Effects of chronic administration of alogliptin on the development of diabetes and β-cell function in high fat diet/streptozotocin diabetic mice

Abstract

Alogliptin is a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor. The aim of this study was to determine its effects on glucose control and pancreas islet function and to identify the underlying molecular mechanisms after chronic administration, in a non-genetic mouse model of type 2 diabetes. Alogliptin (5, 15 and 45 mg/kg) was orally administered to high fat diet/streptozotocin (HFD/STZ) diabetic mice daily for 10 weeks. Postprandial and 6-h fasting blood glucose levels, blood A1C level, oral glucose tolerance and pancreas insulin content were measured during or after the treatment period. Alogliptin plasma concentration was determined by an LC/MS/MS method. Islet morphology and architectural changes were evaluated with immunohistochemical analysis. Islet endocrine secretion ability was assessed by measuring insulin release from isolated islets which were challenged with 16 mM glucose and 30 mM potassium chloride, respectively. Gene expression profiles of the pancreas were analysed using the mouse diabetes RT(2) Profiler PCR array which contains 84 genes related to the onset, development and progression of diabetes. Alogliptin showed dose-dependent reduction of postprandial and fasting blood glucose levels and blood A1C levels. Glucose clearance ability and pancreas insulin content were both increased. Alogliptin significantly restored the β-cell mass and islet morphology, thus preserving islet function of insulin secretion. Expression of 10 genes including Ins1 was significantly changed in the pancreas of diabetic mice. Chronic alogliptin treatment completely or partially reversed the abnormalities in gene expression. Chronic treatment of alogliptin improved glucose control and facilitated restoration of islet architecture and function in HFD/STZ diabetic mice. The gene expression profiles suggest that the underlying molecular mechanisms of β-cell protection by alogliptin may involve alleviating endoplasmic reticulum burden and mitochondria oxidative stress, increasing β-cell differentiation and proliferation, enhancing islet architecture remodelling and preserving islet function.