Pharmacological activation of insulin‐degrading enzyme improves insulin secretion and glucose tolerance in diet‐induced obese mice

Abstract

Aim:To investigate the use of synthetic preimplantation factor (sPIF) as a potentialtherapeutic tool for improving glucose-stimulated insulin secretion (GSIS), glucose tol-erance and insulin sensitivity in the setting of diabetes.Materials and Methods:We used a preclinical murine model of type 2 diabetes(T2D) induced by high-fat diet (HFD) feeding for 12 weeks. Saline or sPIF (1 mg/kg/day) was administered to mice by subcutaneously implanted osmotic mini-pumps for25 days. Glucose tolerance, circulating insulin and C-peptide levels, and GSIS wereassessed. In addition,β-cells (Min-6) were used to test the effects of sPIF on GSISand insulin-degrading enzyme (IDE) activity in vitro. The effect of sPIF on GSIS wasalso tested in human islets.Results:GSIS was enhanced 2-fold by sPIF in human islets ex vivo. Furthermore, con-tinuous administration of sPIF to HFD mice increased circulating levels of insulin andimproved glucose tolerance, independently of hepatic insulin clearance. Of note,islets isolated from mice treated with sPIF exhibited restoredβ-cell function. Finally,genetic (shRNA-IDE) or pharmacological (6bK) inactivation of IDE in Min-6 abolished