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Adenovirus-mediated muscle fibers engineering to overcome diabetes-associated deficient glucose disposal

Deliverables

We have demonstrated the efficacy of glucokinase gene transfection to muscle as a means of increasing glucose disposal in-vitro and in-vivo. Transfer of glucokinase gene in vivo restricted to leg muscle was shown to result in prolonged expression of the protein and enhanced glucose disposal and insulin sensitivity in normal and type 2 diabetic experimental models. Therefore, this treatment may be of use in delaying insulin resistance which typically evolves towards hyperglycemia and beta-cell failure. This gene therapy strategy has the advantage of being long acting and devoid of side effects observed with other pharmacological treatments. Promising and further development is eagerly awaited. Rats were treated with the glucokinase gene by injecting adenoviruses bearing this gene to the hind leg. This resulted in transfection limited to the muscles in the injected leg and contiguous abdominal muscles. This treatment increased muscle glucose uptake and whole body glucose tolerance under hyperinsulinemic conditions. In contrast, basal glucose was unaltered. When those viruses were applied to a genetic model of morbid obesity and type 2 diabetes it also lead to increases in whole body insulin sensitivity. This was not sufficient to prevent hyperglycemia or hyperinsulinemia in this model. This suggest that the most important therapeutic activity may be achieved in models of insulin resistance that are not morbidly obese.