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

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A promising biotechnology method for diabetes

Diabetes mellitus refers to a group of diseases characterised by high blood glucose resulting from defects in insulin secretion, insulin action, or both. Especially, in non insulin-dependent diabetes mellitus (NIDDM), muscle is the key tissue for glucose clearance. This method is based on engineering adenovirus-mediated muscle fibres in order to defeat diabetes-associated deficient glucose disposal.

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Hyperglycaemia is caused mainly due to the inability of tissues to clear high levels of blood glucose. Glucose disposal occurs through insulin regulation since it is the insulin that stimulates the glucose consumption in peripheral tissues, such as adipose and muscle tissues. Skeletal muscles, in being massive and energy demanding, are ideal for glucose uptake. Exercise, hypoxia or epinephrine, are other sources that enhance glucose uptake through muscle, but they boost the basal and insulin-stimulated glucose uptake, even in diabetic patients, through an undetermined mechanism. This method manipulated the genetically engineered adenovirus technology to optimise muscle glucose metabolism. More specifically, it presented a new means for increasing glucose clearance in-vitro and in-vivo by augmenting the capacity of muscle fibres for glucose uptake and consumption through genes encoding for glucose metabolising enzymes, namely glycogen phosphorylase and syntheses. This gene therapy presented a prolonged uptake and consumption of glucose by muscles and increased glucose disposal and insulin sensitivity in normal and type 2 diabetic experimental models. Consequently, it may be applied for fighting insulin resistance that is mainly responsible for the impairment of insulin-stimulated muscle activity that develops hyperglycemia and beta-cell failure. Pharmacologically compared to other treatments, it is a longer acting and without any side effects. By injecting adenoviruses bearing this gene in the hind leg muscle of rodent models of NIDDM, the in-vivo test of transfer of glucokinase gene led to transfection limited to the muscles in the injected leg and abdominal muscles. The administration of glycogen enzymes enhanced muscle tissue glucose uptake and reduced the glucose blood levels optimising total body glucose tolerance under hyperinsulinemic conditions. No basal glucose modifying occurred. The method is still insufficient for obese subjects. Many companies interested in metabolic diseases can exploit the platform gene transfer technology that brings together complementary research experiences in the fields of metabolic engineering, adenoviral technology and in-vivo study of glucose disposal. Since, the physiological response to transfection of genes has also been investigated it can also be useful for the studying of genes of unknown function. Most importantly, the method revealed the mechanism for the enhancement of glucose transport and utilisation into muscle, and could be utilised in the design of future strategies of gene therapy for diabetes.

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