Expression of glucokinase in skeletal muscle: A new approach to counteractdiabetic hyperglycemia

Chronic hyperglycemia is responsible for diabetes-specific microvascular an d macrovascular complications. To reduce hyperglycemia, key tissues may be engineered to take up glucose, To determine whether an increase in skeletal muscle glucose phosphorylation leads to increased glucose uptake and to no rmalization of diabetic alterations, the liver enzyme glucokinase (GK) was expressed in muscle of transgenic mice, GK has a high K-m for glucose and i ts activity is not inhibited by glucose 6-phosphate, The presence of GK act ivity in skeletal muscle resulted in increased concentrations of glucose 6- phosphate and glycogen, These mice showed lower glycemia and insulinemia, i ncreased serum lactate levels, and higher blood glucose disposal after an i ntraperitoneal glucose tolerance test. Furthermore, transgenic mice were mo re sensitive to injection of low doses of insulin, which led to increased b lood glucose disposal. In addition, streptozotocin (STZ)-treated transgenic mice showed lower levels of blood glucose than STZ-treated controls and ma intained body weight, Moreover, injection of insulin to STZ-treated transge nic mice led to normoglycemia, while STZ-treated control mice remained high ly hyperglycemic. Thus, these results are consistent with a key role of glu cose phosphorylation in regulating glucose metabolism in skeletal muscle, F urthermore, this study suggests that engineering skeletal muscle to express GK may be a new approach to the therapy of diabetes mellitus.