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


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.
Bindom
Sharell M
SM
Department of Pharmacology and Experimental Therapeutics and the Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Hans
Chetan P
CP
Xia
Huijing
H
Boulares
A Hamid
AH
Lazartigues
Eric
E
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism*; D002455:Cell Division; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000150:complications / Q000628:therapy; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005951:Glucose Tolerance Test; D049452:Green Fluorescent Proteins / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications; D010179:Pancreas / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D049452:Green Fluorescent Proteins; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2