Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice.

Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype. To assure this hypothesis, we have developed recombinant adeno-associated viral vectors expressing insulin receptor isoform A or B under the control of a hepatocyte specific promoter. Our results demonstrate that in the long term, hepatic expression of insulin receptor isoform A in diabetic mice is more efficient than IRB ameliorating glucose intolerance. Consequently, it impairs the induction of compensatory mechanisms through beta-cell hyperplasia/hypertrophy that finally lead to beta-cell failure, reverting the diabetic phenotype in about 8 weeks. Our data suggest that long-term hepatic expression of insulin receptor isoform A could be a promising therapeutic approach for the treatment of type 2 diabetes mellitus.