Neprilysin inhibition in mouse islets enhances insulin secretion in a GLP-1 receptor dependent manner

ABSTRACTNeprilysin, a widely expressed peptidase upregulated in type 2 diabetes, is capable of cleaving and inactivating the insulinotropic glucagon-like peptide-1(GLP-1). Like dipeptidyl peptidase-4 (DPP-4), inhibition of neprilysinactivity under diabetic conditions is associated with increased active GLP-1 levels and improved glycemic control. While neprilysinexpression has been demonstrated in islets, its local contribution to GLP-1-mediated insulin secretion remains unknown. We investigated in vitro whether islet neprilysininhibition enhances insulin secretion in response to glucose and/or exogenous GLP-1, and whether these effects are mediated by GLP-1 receptor (GLP-1R). Further, we compared the effect of neprilysinversus DPP-4 inhibition on insulin secretion. Isolated islets from wild-type (Glp1r+/+) and GLP-1 receptor knockout (Glp1r−/−) mice were incubated with or without the neprilysininhibitor thiorphanand/or the DPP-4 inhibitor sitagliptinfor 2.5 hours. During the last hour, insulin sec...