Lands cycle and skeletal muscle insulin action

项目摘要 骨骼肌胰岛素抵抗是2型糖尿病发生的早期和根本性缺陷。 肥胖促进肌肉胰岛素抵抗的分子机制仍不完全清楚， 但多条证据表明，脂肪代谢异常可能是致病因素之一。最近，我们实验室 已发表的研究结果表明，加速溶血磷脂代谢(Lands Cycle)可使骨骼肌减敏 促进糖尿病的胰岛素受体。在人类中，肥胖增加了骨骼肌溶解磷脂酰胆碱 (lyso-PC)酰基转移酶-3(LPCAT3)和Lyso-PC减少伴随着胰岛素敏感性的降低。 在小鼠中，LPCAT3的遗传或药物抑制增加了Lyso-PC和增强了骨骼肌 全身性胰岛素敏感性。在这个提案中，我们将进一步利用骨骼肌土地周期来了解 它在调节胰岛素作用中的作用。我们假设：1)土地循环调节质膜 微域聚集放大胰岛素信号，2)药物抑制Lands周期可改善 Zucker糖尿病肥胖大鼠的高血糖，3)运动训练提高骨骼肌胰岛素 土地周期减速的响应性。

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.