A study of the expression of IRS-1, a putative component of the insulin signaling pathway
Rice, K. Michael
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The study of insulin signaling is important because of its relevancy to the disease non-insuUn dependent diabetes mellitus (NIDDM). NIDDM is die most common endocrine and serious metabolic disorder in industrialized nations. The sequelae of the disease are serious multi-system disorders with high morbidity and mortality. The enormity of the disease has been the impetus fueling research of NIDDM for many years. Current understanding of the etiology of NIDDM implicates insulin resistance as the primary symptom responsible for causing the disease. Insulin resistance refers to the inability of insulin to signal intracellular responses. In general, research data best support a hypothesis that insulin resistance is due to an unknown post-receptor defect in the insulin-signaling mechanism. My dissertation deals with the investigations how the protein IRS-1 (insulin receptor substrate), a putative second messenger in the phosphoprotein pathway a component of the insulin signaling pathway, is regulated and the relationship of IRS-1 regulation to insulin responsiveness. Cellular concentrations of IRS-1 in 3T3-L1 adipocytes were found to be upregulated in an insulin- and dexamethasone-dependent manner during the differentiation of these cells from fibroblasts. This result suggested that IRS-1 might also be regulated by these substances in the mature adipocytes. Subsequent research has revealed that IRS- 1 was down-regulated by these substances in the adipocytes. Elucidation of the insulin mechanism down-regulating IRS-1 can be explained by destabilization of the protein without contribution from IRS-1 mRNA regulation. The mechanism by which the degradation of IRS-1 is signaled has been determined to be dependent upon a phosphorylation event and intracellular calcium. Although the exact physiological function of IRS-1 is unknown, it has been ascertained that the development of insulin resistance, as measured by 2-deoxyglucose uptake, has similar kinetics as the down-regulation of IRS-1 induced by insulin. Removal of insulin and the subsequent recovery of insulin responsiveness and IRS-1 concentrations have similar kinetics. The ED50 values for the down-regulation of both IRS-1 and 2-deoxyglucose uptake are approximately the same and occur at physiological levels. Results from these experiments provide support that insulin regulates IRS-1 by a mechanism involving the degradation of the protein and provides a working hypothesis on which to investigate the role of IRS-1 in the etiology of insulin resistance.
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