Combined treatment with a gastric inhibitory polypeptide receptor antagonist and a peptidyl peptidase-4 inhibitor improves metabolic abnormalities in diabetic mice

OBJECTIVES: Dipeptidyl peptidase-4 inhibition and gastric inhibitory polypeptide (GIP) receptor antagonism have therapeutic effects in type 2 diabetes mellitus. We assessed the effects of sitagliptin and Pro(3)(GIP) in a mouse model of diabetes. METHODS: Diabetes was induced in C57BL/6J mice by a high-fat diet and intraperitoneal injection of streptozocin. Blood glucose was assessed weekly. Six weeks later, serum triglycerides, total cholesterol and glucose tolerance were assessed and pancreatic and adipose tissues were collected. RESULTS: Combination therapy with sitagliptin and Pro(3)(GIP) resulted in significantly greater reductions of blood glucose and triglycerides than either monotherapy. Combination therapy also improved insulin sensitivity and glucose tolerance. β-cell mass and insulin-positive cell percentage in the pancreas was higher in mice receiving combination therapy compared with either monotherapy. Crown-like structures, inflammatory markers in adipose tissue, and serum leptin concentrations were decreased in mice receiving combination therapy compared with either monotherapy. CONCLUSIONS: Combination therapy with Pro(3)(GIP) and sitagliptin improved metabolic abnormalities in diabetic mice. Changes in serum leptins and reduced inflammatory cell infiltration in adipose tissue might account for the observed effects.