One of insulin's major biologic effects is stimulation of glucose transport, and detailed knowledge of the molecular events which mediate this bioeffect will lead to improved understanding of mechanisms of insulin action as well as disease states characterized by insulin resistance. The thiazoladinedione (TZD) class of insulin sensitizers binds to the PPARgamma receptor, and this finding has led to an enormous interest into PPARgamma receptor biology, TZD action, and the treatment of insulin resistance. Thus, the overall goals of this research proposal are to elucidate the molecular and biochemical events in insulin's intracellular signaling pathway leading to GLUT4 translocation and glucose transport and to explore new mechanisms of insulin resistance. The investigators will study the post receptor signaling events which mediate insulin stimulated glucose transport. These studies are driven by our recent findings that the heterotrimeric G protein, Gq/11, is a necessary signaling molecule in this process, conveying signals from the insulin receptor to PI3 kinase, leading to glucose transport stimulation. The investigators will further study the role of Galphaq/11 in this insulin bioeffect. Insulin resistance is a major pathophysiologic phenomenon. Endothelin-I (ET-I) levels are elevated in Type 2 diabetic patients and other human insulin resistant states, and we have now demonstrated that treatment of 3T3-L1 adipocytes with ET-I produces a state of insulin resistance. The investigators now propose a series of studies to examine the basic mechanisms of heterologous desensitization of insulin stimulated glucose transport by ET-I, as it may represent a new mechanism of insulin resistance in man. PPARgamma nuclear receptors are the presumed target for anti-diabetic TZDs, and this has generated an enormous interest in the biology of this nuclear receptor. The investigators propose detailed studies of PPARgamma biology, in order to help elucidate the role of this receptor, and its downstream target genes, in insulin action and insulin resistance. The proposed studies range from physiologic measurements in PPARgamma knockout (KO) animals, to more basic mechanistic studies of agonist mediated PPARgamma transcriptional events. In summary, the experiments proposed in this application will apply new methodologies to provide mechanistic information and test novel hypotheses, which will further the understanding of insulin action and insulin resistance.
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