1829-P: Acute Inhibition of Intestinal Neprilysin Enhances Glucose-Stimulated Insulin Secretion in Mice

Increased activity of the ubiquitous peptidase neprilysin in obesity and type 2 diabetes (T2D) is associated with impaired glucose homeostasis, and its inhibition has been shown to improve β-cell function. Neprilysin cleaves and inactivates insulinotropic peptides, including some produced in the intestine (e.g., GLP-1, GIP, CCK). While neprilysin is expressed in the intestine, the contribution of intestinal neprilysin to modulate β-cell function remains unknown. Thus, we sought to determine whether acute selective pharmacological inhibition of intestinal neprilysin enhances glucose-stimulated insulin secretion (GSIS) in healthy mice and could be a therapeutic target in T2D. High (20 mg/kg) or low (0.05 mg/kg) dose neprilysin inhibitor thiorphan, or vehicle, was orally administered to chow-fed C57BL/6 mice, then plasma and tissues were collected after 40 minutes to determine neprilysin activity. High dose thiorphan significantly inhibited neprilysin activity in plasma and all tissues listed below (data not shown). In contrast, low dose thiorphan inhibited neprilysin activity by 91±5% in colon, 50±12% in ileum and 62±4% in jejunum vs. vehicle (n=7-8, p -1 , n=6-7, p=0.01) without altering basal insulin (95±21 vs. 114±25 pM, n=6-7, p=0.6). In summary, under physiological conditions, acute selective inhibition of intestinal neprilysin increases GSIS in vivo. Thus, intestinal neprilysin plays a role in modulating β-cell function, and strategies to inhibit neprilysin specifically in the intestine might improve β-cell dysfunction in T2D. Disclosure N. Esser: None. T.O. Mundinger: None. B. Barrow: None. S.M. Mongovin: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. Funding National Institutes of Health (DK098506); Belgian American Educational Foundation; Societe Francophone du Diabete