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

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© 2017 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Proposed NEP/angiotensin-(1–2)/GPRC6A axis of the RAS. Angiotensinogen is cleaved to angiotensin I, which is further cleaved to angiotensin II, angiotensin-(1–9), and angiotensin-(1–7) by previously identified enzymes. Angiotensin-(1–7) has been shown to bind the MasR to mediate beneficial effects. In islets, we show that angiotensin-(1–7) is cleaved by neprilysin to angiotensin-(1–4) and angiotensin-(5–7). Angiotensin-(1–4) is further cleaved to angiotensin-(1–2) and angiotensin-(3–4) by neprilysin. Angiotensin-(1–2) binds GPRC6A to elicit an increase in insulin secretion.