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.
Olson
Darin E
DE
Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Paveglio
Sara A
SA
Huey
Patricia U
PU
Porter
Marty H
MH
Thulé
Peter M
PM
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