Regulation of Insulin Sensitivity by p85alpha PI3-Kinase

p85α PI3 激酶对胰岛素敏感性的调节

• 批准号: 7113550
• 负责人: Carrie E McCurdy
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113550
• 关键词: biological signal transduction; cytokine; diabetes mellitus; diet; dietary lipid; enzyme activity; free fatty acids; gene expression; gene targeting; genetically modified animals; glucose clamp technique; glucose metabolism; glucose transport; hormone regulation /control mechanism; insulin; insulin receptor; insulin sensitivity /resistance; isozymes; laboratory mouse; molecular pathology; nutrition related tag; pathologic process; phosphatidylinositol 3 kinase; phosphorylation; postdoctoral investigator; protein structure; protein structure function; serine; striated muscles

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.

描述（由申请人提供）：最近的估计表明，美国三分之二的成年人超重或肥胖。胰岛素抵抗是肥胖症的一个常见特征，会增加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IRS 1 PI 3-激酶途径的信号传导减少，骨骼肌中葡萄糖摄取和利用减少。两种互补的机制已经出现作为潜在的介导剂减少IRS-1 PI 3激酶信号传导：增强基础IRS-1丝氨酸磷酸化和改变PI 3激酶p85调节亚基的表达。最近，我们观察到人类过度喂养3d会增强p85 a的表达，并与胰岛素敏感性降低相关。我们推测骨骼肌中p85 or的增加是饮食诱导的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p85 cr失调的机制和p85 or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。