Sitagliptin lowers glucagon and improves glucose tolerance in prediabetic obese SHROB rats

Abstract

Inhibitors of dipeptidyl dipeptidase IV (DPP‐IV) are effective hypoglycemic agents in type 2 diabetes through potentiation of incretin hormones that act in the pancreas to increase insulin and decrease glucagon release. We sought to determine whether the DPP‐IV inhibitor sitagliptin might be effective in prediabetes relative to standard therapy with the sulfonylurea glyburide, by using the spontaneously hypertensive obese (SHROB) rat model. SHROB show normal fasting glucose but are insulin resistant and hyperglucagonemic. SHROB were treated for 6 wk with vehicle, sitagliptin (30 mg/kg/d) or glyburide (1 mg/kg/d). Body weight, food intake and fasting glucose were all unchanged in all 3 groups, but glucagon was reduced 33% by sitagliptin while unchanged following glyburide or vehicle. In oral glucose (6g/kg) tolerance testing, both sitagliptin and glyburide lowered plasma glucose. Both sitagliptin and glyburide shifted peak insulin secretion earlier (30 min for glyburide and 60 min for sitagliptin but 240 min for vehicle). Only sitagliptin significantly enhanced insulin secretion. Sitagliptin is effective in normalizing excess glucagon levels and delayed exaggerated insulin secretion in response to a glucose challenge in a prediabetic model.