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-(... More
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.
