Glucose-responsive hepatic insulin gene therapy of spontaneously diabetic BB/Wor rats.
Hepatic insulin gene therapy (HIGT) ameliorates hyperglycemia in multiple rodent models of diabetes mellitus, with variable degrees of glucose control. We demonstrate here that adenoviral delivery of a glucose-regulated transgene into rat hepatocytes produces near-normal glycemia in spontaneously diabetic BB/Wor rats without administration of exogenous insulin. We compared growth, glycemia, counterregulatory hormones, and lipids in HIGT-treated diabetic rats to nondiabetic rats and diabetic rats treated with either insulin injections or sustained-release insulin pellets. HIGT-treated rats achieved near-normal blood glucose levels within 1 week and maintained glycemic control for up to 3 months. Rats treated with sustained release insulin implants had similar blood sugars, but more hypoglycemia and gained more weight than HIGT-treated rats. HIGT-treated rats normalized blood glucose within 2 hr after a glucose load, and tolerated a 24-hr fast without hypoglycemia. HIGT treatment suppressed ketogenesis similarly to peripheral insulin. However, glucagon levels and free fatty acids were increased in HIGT-treated rats compared to either nondiabetic controls or rats treated with exogenous insulin. In addition to extending successful application of HIGT to a rat model of autoimmune diabetes, these findings emphasize the relative contribution of hepatic insulin effect in the metabolic stabilization of diabetes mellitus.
Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Darin E
DE
Olson
Sara A
SA
Paveglio
Patricia U
PU
Huey
Marty H
MH
Porter
Peter M
PM
Thulé
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000627:therapeutic use*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon; D005947:Glucose; D020155:3-Hydroxybutyric Acid