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Am J Physiol Endocrinol Metab. 2015 Oct 1;309(7):E621-31. doi: 10.1152/ajpendo.00054.2015. Epub 2015 Aug 4.

ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice.

Author information

1
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
2
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky lcassis@uky.edu.

Abstract

Drugs that inhibit the renin-angiotensin system (RAS) decrease the onset of type 2 diabetes (T2D). Pancreatic islets express RAS components, including angiotensin-converting enzyme 2 (ACE2), which cleaves angiotensin II (Ang II) to angiotensin-(1-7) [Ang-(1-7)]. Overexpression of ACE2 in pancreas of diabetic mice improved glucose homeostasis. The purpose of this study was to determine if deficiency of endogenous ACE2 contributes to islet dysfunction and T2D. We hypothesized that ACE2 deficiency potentiates the decline in β-cell function and augments the development of diet-induced T2D. Male Ace2(+/y) or Ace2(-/y) mice were fed a low-fat (LF) or high-fat (HF) diet for 1 or 4 mo. A subset of 1-mo HF-fed mice were infused with Sal (Sal), losartan (Los), or Ang-(1-7). At 4 mo, while both genotypes of HF-fed mice developed a similar level of insulin resistance, adaptive hyperinsulinemia was reduced in Ace2(-/y) vs. Ace2(+/y) mice. Similarly, in vivo glucose-stimulated insulin secretion (GSIS) was reduced in 1-mo HF-fed Ace2(-/y) compared with Ace2(+/y) mice, resulting in augmented hyperglycemia. The average islet area was significantly smaller in both LF- and HF-fed Ace2(-/y) vs. Ace2(+/y) mice. Additionally, β-cell mass and proliferation were reduced significantly in HF-fed Ace2(-/y) vs. Ace2(+/y) mice. Neither infusion of Los nor Ang-(1-7) was able to correct impaired in vivo GSIS of HF-fed ACE2-deficient mice. These results demonstrate a critical role for endogenous ACE2 in the adaptive β-cell hyperinsulinemic response to HF feeding through regulation of β-cell proliferation and growth.

KEYWORDS:

ACE2; diabetes; β-cell

PMID:
26389599
PMCID:
PMC4593774
DOI:
10.1152/ajpendo.00054.2015
[Indexed for MEDLINE]
Free PMC Article

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