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

Abstract

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.

Early-Life Nutritional Factors and Mucosal Immunity in the Development of Autoimmune Diabetes

“…By contrast, the growth of Bifidobacterium breve and Bifidobacterium longum were moderate on total HMOS; however, B. breve showed high levels of growth on the oligosaccharides lacto- N -tetraose and lacto- N -neotetraose (LNnT) ( 98 , 100 ). Consistently, a recent study has shown that addition with specific HMOS, 2′-fucosyllactose (2′-FL) into formula led to more abundant Bifidobacterium in infants compared with no prebiotic supplemented ( 101 ). Regarding the mechanisms whereby those mutualists may benefit the development of T1D, it has been shown that Bifidobacteria, including B. infantis and B. bifidum , grown on HMOS reduce occludin relocalization and enhance the expression of junction adhesion molecule and occludin in Caco-2 cells.…”

Cardiovascular effects of small peptides of the renin angiotensin system

“…Recently, Brar et al. () showed that Ang‐(1–2) is responsible for increasing the insulin secretion in vitro, a result previously attributed to Ang‐(1–7). They observed that both neprilysin and ACE2 are required for Ang‐(1–7) to enhance insulin secretion in vitro.…”

Neprilysin inhibition: a new therapeutic option for type 2 diabetes?

“…Indeed, adrenomedullin, which increases with neprilysin inhibition [36], impairs glucose tolerance by inhibiting insulin release [37]. Neprilysin is also a component of the RAS, where it cleaves angiotensins I and II and generates the peptides angiotensin-(1-7) [38] and angiotensin-(1-2) [6], both of which have been shown to have glucose-lowering/ insulinotropic effects [39]. In this context, we recently showed that loss of neprilysin activity in murine pancreatic islets prevents the insulinotropic effect of angiotensin-(1-7) [39].…”

“…Neprilysin is also a component of the RAS, where it cleaves angiotensins I and II and generates the peptides angiotensin-(1-7) [38] and angiotensin-(1-2) [6], both of which have been shown to have glucose-lowering/ insulinotropic effects [39]. In this context, we recently showed that loss of neprilysin activity in murine pancreatic islets prevents the insulinotropic effect of angiotensin-(1-7) [39]. Moreover, neprilysin inhibition alone has been shown to increase angiotensin II levels [28], which may promote insulin resistance and beta cell dysfunction.…”