Lands cycle and skeletal muscle insulin action

陆地循环和骨骼肌胰岛素作用

基本信息

批准号：
10516491
负责人：
Katsuhiko Funai
金额：
$ 48.93万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10516491
关键词：
Acyltransferase Affect Arachidonic Acids Biochemical Cell membrane Data Deceleration Defect Development Diabetes Mellitus Diet Exercise Gene Expression Genetic Glucose Glucose Clamp Heterodimerization Human Hyperglycemia Individual Insulin Insulin Receptor Insulin Resistance Islets of Langerhans Laboratories Lipids Lysophosphatidylcholines Lysophospholipids Measures Mediating Membrane Microdomains Metabolism Molecular Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pharmacology Phosphorylation Publishing Rattus Receptor Signaling Role Signal Transduction Skeletal Muscle Testing Tissues Type 2 diabetic Tyrosine Phosphorylation desensitization diabetic diet-induced obesity exercise training glucose uptake insulin secretion insulin sensitivity insulin sensitizing drugs insulin signaling lipid metabolism overexpression prevent stable isotope

项目摘要

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.

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尚不完全理解，但是多种证据表明，异常的脂质代谢可能是可能的贡献者。最近，我们的实验室发表的发现，加速了溶菌磷脂代谢（土地周期）使骨骼肌脱敏胰岛素受体可促进糖尿病。在人类中，肥胖增加了骨骼肌溶酶 - 磷脂酰胆碱（lyso-PC）酰基转移酶3（LPCAT3），并降低溶血-PC伴随胰岛素敏感性的降低。在小鼠中，LPCAT3的遗传或药理抑制增加了溶血-PC，并增强了骨骼肌肉和系统性胰岛素灵敏度。在此提案中，我们将进一步利用骨骼肌土地循环以了解它在调节胰岛素作用中的作用。我们假设：1）降落循环调节质膜微区域聚类以扩增胰岛素信号传导，2）土地循环的药理抑制可以改善扎克糖尿病脂肪大鼠中的高血糖，3）运动训练增强了骨骼肌胰岛素土地周期减速的响应能力。