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.

概括 2型糖尿病及其前体胰岛素抵抗（IR）继续上升并驱动心血管并发症全世界。 IR基础的机制尚未完全理解。流行病学研究已有一贯揭示血浆分支链氨基酸（BCAA）的特征糖尿病或IR，以及将继续发展IR的受试者。全球实验室的老鼠研究表明全身抑制BCAA分解代谢会使IR恶化，而全身激活BCAA分解代谢（最常使用BCKDK的特定抑制剂BT2，而BCKDH又抑制了BCAA的限制步骤分解代谢）改善了IR。因此，对靶向这一途径和多个药物有浓厚的兴趣公司正在开发基于BT2的新型分子系列。尽管做出了这些努力，但如何进行全身激活 BCAA分解代谢改善了IR仍然令人惊讶的是未知。在我们寻找潜在机制时，我们发现BT2会促进血管舒张并降低血压，并且它独立于一硝内皮细胞产生的氧化物（NO），表明BT2代替了平滑肌细胞（SMC）。大量文献表明，胰岛素刺激的血管舒张有助于葡萄糖摄取，尽管如何胰岛素促进血管舒张仍然不完全理解。这些观察和额外的初步数据使我们提出了胰岛素促进SMC中BCAA的分解代谢的假设，进而促进血管舒张和葡萄糖耐受性，从而解释了BCAA全身激活的代谢益处分解代谢。我们将通过新颖的遗传鼠模型检验这一假设。带有最先进的血管生理测定；与高胰岛素的葡萄糖夹；并通过人类研究来测试这一影响人类血管张力和反应性的途径。这些高度重点的研究将阐明BCAA的作用调节血管反应性和葡萄糖耐受性（包括人类研究）的分解代谢。