The
peptidase neprilysin modulates
glucose homeostasis by cleaving and inactivating insulinotropic
peptides, including some produced in the intestine such as
glucagon-like peptide-1 (GLP-1). Under diabetic conditions, systemic or islet-selective inhibition of
neprilysin enhances beta-cell function through
GLP-1 receptor (GLP-1R) signaling. While
neprilysin is expressed in intestine, its local contribution to modulation of beta-cell function remains unknown. We sought to determine whether acute selective pharmacological inhibition of intestinal
neprilysin enhanced
glucose-stimulated insulin secretion under physiological conditions, and whether this effect was mediated through GLP-1R. Lean chow-fed Glp1r+/+ and Glp1r-/- mice received a single oral low dose of the
neprilysin inhibitor
thiorphan or vehicle. To confirm selective intestinal
neprilysin inhibition,
neprilysin activity in plasma and intestine (ileum and colon) was assessed 40 minutes after
thiorphan or vehicle administration. In a separate cohort of mice, an oral
glucose tolerance test was performed 30 minutes after
thiorphan or vehicle administration to assess
glucose-stimulated insulin secretion. Systemic active
GLP-1 levels were measured in plasma collected 10 minutes after
glucose administration. In both Glp1r+/+ and Glp1r-/- mice,
thiorphan inhibited
neprilysin activity in ileum and colon without altering plasma
neprilysin activity or active
GLP-1 levels. Further,
thiorphan significantly increased insulin secretion in Glp1r+/+ mice, whereas it did not change insulin secretion in Glp1r-/- mice. In conclusion, under physiological conditions, acute pharmacological inhibition of intestinal
neprilysin increases
glucose-stimulated insulin secretion in a GLP-1R-dependent manner. Since intestinal
neprilysin modulates beta-cell function, strategies to inhibit its activity specifically in the intestine may improve beta-cell dysfunction in
type 2 diabetes.