Recent estimates indicate that -two-thirds of adults in the US are overweight or obese. Insulin resistance, acommon feature associated with obesity, increases the risk of type 2 diabetes. The cellular mechanismsresponsible for the development of diet-induced insulin resistance are complex and not fully understood.However, a key observation has been the reduced signaling through the IRS1 PI 3-kinase pathway anddiminished glucose uptake and utilization in skeletal muscle. Two complementary mechanisms haveemerged as potential mediators of the reduced IRS1 PI 3-kinase signaling: enhanced basal IRS-1 serinephosphorylation and altered expression of the PI 3-kinase p85 regulatory subunits. Recently, we observedthat 3d of overfeeding in humans enhanced p85a expression and correlated with the reduced insulinsensitivity. We hypothesize that increased p85or in skeletal muscle is an early defect in the development ofdietary-induced insulin resistance and accompanies the key changes in IRS-1 serine phosphorylation. Ourstudies will focus on identifying the mechanisms for diet-induced dysregulation of p85cr and the relationshipbetween p85or and IRS-1 serine phosphorylation as mediators of skeletal muscle insulin resistance.
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