Mechanisms of stress-induced insulin resistance in muscle and potential treatment interventions

Being inactive, in a heightened inflammatory state and overweight and/or obese is associated with increased risk of becoming insulin resistant, which is a central feature of the metabolic syndrome and type 2 diabetes mellitus. Metabolic syndrome is the underlying condition of impaired glucose tolerance, loss of control of intermediary metabolism (high circulating blood cholesterol and triglycerides), and cardiovascular decline. We have demonstrated via several publications that the activation of the mitochondrial pyruvate dehydrogenase complex (PDC) in skeletal muscle, the gatekeeper of cellular carbohydrate oxidation, is impaired in all of the above conditions, and that FOXO transcription factor signalling is involved by upregulating pyruvate dehydrogenase kinase mediated inhibition of PDC. In this project, we aim to explore the mechanistic basis of these observations in muscle cell culture using siRNA gene knockdown, a variety substrate and pharmacological interventions, and a number of analytical approaches including intermediary metabolism, molecular biology and mitochondrial function measurements.