectively. The finding, hence, point to the presence of natural agents that possess incretin-like action and that mimic exendin-4.

ROLES OF ENDOGENOUS OPIOIDS ON GLUCOSE HOMEOSTASIS

Apart from the well known pharmacological actions of opiates, their binding to opioid receptors located in the pancreatic β-cells and their ability to manipulate diabetic disorders has been documented[166]. The opioid peptide β-endorphin, secreted from the adrenal gland[167] has been shown to induce insulin secretion also via activating the pancreatic opioid receptors[168]. Besides, this peptide also was found to regulate glucagon and somatostatin release from isolated islets of Langerhans[169,170]. Therefore, increased glucose utilization and decreased hepatic output may be a consequence to the increased release of β-endorphin and the activation of peripheral opioid μ-receptors (MOR). Activation of these receptors might enhance the expression of muscle GLUT and/or reduce hepatic gluconeogenesis at the gene level[171]. MOR-induced glucose uptake is accomplished by increased gene expression of GLUT-4 via a phospholipase C-protein kinase (PLC-PKC) dependent pathway[172]. It has also been observed that stimulation of α₁-adrenoceptors in the adrenal gland provokes the secretion of β-endorphin[173] depending also on the PLC-PKC pathway[174,175].

In STZ-diabetic rats, Hsu et al[176] stated that β-endorphin biosynthesis increases in the adrenal gland, along with the opioid μ-receptors gene expression[177]; events that may compensate for the glucose disturbed homeostasis. Therefore, development of pharmaceutical or nutraceutical agents that target β-endorphin secretion and/or stimulate peripheral MOR, via an insulin-independent action, donates a new hit that may have merit in glycemic control.

Since application of herbal plants or their products in the management of glucose metabolism is extensively searched, investigations were conducted to study their potential effect on β-endorphin and peripheral opioid μ-receptor. One of the early studies in this regard, is that carried out by Hsu et al[178] using caffeic acid, which is a phenolic compound contained in the fruit of Xanthium strumarium. After an intravenous injection of caffeic acid into diabetic rats of both STZ-induced and insulin-resistant models, a dose-dependent decrease in the plasma glucose was observed; moreover, it increased the glucose uptake in isolated adipocytes. This trial was followed by another study[179] to verify the mechanism of caffeic acid using STZ-induced diabetic rat. In this experiment, caffeic acid increased the release of β-endorphin from the adrenal gland through the activation of α_1A -adrenoceptors. These receptors were adopted as one of the antidiabetic mechanisms of andrographolide present in the leaves of Andrographis paniculata (Burm. f.) Nees. Using cultured myoblast C2C12 cells, andrographide was documented to activate these adrenoceptors via PLC-PKC dependent pathway to fascilitate glucose uptake[180]. Inhibiting α-glucosidase[19] and increasing GLUT-4 mRNA[91] were other mechanisms mediated by this active constituent. A recent study by Yu et al[181] validated the andrographolide-induced α_1A-adrenoceptors activation in type I diabetes-like animals, which enhance β-endorphin release that in turn stimulates the opioid micro-receptors. The authors reported also an increased expression of the GLUT-4 in soleus muscle and a reduced expression of PEPCK in liver, effects that may explain the registered reduction in hepatic gluconeogenesis and enhancement of the glucose uptake. A similar pattern was recorded to rationalize the antidiabetic mechanisms of myricetin, the active principle of Abelmoschus moschatus (Malvaceae) using STZ-diabetic rats[182]. Myricetin, in insulin-deficient animals, activated peripheral MOR, in response to increased β-endorphin secretion. Opioid μ-receptor activation is held responsible for the enhancement of muscle GLUT-4 gene expression and the attenuation of hepatic PEPCK gene expression observed in these myricetin-treated diabetic animals.

Another study was carried out to investigate the antihyperglycemic mechanisms of syringin, an active principle purified from the rhizome and root parts of Eleutherococcus senticosus (Araliaceae). STZ-diabetic rats showed an increased release of β-endorphin from the adrenal medulla after receiving a bolus intravenous injection of syringing[183]. Niu et al[183] concluded that the decreased plasma glucose, in the diabetic rats lacking insulin, is mediated by the effect of β-endorphin on peripheral micro-opioid receptors.

The antidiabetic potency of isoferulic acid, one of the active components in Cimicifugae rhizoma, is attained by lowering glucose level, improving glucose uptake in skeletal muscle along with inhibiting hepatic gluconeogenesis in rats with an insulin deficiency[184]. For precise clarification of its mode of action, Liu et al[185] tested its impact on the α_1A-adrenoceptor/β-endorphin system in a STZ diabetic rats. Formerly, Liu et al[186] showed that isoferulic acid can activate α_1A-adrenoceptor, leading to increased glucose uptake into cultured mouse myoblast C2C12 cells; however, the role of β-endorphin in the plasma glucose-lowering action of isoferulic acid is still unclear. In this work[187], the authors proved that isoferulic acid increased β-endorphin level via affecting α_1A-adrenoceptors, leading to stimulation of peripheral opioid receptors, resulting in increased expression of GLUT-4, and reduction of hepatic gluconeogenesis. Moreover, the same laboratory examined the mechanism(s) of plasma glucose lowering action of puerarin in STZ-induced diabetic rats and concluded that this isoflavone can act as a ligand to activate α_1A-adrenoceptors on the adrenal gland to initiate the aforementioned cascades[187].

ANTIOXIDANTS

In the course of normal aerobic metabolism, oxygen free radicals are produced during the reduction of oxygen into water. Since these radicals are inherently toxic, cells have built up defense systems to quench them. These defense systems are either enzymatic, including superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione reductase and glucose-6-phosphate dehydrogenase, or non-enzymatic, such as vitamins C and E as well as thiols, especially the reduced glutathione molecule[188]. If these oxygen free radicals, referred as reactive oxygen species (ROS), are excessively produced and are able to overwhelm the endogenous defense systems, then a state of oxidative stress originates. These ROS can bind with most normal cellular components to “pair up” its unpaired electrons; thus, they react with the unsaturated bonds of membrane lipids, denature proteins, and attack nucleic acids, resulting in cellular oxidative damage[189]. It has been suggested that oxidative stress plays an important role in many diseases, including DM, since hyperglycemia alone could not be exclusively responsible for the later complications associated with the disease[190]. ROS are considered an important independent risk factor that is developed in DM via what is known as “auto-oxidative glycosylation, a process which is relevant at elevated blood glucose level[191]. Hyperglycemia may also raise aldose reductase which depletes NADPH cell stores, thus perturbing defense system[192]. The elevated blood glucose level causes also non-enzymatic glycation of plasma proteins[193] leading to the production of more powerful oxidizing species[194]. Furthermore, it induces mitochondrial superoxide overproduction, which influences again the previous steps[195], creating what is known as “hyperglycemic memory”[196]. As oxidative stress plays a key role in insulin-resistance and β-cell dysfunction[197], ample of data allows the hypothesis that a viscous circle exists between hyper-insulinemia and free radicals that may be responsible for deterioration of insulin action[198], possibly via down-regulating insulin-mediated glucose uptake[199].

Given that antioxidants are favorably used as complementary agents in diabetic patients to reduce diabetic complications[200-203], attempts to discover antioxidants as useful drug candidates to combat diabetic complications are going on persistently.

Of the plants that exert their positive effects in experimental DM through their antioxidant characters are Ficus carica via restoring levels of fatty acids and vitamin E[204], as well as some Indian herbs, viz., Allium sativum, Azadirachta indica, Momordica charantia, and Ocimum sanctum extracts, which not only lowered the blood glucose level, but also inhibited the formation of lipid peroxides, reactivated the antioxidant enzymes, and restored levels of GSH and metals[124]. These results may authorize the use of the aforementioned herbs in the prevention of diabetes-associated complications. In addition, Momordica grosvenori, a traditional medicinal herb in China used as a substitute sugar for obese and diabetic patients, was tested in alloxan-induced diabetic mice[205]. The plant corrected the altered glucose level and effectively regulated the immune imbalance in diabetic mice. The authors assigned these effects to the plant-induced upregulation of heme oxygenase-1 (HO-1) protein, which has anti-inflammatory activities and antioxidant properties.

The ethanolic extract of Scutellaria baicalensis, as well, proves its antioxidant role in a STZ-induced diabetic model, and enhances the antidiabetic effect of metformin[206]. In addition, in a study on the antioxidant and antiglycation properties of some traditional Chinese medicine used to treat DM, Aralia taibaiensis outperformed other extracts in most of the assays except for the inhibition of early glycation products formation which was mostly inhibited by Acanthopanax senticosus extract[207]. The antioxidant and antiglycation activities of these extracts were correlated with their saponin content[207]. The aqueous extract of Albizzia lebbeck was also verified for its antioxidant property using alloxan-induced diabetic rats[208]. The authors registered that the extract rescued all altered parameters caused by alloxan which confirmed the ability of the herb to resist the oxidative insult.

The hypoglycemic and hypolipidemic effects of Lycium barbarum fruit extract, its crude polysaccharides (LBP) extract and purified polysaccharide fractions (LBP-X), were documented in alloxan-induced diabetic rabbits[209]. Although the hypoglycemic effect of LBP-X surpassed the other extracts, yet the latter exhibited stronger antioxidant activity because crude extracts were identified to be rich in antioxidants (e.g., carotenoids, riboflavin, ascorbic acid, thiamine, nicotinic acid). In Li[210] has isolated Lycium barbarum polysaccharides (LBP), which are identified as one of the active ingredients of the fruits, and tested its capacity to stand the oxidative insult using a STZ-induced hyperglycemic model. The author found again that the LBP reinstated the STZ-induced abnormal oxidative indices, results that are in line with another study by Wu et al[211], who also studied the antidiabetic effects of these polysaccharides, using rats with NIDDM. The authors found that LBP can control blood glucose and modulate the metabolism of glucose, leading to a significant improvement of oxidative stress markers (SOD, MDA), in addition to its ability to decrease DNA damage, possibly via leveling off oxidative stress. These findings point to the potential protective effect of LBP against deleterious oxidative stress, hence, preventing the development of diabetic complications.

Additionally, Strobilanthes crispus (Acanthaceae), which is used traditionally for the treatment of several ailments including DM, has shown antihyperglycemic and antilipidemic properties when tested in STZ-induced diabetic rats. The antioxidant effect of the herbal hot water extract (fermented and unfermented) contributed possibly to its and polyphenol contents[212].

Clinically, the valuable antioxidant effect of the herbal medicine, Silybum marianum seed extract (silymarin), was confirmed in a randomized, double-blind, placebo-controlled, clinical study of 51 type II diabetic patients[213], where this extract induced a marked improvement in the glycemic profile of these patients.

In an attempt to study the effect of some herbal components against free radicals, Xiong et al[214] assessed the protective effect of puerarin, an isoflavone purified from Chinese herb radix of Pueraria lobata, on hydrogen peroxide (H₂O₂)-induced rat pancreatic islets damage. The results emphasize that puerarin can preserve islet cells from the ROS-induced damage. Likewise, the extract of Plantago depressa var. montata. was able to correct glucose and lipid homeostasis and to restore redox status in alloxan-induced diabetic mice, effects that are probably due to its antioxidant and free radical scavenging properties[215].

Another herbal drug evaluated for its hypoglycemic and anti-oxidant activities is the dried roots of Morinda officinalis, which was tested in STZ-treated rats and resulted in a decrease in fasting glucose and lipid peroxide levels, along with the restoration of the assessed redox indices. The study concluded that Morinda officinalis has anti-diabetic and antioxidant potentials[216]. Similarly, Amaranthus esculantus grain and oil fraction were found effective as both antioxidant and anti-diabetic, suggesting their beneficial effect in correcting hyperglycemia and preventing diabetic complications[217].

In the Turkish folkloric medicine Gentiana olivieri Griseb. (Gentianaceae) is used as a hypoglycemic plant, an effect that was verified by a recent study[218]. The hypoglycemic effect was attributed to its main active constituent, isoorientin, a compound that was documented for its favorable action on glucose homeostasis[219] partly via saving β-cells from oxidative damage by virtue of its potent antioxidant properties. Additionally, this compound may sensitize the insulin receptor to insulin or stimulate the stem cell of islets of Langerhans in pancreas of STZ-induced diabetic rats to restore plasma level of insulin[219]; however, these assumptions need to be tested.

Moreover, the ability of ginseng to scavenge free radicals is thought to add to its antidiabetic mechanisms[220]. Ginseng was found to decrease the rate of monosaccharide auto-oxidation, to elevate the activity of defence enzymes as SOD; and directly eliminate the superfluous free radicals. The same hold true for garlic (Allium sativum L., Liliaceae) which mediates its antidiabetic action by acts by its antioxidant character and by increasing insulin secretion[221].

The methanolic extract of Phyllanthus amarus (Euphorbiaceae), used traditionally in Indian herb medicine, was found to have a potent antioxidant activity added to its antihyperglycemic efficacy tested in alloxan-induced diabetic rats[222]. Other plants known for their antioxidant properties include Capparis deciduas, Camellia sinensis, Emblica officinalis, Ficus bengalensis, Musa sapientum and Punica granatum[151]. Additionally, the antidiabetic effects of fruit of Vaccinium arctostaphylos L. (Ericaceae), which is traditionally used in Iran for improving of health status of diabetic patients, was found to encounter several machinaries among which were the notable rising of the erythrocyte superoxide dismutase (57%), glutathione peroxidase (35%) and catalase (19%) activities of the alloxan-treated rats[223].

Hyperglycemia-induced aldose reductase activation results in the depletion of NADPH which is required for GSH reductase, hence, altering endogenous defense system. Therefore, inhibitors of aldose reductase could offer new approaches for the treatment of diabetes. Feng et al[224] reported in his study that some herbal active constituents, viz., flavonoid compounds and their derivates, have the ability to inhibit the activity of this enzyme, such as quercetin, silymarin, puerarin, and others. In addition, some Salacia root species possess this function, for example, the crude methanolic extract and ethyl acetate soluble fractions of S. oblonga showed inhibitory activity on rat lens-derived aldose reductase[43]. In addition, the extract of S. reticulata stems, with its active constituent mangiferin, exhibited aldose reductase inhibitory activity[225], as well as the aqueous methanolic extract of S. chinensis[45].

CONCLUSION

From the previous data reviewed in the current article, it is obvious that herbs and/or their active constituents could attack several pathways of the hyperglycemic process. The multi-modes of their action allow them to outperform the conventional diabetic agents, besides the cost effectiveness and higher safety profile. These plants could be used as valuable therapeutic agents or as add-on conventional therapies for controlling glucose homeostasis. Although the evidenced-based therapeutic usage of many plants is scarce, the plants cited in this review are those reputed traditionally for their antidiabetic effect and that were verified, either experimentally or clinically.