Herbs have been used for medicinal purposes, including the treatment of diabetes, for centuries. Plants containing flavonoids are used to treat diabetes in Indian medicine and the green tea flavonoid, epigallocatechin gallate (EGCG), is reported to have glucose-lowering effects in animals. We show here that the regulation of hepatic glucose production is decreased by EGCG. Furthermore, like insulin, EGCG increases tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), and it reduces phosphoenolpyruvate carboxykinase gene expression in a phosphoinositide 3-kinase-dependent manner. EGCG also mimics insulin by increasing phosphoinositide 3-kinase, mitogen-activated protein kinase, and p70 s6k activity. EGCG differs from insulin, however, in that it affects several insulin-activated kinases with slower kinetics. Furthermore, EGCG regulates genes that encode gluconeogenic enzymes and protein-tyrosine phosphorylation by modulating the redox state of the cell. These results demonstrate that changes in the redox state may have beneficial effects for the treatment of diabetes and suggest a potential role for EGCG, or derivatives, as an antidiabetic agent.

T-1095A and T-1095 are synthetic agents derived from phlorizin, a specific inhibitor of Na+-glucose cotransporters (SGLTs). Unlike phlorizin, T-1095 is absorbed into the circulation via oral administration, is metabolized to the active form, T-1095A, and suppresses the activity of SGLTs in the kidney. Orally administered T-1095 increases urinary glucose excretion in diabetic animals, thereby decreasing blood glucose levels. Indeed, the postprandial hyperglycemia after a meal load was shown to be suppressed by this compound in streptozotocin (STZ)-induced diabetic rats. With long-term T-1095 treatment, both blood glucose and HbA1c levels were reduced in STZ-induced diabetic rats and yellow KK mice. In addition, there was amelioration of abnormal carbohydrate metabolism, i.e., hyperinsulinemia and hypertriglyceridemia, and of the development of microalbuminuria, in yellow KK mice. Thus, T-1095 may be a useful antidiabetic drug, providing a novel therapeutic approach for diabetes.

1 The therapeutic e ects of an orally active inhibitor of Na + -glucose cotransporter (SGLT), T-1095 (a derivative of phlorizin; 3-(benzo [b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-b-D-glycopyranoside)) were examined in C57BL/KsJ-db/db (db/db) mice, a genetic animal model of obese type 2 diabetes. 2 The higher renal SGLT activity in db/db mice than normoglycaemic C57BL/KsJ-db/+m (db/ +m) mice may support the rationale for using an SGLT inhibitor in the treatment regimen for type 2 diabetes. Both T-1095 and its metabolite, T-1095A, which had approximately 10 times more potency, e ectively inhibited renal SGLT activity of these mice in vitro.3 Single oral administration of T-1095 (10, 30, 100 mg kg 71 , p.o.) to db/db mice caused a dosedependent reduction in blood glucose levels and a concomitant increase in glucose excretion into urine. In contrast, T-1095 only slightly a ected blood glucose levels in db/+m mice. 4 Chronic administration of T-1095 (0.1% w w 71 pellet chow, for 12 weeks) decreased blood glucose and haemoglobin A 1C levels, and improved glucose intolerance in db/db mice. The agerelated decrease in plasma insulin levels was markedly inhibited and there was a 2.5 fold increase of insulin content in the pancreas of T-1095-treated db/db mice. Food consumption was not changed, while impaired body weight gain was ameliorated by T-1095 treatment. 5 Both the development of albuminuria and the expansion of glomerular mesangial area in db/db mice were signi®cantly suppressed by chronic T-1095 treatment, indicating the prevention of the progression of diabetic nephropathy. 6 These results demonstrate that the SGLT inhibitor T-1095 is able to improve the metabolic abnormalities and inhibit the development of diabetic complications in db/db mice. Thus, T-1095 can be used for therapy of type 2 diabetic patients.

Background —Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Reactive oxygen species induce apoptosis in many types of cells including cardiomyocytes. Because insulin has been reported to have protective effects, we examined whether insulin prevents cardiomyocytes from oxidative stress–induced apoptotic death. Methods and Results —Cultured cardiomyocytes of neonatal rats were stimulated by hydrogen peroxide (H 2 O 2 ). Apoptosis was evaluated by means of the TUNEL method and DNA laddering. Incubation with 100 μmol/L H 2 O 2 for 24 hours increased the number of TUNEL-positive cardiac myocytes (control, ≈4% versus H 2 O 2 , ≈23%). Pretreatment with 10 − 6 mol/L insulin significantly decreased the number of H 2 O 2 -induced TUNEL-positive cardiac myocytes (≈12%) and DNA fragmentation induced by H 2 O 2 . Pretreatment with a specific phosphatidylinositol 3 kinase (PI3K) inhibitor, wortmannin, and overexpression of dominant negative mutant of PI3K abolished the cytoprotective effect of insulin. Insulin strongly activated both PI3K and the putative downstream effector Akt . Moreover, a proapoptotic protein, Bad , was significantly phosphorylated and inactivated by insulin through PI3K. Conclusions —These results suggest that insulin protects cardiomyocytes from oxidative stress–induced apoptosis through the PI3K pathway.

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