Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice

Objectives: Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet. Design: In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 mumol/g body weight) was administered in the drinking water for an 8 week period. Results: DPPIV inhibition reduced plasma DPPIV activity to 0.01 +/- 0.03 mU/ml vs 3.26 +/- 0.19 mU/ml in controls (P < 0.001). Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet (P = 0.029) and in mice fed a high-fat diet (P = 0.036). This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P < 0.05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16.7 +/- 2.6 x 10(3) mum(2) in controls to 7.6 +/- 1.0 X 10(3) mum(2) (p = 0.0019). Conclusion: Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance.