901. Recovery from Type 1 Diabetes by Insulin and Glucokinase Expression in Skeletal Muscle

Type 1 diabetes results from autoimmune destruction of insulin-producing |[beta]|-cells in pancreatic islets. Chronic hyperglycemia, due to failure to maintain proper glycemic control by insulin treatment, leads to the development of diabetes-specific microvascular pathology in the retina and renal glomerulus, and neurological and macrovascular complications. Skeletal muscle is the most important site of glucose removal from blood: it accounts for about 70% of glucose disposal after a meal. Skeletal muscle can be engineered to produce basal levels of insulin and express the liver enzyme glucokinase (GK), both of which increase glucose removal from blood. To obtain long-term expression of insulin and GK genes we examined the use of adeno-associated (AAV-1 serotype) viral vectors to transduce skeletal muscle. Co-expression of insulin and GK in skeletal muscle of diabetic mice treated with AAV1 vectors, restored normoglycemia and reverted all metabolic alterations. Moreover, the normalization of glycemia was parallel to normalization of fluid and food intake. Furthermore, these Ins+GK-treated diabetic mice did not develop secondary complications, such as peripheral neuropathy and nephropathy. Thus, we report evidence that a novel viral gene-therapy approach provides blood glucose concentration-dependent regulation of glucose homeostasis in diabetic animals. This is achieved by a combination of basal insulin production and the |[ldquo]|glucose sensor|[rdquo]| activity of GK in skeletal muscle. The significance of this work is that since normalization of glycemia is achieved, secondary complications of type 1 diabetes may not develop. This would greatly improve the quality of life of diabetic patients.