权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Keeping fat out of muscle - Role of Branched Amino AcidsAmino Acids in Insulin Resistance

保持肌肉中的脂肪 - 支链氨基酸氨基酸在胰岛素抵抗中的作用

基本信息

批准号：
10736605
负责人：
Zoltan P Arany
金额：
$ 57.31万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736605
关键词：
Acids Address Affect Alleles Aorta Biological Assay Biology Biotechnology Blinded Blood Pressure Blood Vessels Branched-Chain Amino Acids Cardiovascular system Catabolism Clinical Complex Cross-Over Studies Data Diabetes Mellitus Diet Endothelial Cells FRAP1 gene Fatty acid glycerol esters Funding GLUT 4 protein Genes Genetic Glucose Clamp Homeostasis Human Human Volunteers Hyperinsulinism Insulin Insulin Resistance Kidney Failure Laboratories Light Link Literature Liver Mediating Metabolic Metabolism Molecular Morbidity - disease rate Mus Muscle Myography Negative Finding Nitric Oxide Nitrogen Non-Insulin-Dependent Diabetes Mellitus Nutrient Pathology Pathway interactions Patients Pharmacologic Substance Phosphorylation Physiological Physiology Placebo Control Plasma Process Production Protein Dephosphorylation Role Series Signal Transduction Site Skeletal Muscle Smooth Muscle Smooth Muscle Myocytes Telemetry Testing Therapeutic Time Vasodilation blood glucose regulation blood pressure reduction diabetic epidemiology study experimental study gain of function glucose disposal glucose tolerance glucose uptake improved in vivo inhibitor insight interest loss of function mortality mouse model novel response success volunteer

项目摘要

SUMMARY Type 2 Diabetes and its precursor insulin resistance (IR) continue to rise and drive cardiovascular complications worldwide. The mechanisms underlying IR remain incompletely understood. Epidemiological studies have consistently revealed a signature of elevated plasma branched chain amino acids (BCAAs) in patients with diabetes or IR, as well as subjects who will go on to develop IR. Mouse studies in laboratories worldwide have shown that systemic suppression of BCAA catabolism worsens IR, while systemic activation of BCAA catabolism (most often with BT2, a specific inhibitor of BCKDK, which in turn inhibits BCKDH, the rate-limiting step of BCAA catabolism) improves IR. There is thus strong interest in targeting this pathway, and multiple pharmaceutical companies are developing novel BT2-based molecule series. Despite these efforts, how systemic activation of BCAA catabolism improves IR remains surprisingly unknown. In our search for potential mechanisms, we discovered that BT2 promotes vasodilation and lowers blood pressure, and that it does so independently of nitric oxide (NO) production by endothelial cells, suggesting that BT2 acts on smooth muscle cells (SMCs) instead. Substantial literature indicates that insulin-stimulated vasodilation contributes to glucose uptake, although how insulin promotes vasodilation remains incompletely understood. These observations and additional preliminary data have led us to the hypothesis that insulin promotes BCAA catabolism in SMCs, in turn promoting vasodilation and glucose tolerance, thereby explaining the metabolic benefits of systemic activation of BCAA catabolism. We will test this hypothesis with novel genetic murine models; with state-of-the-art vascular physiology assays; with hyperinsulinemic euglycemic clamps; and with human studies to test the impact of this pathway on human vascular tone and reactivity. These highly focused studies will elucidate the role of BCAA catabolism in regulating vascular reactivity and glucose tolerance, including human studies.

摘要 2型糖尿病及其前驱胰岛素抵抗(IR)持续上升并导致心血管并发症全世界。IR的机制仍不完全清楚。流行病学研究表明持续显示出患者血浆支链氨基酸(BCAA)升高的特征糖尿病或胰岛素抵抗，以及将继续发展为胰岛素抵抗的受试者。在世界各地的实验室进行的小鼠研究已经结果表明，全身性抑制支链氨基酸分解代谢会恶化IR，而全身性激活支链氨基酸分解代谢 (最常见的是BT2，BCKDK的一种特定抑制剂，BCKDK反过来又抑制BCKDH，BCAA的限速步骤分解代谢)提高IR。因此，人们对靶向这一途径和多种药物产生了浓厚的兴趣各公司正在开发基于BT2的新型分子系列。尽管做出了这些努力，但系统激活令人惊讶的是，支链氨基酸分解代谢改善IR仍不清楚。在我们寻找潜在机制的过程中，我们发现BT2促进血管扩张和降低血压，而且这种作用不依赖于一氧化氮内皮细胞产生氧化物(NO)，提示BT2作用于平滑肌细胞(SMC)。大量文献表明，胰岛素刺激的血管扩张有助于葡萄糖的摄取，尽管胰岛素促进血管扩张仍不完全清楚。这些观察结果和其他初步报告数据已引导我们假设，胰岛素促进SMC中支链氨基酸的分解代谢，进而促进血管扩张和糖耐量，从而解释了系统激活支链氨基酸的代谢益处分解代谢。我们将用新的小鼠遗传模型来验证这一假设；用最先进的血管生理学分析；用高胰岛素正血糖钳夹；以及用人体研究来测试这一影响人体血管紧张性和反应性的途径。这些高度集中的研究将阐明支链氨基酸的作用分解代谢在调节血管反应性和糖耐量中的作用，包括人体研究。