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Role of ACE2 In Glucose Homeostasis in Type 2 Diabetes
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Role of ACE2 In Glucose Homeostasis in Type 2 Diabetes
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Role of ACE2 In Glucose Homeostasis in Type 2 Diabetes
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Dissertation
Role of ACE2 In Glucose Homeostasis in Type 2 Diabetes
2009
Overview
Angiotensin Coverting Enzyme (ACE) 2, a recently discovered ACE homologue, counter-balances the renin-angiotensin system (RAS) activity by cleaving Angiotensin (Ang) II to generate Ang-(1-7). Recently, loss of ACE2 was found to cause pancreatic β-cell dysfunction. Ang-(1-7) was shown to improve insulin signaling and prevent fructose-induced insulin resistance. Therefore, we hypothesized that ACE2 would ameliorate glycemic control in diabetic mice. Adenovirus coding for human ACE2 (Ad-hACE2-eGFP) or a control virus coding for GFP (Ad-GFP) was administered via direct injection to the pancreas (5x107 particle forming units (pfu) in a total volume of 100 μ1-11 of 0.9% w/v saline) of leptin receptor deficient diabetic mice (db/db) and non-diabetic controls (db/m). To assess glycemic homeostasis, glucose tolerance, insulin tolerance and firstphase insulin secretion were assessed. In both 8 and 16 week old mice, ACE2 over-expression improved fasting blood glucose, glucose tolerance and firstphase insulin secretion in db/db mice in comparison to Ad-eGFP treated db/db mice, but had no effect on insulin sensitivity. ACE2 over-expression had no effect on fasting blood glucose, insulin sensitivity or first phase insulin secretion in db/m mice. Ad-hACE2-eGFP expression also enhanced islet insulin content. Infusion with D-Ala7-Ang-(1-7) (600 ng/kg/min, 7 days sc), a MAS receptor antagonist in 8 week old mice prevented ACE2 mediated changes in fasting blood glucose, but had no effect on Ad-GFP diabetic mice. D-Ala7-Ang-(1-7) infusion also prevented ACE2 mediated improvements in glucose tolerance but did not affect Ad-GFP treated mice. To determine the effect of ACE2 over-expression on islet function, we measured islet insulin content, proliferation and apoptosis. ACE2 overexpression increased islet insulin content, and pancreatic β-cell proliferation and decreased apoptosis in 8 week old db/db mice in comparison to Ad-GFP treated controls, but had no effect on 16-week old db/db mice. D-Aia7-Ang-(1-7) infusion prevented ACE2-mediated improvements in insulin content and islet apoptosis and proliferation. ACE2 over-expression reduced islet TGF-13 expression, but had no effect on islet fibrosis in 8 week old db/db mice. ACE2 had no effect on TGF-13 expression or islet fibrosis of 16 week old db/db mice. These data indicate that ACE2 may improve glucose homeostasis through Ang-(1-7) mediated improvement in pancreatic 13-cell function.
