Phenotypic correction of diabetic mice by adenovirus-mediated glucokinase expression

Hyperglycemia of diabetes is caused in part by perturbation of hepatic gluc ose metabolism. Hepatic glucokinase (GK) is an important regulator of gluco se storage and disposal in the liver. GK levels are lowered in patients wit h maturity-onset diabetes of the young and in some diabetic animal models. Here, we explored the adenoviral vector-mediated overexpression of GK in a diet-induced murine model of type 2 diabetes as a treatment for diabetes. D iabetic mice were treated by intravenous administration with an E1/E2a/E3-d eleted adenoviral vector encoding human hepatic GK (Av3hGK). Two weeks post treatment, the Av3hGK-treated diabetic mice displayed normalized fasting bl ood glucose levels (95 +/- 4.8 mg/dl; P < 0.001) when compared with Av3Null (135 +/- 5.9 mg/dl), an analogous vector lacking a transgene, and vehicle- treated diabetic mice (134 +/- 8 mg/dl). GK treatment also resulted in lowe red insulin levels (632 +/- 399 pg/ml; P < 0.01) compared with the control groups (Av3Null, 1,803 +/- 291 pg/ml; vehicle, 1,861 +/- 392 pg/ml), and th e glucose tolerance of the Av3hGK-treated diabetic mice was normalized. No significant increase in plasma or hepatic triglycerides, or plasma free fat ty acids was observed in the Av3hGK-treated mice. These data suggest that o verexpression of GK may have a therapeutic potential for the treatment of t ype 2 diabetes.