CS-917, a fructose 1,6-bisphosphatase inhibitor, improves postprandial hyperglycemia after meal loading in non-obese type 2 diabetic Goto-Kakizaki rats

Abstract

Postprandial hyperglycemia is one of the features of type 2 diabetes. Increased hepatic gluconeogenesis is a predominant cause of postprandial hyperglycemia in type 2 diabetes. In this study, we evaluated the effect of gluconeogenesis inhibition on postprandial hyperglycemia using CS-917, a novel inhibitor of fructose 1,6-bisphphosphatase (FBPase) which is one of the rate-limiting enzymes of gluconeogenesis. The suppressive effect of CS-917 on postprandial hyperglycemia was evaluated in a meal loading test in Goto-Kakizaki (GK) rats, non-obese type 2 diabetic animal model characterized by impaired insulin secretion. In addition, we describe acute effect of CS-917 on fasting hyperglycemia in overnight-fasted GK rats and chronic effect of CS-917 in multiple dosing GK rats.CS-917 suppressed plasma glucose elevation after meal loading in a dose-dependent manner at doses ranging from 10 to 40 mg/kg. In an overnight-fasted state, CS-917 decreased the plasma glucose levels dose-dependently at doses ranging from 2.5 to 40 mg/kg. Consistent with the inhibition of FBPase, glucose-lowering was associated with an accumulation of hepatic d-fructose 1,6-bisphosphate and a reduction in hepatic d-fructose 6-phosphate. Chronic treatment of CS-917 decreased plasma glucose significantly, and no significant increase in plasma lactate and no profound elevation in plasma triglycerides were observed by both acute and chronic treatment of CS-917 in GK rats.These findings suggest that enhanced gluconeogenesis contributes to hyperglycemia in postprandial conditions as well as in fasting conditions, and that CS-917 as an FBPase inhibitor corrects postprandial hyperglycemia as well as fasting hyperglycemia.