(1) Modulators of carbohydrate metabolism/ disposition, (2) Fat cell and lipid level modulators, (3) Modulators with pleiotropic effects on carbohydrate, lipid, and protein metabolism and (4) Modulators of insulin sensitivity and inflammation.

Flavonoids from the medicinal plants have benzopyran-4-one ring

Flavonoids are naturally occurring polyphenols, which have the basic benzopyran-4-one ring (or γ – benzopyrone ring) substituted with phenyl group at position 2. Naturally occurring coumarins have α-benzopyrone ring. Chemically, flavones are 2-phenyl-γ–benzopyrones, which are also referred to as 2-phenylchromen-4-one or 2-phenyl-1-benzopyran-4-one (Fig. 2)¹³. Similar naturally available plant flavonoids were reported for their antidiabetic activity in DM. The flavonoids such as kaempferol, baicalein, luteolin, apigenin, diosmetin, genestein, naringenin, chrysin, hesperidin, hesperitin, epicatechin, epigallocatechin, diadzein, myricetin, shamimin etc. were excellent leads for DM in animal models ¹⁴.The α, β unsaturated ketone group in benzopyran-4-one ring of flavonoid is believed to be responsible for most of their biological activity.

Figure 2: Benzopyran-4-one ring in flavonoids

In plants, flavonoids play a vital role in protecting the plant against pathogenic organisms, especially the roots. They also give a bitter taste to the plant and thus protect the plants from foraging by higher animals. In flowers, they give special colour owing to their quinoid structure, which attracts pollinating insects. The observation of low cardiovascular mortality rate in Mediterranean populations was associated with red wine (rich in flavonoids) consumption (in spite of a high calorie diet) has led to increased research in the field of flavonoids. This paradoxical benefit from drinking red wine is called as ‘French paradox’. In 1930, a new substance was isolated from oranges, which was believed to belong to a new class of vitamins and was designated as ‘vitamin P’ ¹⁵^,¹⁶. When it became clear that this substance was a flavonoid (rutin, Fig. 3), a flurry of research began in an attempt to isolate various flavonoids from plants, along with some synthetic approaches to prepare analogues and to study the possible mechanisms by which they act. Later, in 1950, the term ‘vitamin P’ was recommended to discontinue ¹⁷.

Figure 3: Structure of rutin: [Synonyms: quercetin- 3-rutinoside; quercetin-3-α-(L-rhamnopyranosyl(1®6)-β-D-glucopyranosyl)

Today more than 8000 varieties of flavonoids have been reported ¹⁸. Natural and synthetic analogues of flavonoids and their various biological activities have been major areas of research in the last few decades. One of the previous reports from our department research revealed that the extract of medicinal plants Dodonaeaviscosa (L). and Ficusracemosa showed antidiabetic dietary models of insulin resistant animals and also instreptozotocin (STZ) induced diabetes models. The major constituent responsible was a flavonoid quercetin ^19-21. Further, we have made attempts to modulate the benzopran-4-one moiety present in the flavonoids to optimize the antidiabetic activity (unpublished data).

Benzopyran-4-one leads from natural sources and synthetic modifications for diabetes

Natural benzopyrones (flavonoids) were extensively studied and reported in huge numbers. They are well known for their antioxidant activity. Many of these molecules have been reported to possess potent antidiabetic activity. Studies have been demonstrated the hypoglycemic effects of flavonoids in animal models and in clinical trials.

Efforts have been made to synthesis of flavonoids and their derivatives by analogues synthesis using benzopyran-4-one as basic scaffold. Some reports are available but they are targeted for conditions other than diabetes by synthetic flavonoids. Most of the published literature on synthetic analogs of flavonoids focus on antimicrobial enzymes, anti-inflammatory and analgesic activities ^22-24. In 1990’s, research on flavonoids revealed that phosphatidylinositol 3-kinase (PI3K) was inhibited by quercetin with an IC₅₀ of 3.8 μM. Various analogues of quercetin were subsequently synthesised and one compound, viz. 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (also known as 2-(4-morpholinyl)-8-phenylchromone, LY294002; Fig. 4), was found to completely and specifically abolish PI3K activity (IC₅₀ = 1.40 μM) ²⁵. Wortmannin and LY294002 were also reported to inhibit insulin-induced down-regulation of IRS-1 in 3T3-L1 adipocytes ²⁶. The same molecule LY294002 activated phospholipase D (PLD) through an indirect PI3K pathway, which was proposed to be beneficial in proliferative diseases ²⁷. The molecule LY294002, strongly suppressed the production of iNOS and cytokines, in vitro mouse macrophage cell line RAW-264.7 ²⁸. Also, LY294002 induces hemeoxygenase-1 (HO-1) signaling through p38-MAPK, NF-kB, and Nrf2 as well as other unidentified bio-molecules²⁹. Further, chronic administration of LY294002 to diabetic rats, prevented diabetes-induced vascular reactivity through PI3K pathway, but surprisingly, blood glucose levels were not lowered³⁰.

Figure 4: Structure of LY294002

2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one [Specific inhibitor of the activation of mitogen-activated protein kinase kinase (MEK)] Quercetin was also found to possess affinity for aldose reductase enzyme, which plays a role in diabetes-related complications. Later, several derivatives of quercetin were synthesised in order to target this enzyme ³¹. It was subsequently found that the 7-hydroxy-2-substituted-4-H-1-benzopyran-4-one derivatives were better inhibitors of aldose reductaseenzyme ³². Vanadium based flavonoid complexes were designed and studied for their hypoglycemic effect in both oral and intraperitoneal treatments in diabetic rats ³³^,³⁴.

Interestingly, α-glucosidase was also targeted by benzopyran-4-one derivatives. A series of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives were synthesized and evaluated as α-glucosidase inhibitors. Most compounds showed good inhibitory activity with IC₅₀ values ranging from 0.0645 μM to 26.746 μM. The compound 7-hydroxy-6-methoxy-3-[4-(4-methylphenylsulfonamido)-benzoyl]-2H-1-benzopyran-2-one was shown to be the most potent inhibitor ³⁵.

Green tea has been observed to improve glucose metabolism in healthy humans in oral glucose tolerance tests. Green tea also lowered blood glucose levels in diabetic db/db mice and STZ-diabetic mice without affecting the serum insulin level³⁶. Similarly, it improved glucose tolerance and reduced blood glucose levels in normal and alloxan-diabetic rats ³⁷. A recent study says green tea attenuates cardiovascular remodeling and metabolic symptoms in high carbohydrate-fed rats ³⁸. The procyanidins from grape seeds have demonstrated a significant ability to reduce glycemic levels together with an increase in insulin secretion, thus showing a supra-additive hypoglycemic effect in rats. There was also an increased expression of GLUT4 in plasma membranes of 3T3-L1 adipocytes when they were incubated with theprocyanidins from grape seeds ³⁹. Similarly, epigallocatechingallate (EGCG) showed hypoglycemic activity in rats along with serum insulin lowering effects in T2D⁴⁰.

An isoflavonoid, puerarin has been reported to decrease the plasma glucose levels in normal and hyperglycemic rats ⁴¹. Puerarin and daidzin significantly improve glucose tolerance in diabetic C57BL/6J-ob/obmice⁴². Genistein, an isoflavone from soya, a strong antioxidant, inhibited glucose auto-oxidation-mediated atherogenic modification of low density lipoproteins (LDL)⁴³. Chronic treatment with genistein and daidzein in db/db mice and STZ-diabetic rats also ameliorated diabetic conditions. Also, reports suggest that they prevent the onset of diabetes, elevating insulin levels and altering hepatic gluconeogenic and lipogenic enzyme activities in non-obese diabetic (NOD) mice ⁴⁴^,⁴⁵. Further, genistein was said to improve aortic reactivity of STZ-diabetic rats ⁴⁶. Kaempferitrin, a compound isolated from the n-butanol fraction of Bauhinia forficata, showed hypoglycemic effect in diabetic rats but not in normal rats⁴⁷. Quercetin is being extensively studied for its potential role in diabetes. It was also demonstrated that quercetin reduces blood glucose level of diabetic rats but not in normoglycemic rats ⁴⁸.

Myricetin did not show hypoglycemic activity in normal rats but showed 50% decrease in glycemia in diabetic rats ⁴⁹^,⁵⁰. Anti-hyperglycemic and hypoglycemic effects have been demonstrated for chrysin and its derivatives, silymarin, isoquercitrin and rutin⁵¹. Oral administration of rutin for 45 days to diabetic rats decreased plasma glucose levels by up to 60%. However, rutin did not show any significant effect on fasting plasma glucose levels in normal rats⁵². Similarly, long term treatment with hesperidin and naringin was found to lower the blood glucose level of db/dbmice⁵³. Hesperidin glycosides were found to alter the expression of genes encoding PPAR, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCoA), and LDL-receptor (LDL-R) in Goto-Kakizakirats ⁵⁴.

Soya [soybean: Glycine max (L.) Merr] contains genistein and daidzein, two phytoestrogens, which work through the estrogen receptor and cause alterations in serum lipids, bone metabolism, and possibly cognition. They were found to be beneficial in neuropathic pain, neurotrophic and vasculature deficits in diabetic mouse models by reversing the oxidative and inflammatory state⁵⁵. However, a 6-month randomized controlled trial did not support the hypothesis that soya protein with or without isoflavone supplementation had favorable effects on glycemic control and insulin sensitivity among postmenopausal Chinese women⁵⁶. The soya flavonoids could act by multiple mechanisms against oxidative stress induced endothelial injury in diabetes ⁵⁷. In vitro studies have shown that a soybean extract containing the isoflavones, genistein and daidzein inhibit glucose absorption into the intestinal brush border membrane vesicles ⁵⁸. Naringenin, a flavonoid present in large quantities in the citrus fruits and juices, inhibited glucose absorption in the intestine⁵⁹.

Epicatechingallate, myricetin, quercetin, apigenin, epigallocatechin and EGCG were shown to produce marked reduction in glucose absorption from the intestine by competitive inhibition of SGLT-1⁶⁰^,⁶¹. Besides reducing glucose absorption, another possible mechanism that controls blood glucose levels is the inhibition of intestinal brush border enzymes such as α-glucosidase and α-amylase. Inhibitory effects on α-glucosidase activity were demonstrated when luteolin, kaempferol, chrysin and galangin were used, both in vitro and in vivo, to study the potential role in the absorption and metabolism of carbohydrates. The study showed that, of the compounds tested, luteolin, amentoflavone, luteolin 7-O-glucoside and daidzein were the strongest inhibitors⁶². Similarly, many flavonoids were reported for their hypoglycemic activity by inhibiting the intestinal enzymes, which convert polysaccharides, oligosaccharides and disaccharides to monosaccharides⁶³.

Some of the flavonoids have been studied for their effect on renal glucose reabsorption and excretion. Naringenin was shown to inhibit the glucose reabsorption in renal tubular brush border membrane vesicles⁵⁹. Quercetin-fed diabetic rats ameliorate renal dissacharidaseactivity ⁶⁴. Flavonoids such as puerarin, have been reported to ameliorate high-glucose effect on c-fos, c-jun and collagen IV expression in renal glomerular mesangialcells⁶⁵. EGCG administration over a 50 day-period to diabetic rats decreased hyperglycemia, proteinuria and reduced renal AGEs accumulation and related protein expression in the kidney along with pathological conditions associated with nephropathy⁶⁶. Green tea flavonoids can attenuate urinary protein excretion and morphological changes in diabetic nephropathy in terms of blood glucose and glycosylated protein levels in diabetic rats⁶⁷^,⁶⁸. Homoisoflavanones isolated from Polygonatumodoratumrhizomes, namely, 3- (4'-hydroxybenzyl) -5,7 –dihydroxy-6 –methyl -8-methoxy- chroman-4-one, 3-(4'-hydroxybenzyl) -5,7-dihydroxy-6,8-dimethylchroman-4-one and 3-(4'-methoxybenzyl) -5,7-dihydroxy -6-methyl -8-methoxychroman-4-one inhibited in vitro AGEs formation more effectively than the positive control, aminoguanidine⁶⁹. Similarly, grape seed proanthocyanidin modulates cerebral cortex encephalopathy in STZ-induced diabetic rats through AGEs/RAGE/NF-kB pathway modifications ⁷⁰. Also, it was reported that the flavonoid-rich diet is positively associated with antiatherosclerotic enzyme paraoxonasearylesterase activity in diabetic foot-ulcer patients⁷¹.

Molecular mechanism of benzopyran-4-ones as antidiabetics

Benzopyran-4-ones have multiple targets as hypoglycemic agents and to ameliorate insulin resistance in T2D⁷². The natural benzopyran-4-ones (flavonoids) are showed to act by insulinomimetic activity, increased glucose uptake by skeletal muscle, α-glucosidase inhibition, aldose reductase inhibition, AMPK activation, SGLT-2 inhibition, PPAR modulation, PTP-1B inhibition, Inhibition of inhibitor kappa-B kinase-β (IKKβ) and AGEs inhibition. Many flavonoids also restore endothelial functions, thereby alleviating diabetic complications. Moreover, flavonoids are well known antioxidants and can prevent oxidative stress during the progression of disease. Quercetin, reported to be the best antidiabetic natural flavonoid candidate, has been shown to act by multiple mechanisms. Quercetin was recently shown to inhibit 11-β-HSD1. Thus, flavonoids stimulate glucose uptake in peripheral tissues, regulate the activities of the rate-limiting enzymes in the carbohydrate metabolism pathway and act as insulin secretagogues or insulin mimetic, probably, by influencing insulin signaling, to ameliorate the diabetes status.

Genistein supplementation increases plasma insulin of the STZ diabetic rats⁴⁴. In vitro studies showed that genistein can increase insulin secretion from mouse pancreatic islets in the presence of glucose by increasing intracellular cyclic adenosine monophosphate (cAMP). The increase in intracellular cAMP is probably the result of enhanced adenylateclyclase activity and activation of protein kinase A (PKA) by a mechanism which does not involve protein tyrosine kinase (PTK). This demonstrates that genistein directly acts on pancreatic β-cells, leading to activation of the cAMP/PKA signaling cascade and exerts insulinotropic effect ⁷³. Recently, genistein was reported to induce pancreatic β-cell proliferation through activation of multiple signaling pathways and prevents insulin-deficient diabetes (type 1 diabetes) in mice. This could be because of subsequent phosphorylation of Erk1/2 in both INS1 cells and human islet β-cells. Further it was reported that genestein induced protein expression of cyclin D1, a major cell-cycle regulator essential for β-cell growth ⁷⁴. Similarly, genistein reduces the over secretion of extracellular matrix components and transforming growth factor-β (TGF-β) in high-glucose-cultured rat mesangial cells, showing that genistein could be lead molecule for treatment of diabetic nephropathy ⁷⁵.

Chronic oral administration of rutin in diabetic rats has been found to produce significant increase in plasma insulin and C-peptide levels. A histopathological study of the pancreas revealed the protective role of rutin resulting in β-cell proliferation⁵². An increase in the number of pancreatic islets has also been observed in both normoglycemic and diabetic rats treated with quercetin. This effect may be due to increased DNA replication in β-cells. Recently, it was established that quercetin decreases oxidative stress, abolishes iNOS over-expression in diabetic rat liver and modulates the IKK/ NF-kB signal transduction pathway. This might play a role in blocking the production of noxious mediators involved in the development of early diabetes tissue injury and the evolution of late complications⁷⁶. Quercetin was also found to be an allosteric ligand for GLP-1R⁷⁷. Synthetic flavonoids also have allosteric modulatory activity in Chinese-hamster ovary cells expressing the human GLP-1R. They have also reported that the 3-hydroxyl group on the flavone backbone, i.e. a flavonol, was essential for this activity⁷⁸. Further, inhibition of 11β-HSD1 (another diabetes drug target) by quercetin plays a role in modulating insulin resistance⁷⁹.

French maritime pine (Pinusmaritima) bark extract, Pycnogenol^®, a patented combination of bioflavonoids, has a high antioxidant potential. A concentrate of polyphenols, mainly phenolic acids, and procyanidins, the extract is used extensively as a dietary supplement in diabetes ⁸⁰. Pycnogenol^® activates GLUT4 via the PI3K and p38-MAPK pathway in 3T3-L1 adipocytes ⁸¹.

The cyanidin-3-glucoside and delphinidin-3-glucoside have been found to be insulin secretagogues. Also, pelargonidin-3-galactoside and its aglycone, pelargonidin, can cause a significant increase in insulin secretion in the presence of glucose ⁸². Some natural flavones such as pectolinarigenin (full name: 5,7-dihydroxy-4',6-dimethoxyflavone; DDMF) and pectolinarin [full name: pectolinarigenin-7-rhamnosyl-(1à6)-glucoside] were also reported to modulate adiponectin and leptin expression, resulting in improved glucose and lipid homeostasis in diabetic rats ⁸³.

Kaempferitrin (3,7-dirhamnoside of kaempferol), was reported to enhance the glucose uptake in rat soleus muscle⁸⁴. Kaempferol 3-neohesperidoside showed insulinomimetic effects on the rat soleus muscle⁸⁵. Quercetin and EGCG have been found to protect insulin producing INS-1 cells against oxidative stress through anti-apoptotic signals⁸⁶. EGCG promotes GLUT4 translocation in skeletal muscle in vitro⁸⁷. Further EGCG was demonstrated to stimulate glucose uptake through the PI3K mediated pathway in L6 rat skeletal muscle cells ⁸⁸. Similarly, genistein-derivatives from Tetracerascandens stimulate glucose-uptake in L6 myotubes⁸⁹. A recent report says naringenin increases glucose uptake in muscle cells via activation of AMPK ⁹⁰. Similarly, luteolin-7-O-glucoside, from the plant Vernoniaamygdalina, increased both expression and translocation of GLUT4, thereby increasing glucose uptake by skeletal muscles in rats ⁹¹.

Myricetin also stimulated glucose uptake in the soleus muscle of diabetic rats⁹². Myricetin increased rate of glucose uptake without affecting either insulin receptor autophosphorylation, tyrosine kinase activity of the receptor or glucose transporter translocation to the plasma membrane. Myricetin appears to stimulate glucose transporters directly⁴⁹. Further, chronic treatment to diabetic rats with myricetin elevates the GLUT4 mRNA levels and GLUT4 gene expression in the soleus muscle⁷³. Puerarin treatment increased mRNA and GLUT4 transporter protein in soleus muscle after repeated administration in diabetic rats⁴². The hypoglycemic effects of green tea catechins have been confirmed because it increased insulin-stimulated glucose uptake in adipocytes as well as GLUT4 expression⁹³.

Procyanidin (or proanthocyanidins) treatment increases glucose uptake in cell lines, L6E9 myotubes and 3T3-L1 adipocytes; the glucose uptake being sensitive to wortmannin, an inhibitor of PI3K, and to SB203580, an inhibitor of p38-MAPK. Procyanidins also stimulated GLUT4 translocation to the plasma membrane, suggesting that they mimic and/or influence insulin effect by directly acting on specific components of the insulin signaling transduction pathway ³⁹. Proanthocyanidins attenuates cell proliferation in vascular smooth muscle via blocking PI3K-dependent signaling pathways⁹⁴. Similarly, it has been demonstrated for kaempferol 3-neohesperidoside that the stimulatory effect on glucose uptake in muscle is via the PI3K and PKC pathways and is, at least in part, independent of the MEK pathway and the synthesis of new glucose transporters ⁸⁵.

In contrast with several reports regarding the stimulatory effect of flavonoids on insulin signal transduction, GLUT4 translocation and glucose transport, some natural compounds like naringenin act negatively on these pathways. Naringenin does not alter the phosphotyrosine status of the insulin receptor, IRS proteins, or PI3K; but inhibits the phosphorylation of the downstream signaling molecule Akt. In an in vitro PI3K assay, naringenin, like wortmannin, blocked the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by immunoprecipitated PI3K ⁹⁵. Flavonoid genistein generally inhibits tyrosine kinase and also affects the function GLUT4 transporter. This suggests that genistein can interfere with insulin-induced glucose uptake directly, rather than blocking GLUT4 translocation⁹⁶. In the same way, catechin-gallate, quercetin and myricetin inhibit insulin-stimulated methylglucose uptake in rat adipocytes. Moreover, evidence points to the fact that quercetin, myricetin and catechingallate inhibit glucose uptake due to a direct interaction with GLUT4, acting as competitive blockers of glucose transport⁹⁷. However, several papers claim that genistein, quercetin, apigenin and kaempferol have potent tyrosine kinase inhibitory activity ⁸⁹^,⁹⁸^,⁹⁹. Further, genistein was found to increase the glucokinase (GK) level while it suppressed hepatic glucose-6-phosphatase (G6P) and phosphoenolpyruvatecarboxykinase (PEPCK) activity in db/db mice and in the diabetic rats. Also, genistein enhanced hepatic glycogen in diabetic mice⁴⁴.

EGCG increases tyrosine phosphorylation of the insulin receptor and IRS-1, MAPK, p70s6k, and PI3K activity, and reduces PEPCK gene expression mediated by PI3K ¹⁰⁰. Further, EGCG up-regulates GK mRNA expression in the liver of diabetic db/dbmice ¹⁰¹.Hesperidin and naringin can increase GK activity and glycogen in liver. Naringin has also been reported to lower the activity of hepatic G6P and PEPCK. These results suggest that flavonoids interfere with gluconeogenesis⁸⁴. Both hesperidin and naringin significantly increased the GK mRNA, while naringin also lowers the mRNA expression of PEPCK and G6P in the liver¹⁰². In another study, rutin restored the glycogen content and hexokinase (HK) activity in diabetic rats. Activity of enzymes such as G6P and fructose-1,6-bisphosphatase significantly decreased in the liver and muscles of diabetic rats⁵². Quercetin was also found to increase HK and GK activity in diabetic rats without affecting normal rats, and it has a potent inhibitory effect on both glycogen phosphorylase-a (active phosphorylated form) and phosphorylase-b (unphosphorylated inactive form) in isolated muscle ¹⁰³. Similarly, other flavonoids also inhibited rat liver G6P activity. In one of the studies, highest inhibitory activity was shown by quercetin 3-O-α-(2'-galloyl) rhamnoside and kaempferol 3-O-α-(2"-galloyl) rhamnoside. Quercetin 3-O-α-(2'-galloyl) rhamnoside and kaempferol 3-O-α-(2"-galloyl) rhamnoside exhibited the lowest IC₅₀. G6P inhibition by quercetin 3-O-α-(2"-galloyl) rhamnoside might explain the decrease in liver gluconeogenesis and, in turn, reduced glucose levels in diabetic patients ¹⁰⁴^,¹⁰⁵. Also, the luteolin-7-glucoside improves lipid profile and increases liver glycogen through glycogen synthase kinase-3 (GSK) in rats ¹⁰⁶.

Recently a flavonoid, 7-O-methylaromadendrin (7-O-MA), isolated from Inulaviscosa, at 10 μM, significantly stimulated insulin-induced glucose uptake, measured by 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG) in both human hepatocellular liver carcinoma (HepG2) cells and differentiated 3T3-L1 adipocytes. Adipocyte-specific fatty acid binding protein (aP2) gene expression was increased by 7-O-MA in adipocytes, and both gene and protein levels of PPAR-λ2 were also increased. Moreover, 7-O-MA stimulated the reactivation of insulin-mediated phosphorylation of PI3K linked Akt and AMPK in high glucose-induced, insulin-resistant HepG2 cells, while this was blocked by either LY294002 (a PI3K inhibitor) or compound C (AMPK inhibitor). The above results appear to suggest that 7-O-MA might stimulate glucose uptake via PPAR-λ2 activation and improve insulin resistance via PI3K and AMPK-dependent pathways, and thus become a potential candidate for the management of T2D ¹⁰⁷.

Thus, benzopyran-4-one leads have addressed multiple drug targets that are typical of metabolic disorders. PPAR-modulation subsequently became a popular target for diabetes and metabolic disorders. It was found that the 7-hydroxy-benzopyran-4-one moiety (occurring in flavones, flavanones, and isoflavones) is the key pharmacophore of these novel molecules, exhibiting similarity to the core structure of both fibrates and thiazolidinediones¹⁰⁸.

CONCLUSION:

The benzopyran-4-one moiety present in the flavonoidswas proposed to be the responsible for the antidiabetic activities. The modification of benzopyan-4-onepharmacophore has been reported by many researchers to target diabetes. However, many gaps remain in synthesis and evaluation of potency and efficacy of these agents. Further, we still need to study, identify and investigate on the processes such as, absorption, cellular and molecular mechanisms of naturally occurring flavonoids and the basic pharmacophore, benzopyran-4-one can be modified to optimize the lead in diabetes drug discovery.

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