Lands cycle and skeletal muscle insulin action

项目摘要 骨骼肌胰岛素抵抗是2型糖尿病发展的早期和根本缺陷。 肥胖促进肌肉胰岛素抵抗的分子机制仍不完全清楚， 但多方面的证据表明，异常的脂质代谢可能是一个因素。最近，我们的实验室 已发表的研究结果表明，加速溶血磷脂代谢（Lands循环）使骨骼肌脱敏 胰岛素受体促进糖尿病。在人类中，肥胖增加骨骼肌溶血磷脂酰胆碱 （溶血-PC）酰基转移酶-3（LPCAT 3）和溶血-PC减少伴随胰岛素敏感性降低。 在小鼠中，LPCAT 3的遗传或药理学抑制增加了溶血PC，增强了骨骼肌和 全身胰岛素敏感性在这个建议中，我们将进一步利用骨骼肌的Lands循环来了解 其在调节胰岛素作用中的作用。我们推测：1）Lands循环调节质膜 微区聚集放大胰岛素信号传导，2）药理学抑制Lands循环可以改善 高血糖的Zucker糖尿病肥胖大鼠，和3）运动训练提高骨骼肌胰岛素 通过减速的土地周期的响应。

Project Summary Skeletal muscle insulin resistance is an early and fundamental defect in the development of type 2 diabetes. Molecular mechanisms by which obesity promotes muscle insulin resistance remain incompletely understood, but multiple lines of evidence suggest aberrant lipid metabolism as a likely contributor. Recently, our laboratory published findings that accelerated lyso-phospholipid metabolism (Lands cycle) desensitizes skeletal muscle insulin receptor to promote diabetes. In humans, obesity increased skeletal muscle lyso-phosphatidylcholine (lyso-PC) acyltransferase-3 (LPCAT3) and decreased lyso-PC concomitant to a decrease in insulin sensitivity. In mice, genetic or pharmacologic inhibition of LPCAT3 increased lyso-PC and enhanced skeletal muscle and systemic insulin sensitivity. In this proposal, we will further exploit skeletal muscle Lands cycle to understand its role in modulating insulin action. We hypothesize that: 1) Lands cycle modulates plasma membrane microdomain clustering to amplify insulin signaling, 2) pharmacological inhibition of Lands cycle can ameliorate hyperglycemia in the Zucker Diabetic Fatty rats, and 3) exercise training enhances skeletal muscle insulin responsiveness by deceleration of Lands cycle.