The sweeter side of ACE2: physiological evidence for a role in diabetes

Sharell M Bindom, Eric Lazartigues, Sharell M Bindom, Eric Lazartigues

Abstract

Diabetes mellitus is a growing problem in all parts of the world. Both clinical trials and animal models of type I and type II diabetes have shown that hyperactivity of angiotensin-II (Ang-II) signaling pathways contribute to the development of diabetes and diabetic complications. Of clinical relevance, blockade of the renin-angiotensin system prevents new-onset diabetes and reduces the risk of diabetic complications. Angiotensin-converting enzyme (ACE) 2 is a recently discovered mono-carboxypeptidase and the first homolog of ACE. It is thought to inhibit Ang-II signaling cascades mostly by cleaving Ang-II to generate Ang-(1-7), which effects oppose Ang-II and are mediated by the Mas receptor. The enzyme is present in the kidney, liver, adipose tissue and pancreas. Its expression is elevated in the endocrine pancreas in diabetes and in the early phase during diabetic nephropathy. ACE2 is hypothesized to act in a compensatory manner in both diabetes and diabetic nephropathy. Recently, we have shown the presence of the Mas receptor in the mouse pancreas and observed a reduction in Mas receptor immuno-reactivity as well as higher fasting blood glucose levels in ACE2 knockout mice, indicating that these mice may be a new model to study the role of ACE2 in diabetes. In this review we will examine the role of the renin-angiotensin system in the physiopathology and treatment of diabetes and highlight the potential benefits of the ACE2/Ang-(1-7)/Mas receptor axis, focusing on recent data about ACE2.

Figures

Fig. 1
Fig. 1
The role of the RAS in metabolic organ function. Ang-II signaling cascades inhibit insulin release and decrease insulin sensitivity. RAS blockade improves glucose homeostasis by reducing β-cell death and improving insulin secretion and end-organ insulin sensitivity.
Fig. 2
Fig. 2
Consequences of ACE2 gene deletion. (A) Following a 12-h fast, fasting blood glucose levels were measured in females (n = 5) and males (n = 8) ACE2 knockout mice using an Accu-Check® Aviva glucometer (Roche). ACE2 knockout mice have elevated fasting blood glucose in comparison to age-matched littermates. Data are expressed as mean ± S.E.M. *P < 0.05: statistical significance vs. control mice. (B) Mas receptor immunohistochemistry reveals expression of this Ang-(1–7) receptor in the mouse endocrine and exocrine pancreas. Mas receptor expression was reduced in ACE2−/y mice. Pancreas sections (16 μm) were incubated with a rabbit anti-Mas antibody (AbCam) for 18 h at 4 °C and developed using the standard ABC method (Vector Laboratories) using DAB as the chromagen. A brown staining is indicative of Mas receptor immuno-reactivity.
Fig. 3
Fig. 3
Hypothetical model for the role of ACE2 in the pancreas. Ang-II is known to decrease islet blood flow and increase islet oxidative stress, which can cause β-cell apoptosis and decrease insulin secretion. The red arrows emphasize hyperglycemia-induced changes in the islet RAS and its consequences. ACE2 through TGF-β inhibition may reduce amyloid deposition, islet fibrosis and subsequent β-cell apoptosis. Ang-(1–7)-mediated vasodilation may lead to increased blood flow. The combined reduction in β-cell apoptosis and increase in islet blood flow could cause an increase in insulin secretion and preservation of islet function in diabetes. The green arrows highlight hypothetical pathways by which ACE2 may influence islet function.

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