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The inhibition of sodium-glucose transporters (SGLT) has been proposed as a novel therapeutic approach to treat diabetes. Relatively nonselective sodium-glucose cotransporter (SGLT) inhibitors such as phlorizin have been demonstrated to improve ambient plasma glucose levels as well as insulin sensitivity in diabetic animal models. Dapagliflozin (BMS-512148), a novel SGLT2 inhibitor under clinical investigation, selectively inhibits human SGLT2 vs. human SGLT1 in cell based assays (SGLT2 EC]sub 50] = 1.1 nM, SGLT1 EC[sub 50] = 1391 nM). In vivo, dapagliflozin acutely induces renal glucose excretion in normal and diabetic rats at doses of 0.1-1.0 mg/kg without hypoglycemia, improves glucose tolerance in normal rats at 1 and 10 mg/kg, and effectively lowers hyperglycemia in Zucker diabetic fatty (ZDF) rats following single oral doses ranging from 0.1-1.0 mg/kg. At a 1 mg/kg dose, the peak concentration of dapagliflozin in ZDF rat plasma was 1.2 µM with an area under the curve (AUC) over 6 hr of 5.2 µM*hr. In a 15 day study with 17 week old male ZDF rats, dapagliflozin treatment resulted in significantly lowered fasting and fed glucose levels at doses ranging from 0.1-1.0 mg/kg. Dapagliflozin treatment also improved key aspects of metabolic dysregulation in this model as evaluated in a hyperinsulinemic euglycemic clamp procedure. A significant increase in glucose infusion rate (GIR) was accompanied by a significant reduction in hepatic glucose production (HGP) when measured on the third day following the final dose. These data suggest that dapagliflozin has the potential to be an efficacious treatment for human type 2 diabetes. [ABSTRACT FROM AUTHOR]

Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03-50 mg . kg(-1) . day(-1) for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg . kg(-1) . day(-1) for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg . kg(-1) . day(-1) for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high-molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (alpha/gamma) PPAR activator muraglitazar 1) exerts potent and efficacious antidiabetic effects, 2) preserves pancreatic insulin content, and 3) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels.