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) 持续上升并导致心血管并发症全世界。 IR 的潜在机制仍不完全清楚。流行病学研究有一致揭示了患有以下疾病的患者血浆支链氨基酸（BCAA）升高的特征糖尿病或 IR，以及将继续发展 IR 的受试者。世界各地实验室的小鼠研究研究表明，系统性抑制 BCAA 分解代谢会导致 IR 恶化，而系统性激活 BCAA 分解代谢会导致 IR 恶化（最常见的是 BT2，BCKDK 的一种特异性抑制剂，它反过来又抑制 BCKDH，BCAA 的限速步骤分解代谢）改善IR。因此，人们对针对这一途径产生了浓厚的兴趣，并且多种药物公司正在开发基于 BT2 的新型分子系列。尽管做出了这些努力，如何系统性激活 BCAA 分解代谢改善 IR 的情况仍然令人惊讶地未知。在寻找潜在机制的过程中，我们发现 BT2 促进血管舒张和降低血压，并且它的作用独立于硝酸盐内皮细胞产生一氧化氮 (NO)，表明 BT2 作用于平滑肌细胞 (SMC)。大量文献表明，胰岛素刺激的血管舒张有助于葡萄糖的摄取，尽管如何胰岛素促进血管舒张的作用尚不完全清楚。这些观察结果和额外的初步数据使我们得出这样的假设：胰岛素促进 SMC 中的 BCAA 分解代谢，进而促进血管舒张和葡萄糖耐量，从而解释了 BCAA 全身激活的代谢益处分解代谢。我们将用新的基因小鼠模型来检验这一假设；拥有最先进的血管生理学测定；使用高胰岛素正常血糖钳；并通过人体研究来测试这一影响人体血管张力和反应性的途径。这些高度集中的研究将阐明 BCAA 的作用调节血管反应性和葡萄糖耐量的分解代谢，包括人体研究。