Our laboratory is interested in elucidating the molecular basis for the relationship between hypertension, insulin resistance, and obesity and in evaluating the efficacy and mechanisms of action of various complementary and alternative medicine therapies for these diseases. In classical insulin target tissues such as muscle and fat, insulin stimulates glucose uptake primarily by causing translocation of the insulin responsive glucose transporter GLUT4 from an intracellular pool to the cell surface. Decreased sensitivity to this action of insulin (i.e., insulin resistance) plays a major role in the pathogenesis of diabetes and has been strongly correlated with hypertension and obesity. To understand the mechanisms involved in insulin-stimulated glucose transport under both normal and pathological conditions, we have developed a novel method for transient transfection of DNA into rat adipose cells in primary culture. This allows us to dissect the insulin signal transduction pathways related to GLUT4 translocation in a physiologically relevant insulin target cell. We have identified the insulin receptor tyrosine kinase 1RS-1,-2, -3, -4, P13-kinase, Akt, PDK-1, and PKC-zeta as important components of this signal transduction pathway. In addition, we have identified PTP1B and SHP-1 as protein tyrosine phosphatases that can modulate metabolic actions of insulin. We are continuing to investigate signaling molecules downstream from P13-kinase that may contribute to insulin-stimulated translocation of GLUT4 in adipose cells. We are also attempting to identify mechanisms that determine signal specificity such as subcellular compartmentalization of signaling complexes, modulation of signal frequency and amplitude, and signal cross-talk. Recently we have discovered that IRS-1 is a novel substrate for PKC-zeta that participates in a negative feedback pathway. We have also identified an Akt phosphorylation site on PTP1B that participates in a positive feedback pathway for insulin signaling. We also found that IRS-1 is a novel substrate for mPLK and PKC-delta that mediatees cross-talk between inflammation and insulin signaling.
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