Glucokinase gene transfer to skeletal muscle of diabetic Zucker fatty rats improves insulin-sensitive glucose uptake.

Skeletal muscle has a prime role in glucose homeostasis. We have previously demonstrated that adenovirus-mediated glucokinase (GK) gene transfer to skeletal muscle of Wistar rats enhances muscle glucose uptake and whole body glucose disposal under conditions of hyperglycemia and hyperinsulinemia. In this study, we have tested whether GK gene transfer to the muscle of the Zucker Diabetic Fatty rat (ZDF), a genetic model of obesity and type 2 diabetes, could improve glycemic control and prevent the onset of hyperglycemia in obese males. We show that GK delivery results in a doubling of total gastrocnemius muscle glucose phosphorylating activity 9 weeks after gene transfer. GK-treated rats exhibited slightly reduced weight and normal insulin-sensitive glucose uptake, as assessed during an insulin tolerance test, whereas age-matched rats treated with a control virus were clearly insulin resistant. The improved glucose uptake in GK-expressing rats was associated with higher gastrocnemius lactate content, whereas glycogen and triacylglyceride (TAG) levels were unmodified. Remarkably, GK-treated rats showed increased expression of both hexokinase II (HKII) and GLUT4, in accordance with a glucose-dependent regulation of these proteins. Thus, our data show that delivery of GK, despite improving insulin-sensitive glucose disposal in muscle, is not sufficient to prevent or delay the appearance of elevated glucose and insulin levels associated with severe obesity in male ZDF animals.