Angiotensin I-converting enzyme type 2 (ACE2) gene therapy improves glycemic control in diabetic mice

Diabetes. 2010 Oct;59(10):2540-8. doi: 10.2337/db09-0782. Epub 2010 Jul 26.


Objective: 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.

Research design and methods: 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.

Results: 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.

Conclusions: These findings identify ACE2 as a novel target for the prevention of β-cell dysfunction and apoptosis occurring in type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Apoptosis
  • Blood Glucose / metabolism*
  • Cell Division
  • Diabetes Mellitus, Experimental / blood*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / therapy
  • Gene Expression Regulation, Enzymologic
  • Genes, Reporter
  • Genetic Therapy / methods*
  • Glucose Tolerance Test
  • Green Fluorescent Proteins / genetics
  • Homeostasis
  • Humans
  • Insulin / metabolism
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Islets of Langerhans / physiopathology
  • Mice
  • Mice, Transgenic
  • Obesity / complications
  • Pancreas / enzymology
  • Pancreas / pathology
  • Pancreas / physiopathology
  • Peptidyl-Dipeptidase A / genetics*
  • Peptidyl-Dipeptidase A / metabolism


  • Blood Glucose
  • Insulin
  • Green Fluorescent Proteins
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2