title: Adenovirus-mediated expression of glucokinase in the liver as an adjuvant treatment for type 1 diabetes.
abstract: Glucokinase (GK) plays a crucial role in hepatic glucose disposal. Its activity is decreased in patients with maturity-onset diabetes of the young and in some animal models of diabetes. We investigated the feasibility of manipulating GK expression as an adjuvant treatment for type 1 diabetes, using an E1/E3-deleted adenoviral vector (Ad.EF1(alpha)GK) delivered to the liver of streptozotocin-induced type 1 diabetic rats. First, we studied the metabolic impact of constitutive glucokinase expression in the absence of insulin. Normal blood glucose levels were observed after gene transfer, and glucose tolerance was substantially enhanced compared with diabetic control animals, suggesting that hepatic GK expression is a feasible mechanism to enhance glucose disposal. In a second study we administered Ad.EF1(alpha)GK together with subcutaneous insulin injections to determine whether the combined action of insulin plus GK activity would provide better glucose homeostasis than insulin treatment alone. This combination approach resulted in constant, near-normal glucose values under fed conditions. Furthermore, the animals stayed in the normoglycemic range after an overnight fast, indicating that the risk to develop hypoglycemia is not increased by expression of GK. Alterations of other metabolic routes were observed, suggesting that insulin-regulated expression of GK may be necessary to use the strategy as a treatment of type 1 diabetes.
authors.affiliation: Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY 10029-6574, USA. nuria.morral@mssm.edu
authors.forename: Núria
authors.initials: N
authors.lastname: Morral
authors.forename: Robert
authors.initials: R
authors.lastname: McEvoy
authors.forename: Hengjiang
authors.initials: H
authors.lastname: Dong
authors.forename: Marcia
authors.initials: M
authors.lastname: Meseck
authors.forename: Jennifer
authors.initials: J
authors.lastname: Altomonte
authors.forename: Swan
authors.initials: S
authors.lastname: Thung
authors.forename: Savio L C
authors.initials: SL
authors.lastname: Woo
mesh_terms: D000256:Adenoviridae; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000628:therapy*; D015316:Genetic Therapy; D005822:Genetic Vectors; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D014280:Triglycerides; D006003:Glycogen; D005941:Glucokinase; D005947:Glucose