1546-P: Gut-Specific Neprilysin Deletion Increases Insulin Secretion in High-Fat–Fed Mice

Global deletion of the ubiquitous peptidase neprilysin (NEP) protects against high fat diet (HFD)-induced insulin secretory dysfunction. Since NEP is expressed in the gut, it can cleave locally produced insulinotropic peptides. We previously found that under physiological conditions, acute inhibition of gut NEP enhances glucose-stimulated insulin secretion (GSIS) in mice. Thus, we determined whether this beneficial effect on GSIS also occurs in mice with gut-specific NEP deletion that are fed HFD. Mice with conditional deletion of NEP in enterocytes (NEPGut-/-) were generated by crossing Vil1-cre and floxed NEP mice. NEP activity was almost abolished throughout the gut in NEPGut-/- vs control mice (5±2 vs 164±20 vs 120±20 pmol MNA/h/μg, NEP Gut-/- vs Vil1-cre vs NEPfl/fl mice; n=5-6/group; p