A major cause of high circulating levels of glucose in non insulin-dependent diabetes mellitus (NIDDM) is the insulin resistance of skeletal muscle. Since muscle is the prime tissue for glucose disposal, the impairment of insulin-stimulated muscle glucose uptake is considered to lead to hyperglycaemia. The goal of the current proposal is to engineer muscle fibres to increase their capacity for glucose uptake and utilisation by the delivery of genes encoding for enzymes involved in the metabolism of glucose, namely glycogen phosphorylase and syntheses.
Non insulin-dependent diabetes mellitus (NIDDM) is a disease characterised by the increase in the circulating levels of glucose in the blood. One of the major causes of hyperglycaemia is the inability of tissues to clear glucose from blood. Glucose clearance is in a large part insulin dependent since insulin stimulates the uptake of glucose in peripheral tissues (adipose and muscle). Due to its mass and energetic demand, skeletal muscle is one of the major sites for glucose consumption. However, glucose uptake by muscle can be promoted, independently of insulin, by exercise, hypoxia or epinephrine, which increase basal and insulin-stimulated glucose uptake, even in diabetic patients, through an undetermined mechanism. Also, the over expression of glycogen phosphorylase, by means of recombinant adenovirus-mediated gene transfer, in cultured human fibres leads to the acute stimulation of glucose uptake and consumption. The goal of this project is to use recombinant adenovirus technology to engineer muscle glucose metabolism by over expressing glycogen metabolising enzymes and to test the potential utility of genetic engineering for enhancing muscle glucose utilisation when insulin-stimulated glucose disposal is deficient. We will test whether the administration of glycogen phosphorylase or glycogen syntheses in the muscle of rodent models of NIDDM can increase the clearance of glucose by muscle tissue and, consequently, reduce the levels of glucose in the blood. A joint effort, that will bring together complementary research experiences in the fields of metabolic engineering, adenoviral technology and in-vivo study of glucose disposal, will allow this project to provide information about the mechanism by which glucose transport and utilisation into muscle can be enhanced, and thus for the design of future strategies of gene therapy for diabetes involving metabolic engineering of muscle fibres.
Funding SchemeCSC - Cost-sharing contracts
E1 4NS London