Regulation of Insulin Sensitivity by p85alpha PI3-Kinase

描述（由申请人提供）：最近的估计表明-三分之二的美国成年人超重或肥胖。胰岛素抵抗是与肥胖相关的一种常见特征，它会增加患2型糖尿病的风险。导致饮食诱导的胰岛素抵抗的细胞机制是复杂的，尚未完全了解。然而，一个关键的观察结果是，通过IRS1 PI 3-激酶途径的信号传导减少，骨骼肌中葡萄糖的摄取和利用减少。两种互补的机制被认为是IRS1 PI 3激酶信号传导减少的潜在介质：基础IRS-1丝氨酸磷酸化增强和PI 3激酶p85调控亚基表达改变。最近，我们观察到人类的3d过度喂养增强了p85a的表达，并与胰岛素敏感性降低相关。我们假设，骨骼肌中p85or的增加是饮食诱导胰岛素抵抗发展的早期缺陷，并伴随着IRS-1丝氨酸磷酸化的关键变化。我们的研究将集中在确定饮食诱导的p85cr失调的机制，以及p85or和IRS-1丝氨酸磷酸化作为骨骼肌胰岛素抵抗的介质之间的关系。

DESCRIPTION (provided by applicant): Recent estimates indicate that -two-thirds of adults in the US are overweight or obese. Insulin resistance, a common feature associated with obesity, increases the risk of type 2 diabetes. The cellular mechanisms responsible 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 and diminished glucose uptake and utilization in skeletal muscle. Two complementary mechanisms have emerged as potential mediators of the reduced IRS1 PI 3-kinase signaling: enhanced basal IRS-1 serine phosphorylation and altered expression of the PI 3-kinase p85 regulatory subunits. Recently, we observed that 3d of overfeeding in humans enhanced p85a expression and correlated with the reduced insulin sensitivity. We hypothesize that increased p85or in skeletal muscle is an early defect in the development of dietary-induced insulin resistance and accompanies the key changes in IRS-1 serine phosphorylation. Our studies will focus on identifying the mechanisms for diet-induced dysregulation of p85cr and the relationship between p85or and IRS-1 serine phosphorylation as mediators of skeletal muscle insulin resistance.