Neprilysin Is Required for Angiotensin-(1-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2)

Diabetes. 2017 Aug;66(8):2201-2212. doi: 10.2337/db16-1318. Epub 2017 May 30.


Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS. However, a more widely expressed islet peptidase, neprilysin, degrades angiotensin-(1-7) into several peptides. In neprilysin-deficient mouse islets, angiotensin-(1-7) and neprilysin-derived degradation products angiotensin-(1-4), angiotensin-(5-7), and angiotensin-(3-4) failed to enhance GSIS. Conversely, angiotensin-(1-2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein-coupled receptor (GPCR) MasR, angiotensin-(1-2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1-7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1-7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1-7) compounds and neprilysin inhibitors as therapies for diabetes.

MeSH terms

  • Angiotensin I / physiology*
  • Angiotensin-Converting Enzyme 2
  • Angiotensins / metabolism*
  • Animals
  • Glucose / physiology
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / enzymology
  • Insulin-Secreting Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neprilysin / deficiency*
  • Neprilysin / physiology
  • Peptide Fragments / physiology*
  • Peptidyl-Dipeptidase A / metabolism
  • Proteolysis
  • Receptors, G-Protein-Coupled / physiology
  • Renin-Angiotensin System / physiology*
  • Signal Transduction


  • Angiotensins
  • Insulin
  • Peptide Fragments
  • Receptors, G-Protein-Coupled
  • Angiotensin I
  • Peptidyl-Dipeptidase A
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • Neprilysin
  • angiotensin I (1-7)
  • Glucose