Skeletal muscle is the largest insulin sensitive bodily organ and plays a major role in determining glucose homeostasis. Impaired insulin action in skeletal muscle is one of the earliest steps leading Type 2 diabetes mellitus (T2DM); a metabolic disease of increasing proportions. Current therapies to treat T2DM are insufficient and insight into the molecular cause of this disease is limited. Genetic and environmental factors play a role of the development of T2DM. Therefore, elucidation of the factors deter mining insulin sensitivity in skeletal muscle is of clinical importance to prevent and treat this disease. The major goal of this proposal is to elucidate the signaling pathways that regulate gene expression and insulin sensitivity on glucose metabolism in skeletal muscle from healthy and T2D people. During my doctoral studies I established muscle cultures for studies of insulin action, which I will use here to create an siRNA library to identify the role of specific protein kinases in insulin action. I will establish a 'diabetogene identification platform' based on gene expression profiling of skeletal muscle from well-characterized healthy and T2D people, as well as cultured muscle cells exposed to diverse metabolic components of the insulin resistant phenotype. I will also test whether serine phosphorylation of insulin signaling proteins impairs glucose metabolism and gene expression and whether pharmacological intervention prevents this event. I will leverage the expertise of Prof. Juleen Zierath and Dr Anna Krook to create novel reagents to ask physiologically relevant questions related to T2DM pathogenesis. This work will identify the link between constitutes of the insulin signaling pathway important for glucose metabolism and gene regulatory events. Moreover, we anticipate the results will identify the potential cause of insulin resistance and refine future T2DM treatment, which may one day impact European health care.
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