Journal Article

Angiotensin I–Converting Enzyme Type 2 ( ACE2 ) Gene Therapy Improves Glycemic Control in Diabetic Mice

Boulares, A. Hamid, Bindom, Sharell M., Hans, Chetan P., Lazartigues, Eric, Xia, Huijing

2010

Overview

Several clinical studies have shown the benefits of renin-angiotensin system (RAS) blockade in the development of diabetes, and a local RAS has been identified in pancreatic islets. Angiotensin I-converting enzyme (ACE)2, a new component of the RAS, has been identified in the pancreas, but its role in β-cell function remains unknown. Using 8- and 16-week-old obese db/db mice, we examined the ability of ACE2 to alter pancreatic β-cell function and thereby modulate hyperglycemia. Both db/db and nondiabetic lean control (db/m) mice were infected with an adenovirus expressing human ACE2 (Ad-hACE2-eGFP) or the control virus (Ad-eGFP) via injection into the pancreas. Glycemia and β-cell function were assessed 1 week later at the peak of viral expression. In 8-week-old db/db mice, Ad-hACE2-eGFP significantly improved fasting glycemia, enhanced intraperitoneal glucose tolerance, increased islet insulin content and β-cell proliferation, and reduced β-cell apoptosis compared with Ad-eGFP. ACE2 overexpression had no effect on insulin sensitivity in comparison with Ad-eGFP treatment in diabetic mice. Angiotensin-(1-7) receptor blockade by D-Ala(7)-Ang-(1-7) prevented the ACE2-mediated improvements in intraperitoneal glucose tolerance, glycemia, and islet function and also impaired insulin sensitivity in both Ad-hACE2-eGFP- and Ad-eGFP-treated db/db mice. D-Ala(7)-Ang-(1-7) had no effect on db/m mice. In 16-week-old diabetic mice, Ad-hACE2-eGFP treatment improved fasting blood glucose but had no effect on any of the other parameters. These findings identify ACE2 as a novel target for the prevention of β-cell dysfunction and apoptosis occurring in type 2 diabetes.

• Publisher: American Diabetes Association
• Subject: Adenovirus / Adenoviruses / Angiotensin converting enzyme / Animals / Apoptosis / Biological and medical sciences / Blood glucose / Blood Glucose - metabolism / Blood sugar / Cell Division / Control / Diabetes / Diabetes Mellitus, Experimental - blood / Diabetes Mellitus, Experimental - complications / Diabetes Mellitus, Experimental - therapy / Diabetes therapy / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrine system / Endocrinopathies / Enzymes / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Gene Expression Regulation, Enzymologic / Gene therapy / Genes, Reporter / Genetic Therapy - methods / Glucose / Glucose Tolerance Test / Green Fluorescent Proteins - genetics / Health aspects / Homeostasis / Humans / Insulin / Insulin - metabolism / Islet Studies / Islets of Langerhans - metabolism / Islets of Langerhans - pathology / Islets of Langerhans - physiopathology / Laboratories / Measurement / Medical sciences / Methods / Mice / Mice, Transgenic / Obesity - complications / Oxidative stress / Pancreas / Pancreas - enzymology / Pancreas - pathology / Pancreas - physiopathology / Peptides / Peptidyl-Dipeptidase A - genetics / Peptidyl-Dipeptidase A - metabolism / Proteins / Research design