Investigating Branched Chain Amino Acid Oxidation in Skeletal Muscle and its Contribution to Insulin Resistance

研究骨骼肌中的支链氨基酸氧化及其对胰岛素抵抗的影响

• 批准号: 10462999
• 负责人: Megan Chandler Blair
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462999
• 关键词: Address; Adipose tissue; Back; Biochemical; Biological Assay; Branched-Chain Amino Acids; Carbon; Catabolism; Citric Acid Cycle; Clinical; Complex; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Disease; Essential Amino Acids; Fatty acid glycerol esters; Genetic; Glucose Clamp; Glucose tolerance test; Goals; High Fat Diet; Infusion procedures; Insulin; Insulin Resistance; Isoleucine; Isotopes; Knock-out; Knockout Mice; Label; Lead; Learning; Leucine; Link; Lipids; Liver; Measures; Mendelian randomization; Metabolic; Methodology; Modeling; Modification; Mus; Muscle; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Oils; Oxidoreductase; Palmitates; Pathogenesis; Pathway interactions; Patients; Persons; Phosphotransferases; Plasma; Research; Resistance development; Role; Site; Skeletal Muscle; Stains; Techniques; Testing; Therapeutic; Triglycerides; United States; Validation; Valine; Work; base; career; db/db mouse; fasting glucose; gain of function; glucose disposal; in vivo; interest; lipidomics; loss of function; mouse model; oxidation; oxidized lipid; response; targeted treatment; uptake

Project Summary Branched chain amino acids (BCAAs) are essential amino acids, and their catabolism is controlled by the rate- limiting BCAA dehydrogenase complex (BCKDH) and its inhibitory kinase BCKDK. Elevated plasma levels of BCAAs have been associated with type 2 diabetes since the 1960s. Recent studies have suggested that elevated BCAAs contribute to insulin resistance and the development of type 2 diabetes. However, the mechanisms through which BCAAs drive insulin resistance remain unknown. We have previously shown through steady-state in vivo heavy isotopic tracing that the db/db mouse model of insulin resistance and type 2 diabetes has increased BCAA oxidation in skeletal muscle and decreased oxidation in liver and adipose tissue. High BCAA oxidation in skeletal muscle may lead to insulin resistance by a few potential mechanisms including the promotion of fat uptake into muscle cells, as well as the inhibition of fat catabolism. Both of these mechanisms would be predicted to cause an accumulation of lipids in skeletal muscle, leading to insulin resistance. Based on these observations, I hypothesize that elevated BCAA oxidation in skeletal muscle promotes the development of insulin resistance. To test this hypothesis, we have developed skeletal muscle- specific BCKDH gain-of-function and loss-of-function mouse models. I will use a variety of techniques including steady-state in vivo infusions of 13C-labeled nutrients and hyperinsulinemic-euglycemic clamps to determine if increased BCAA oxidation in muscle suppresses fat oxidation and promotes systemic insulin resistance. With these techniques and mouse models at my disposal, I will delineate specific mechanisms by which BCAAs contribute to the development of insulin resistance and type 2 diabetes, which could lead to better, more targeted treatment of patients with this disease.

项目概要 支链氨基酸 (BCAA) 是必需氨基酸，其分解代谢受速率控制 限制性支链氨基酸脱氢酶复合物 (BCKDH) 及其抑制性激酶 BCKDK。血浆水平升高 自 20 世纪 60 年代以来，BCAA 就与 2 型糖尿病相关。最近的研究表明 BCAA 升高会导致胰岛素抵抗和 2 型糖尿病的发生。然而， BCAA 驱动胰岛素抵抗的机制仍不清楚。我们之前已经展示过 通过稳态体内重同位素示踪发现db/db小鼠模型胰岛素抵抗和2型 糖尿病增加了骨骼肌中支链氨基酸的氧化，并减少了肝脏和脂肪组织中的氧化。 骨骼肌中的高支链氨基酸氧化可能通过一些潜在机制导致胰岛素抵抗，包括 促进脂肪摄入肌肉细胞，以及抑制脂肪分解代谢。这两个 预计机制会导致骨骼肌中脂质积累，从而导致胰岛素 反抗。根据这些观察结果，我推测骨骼肌中的 BCAA 氧化增加 促进胰岛素抵抗的发展。为了检验这个假设，我们开发了骨骼肌—— 特定的 BCKDH 功能获得和功能丧失小鼠模型。我将使用多种技术，包括 稳态体内输注 13C 标记的营养物质和高胰岛素正常血糖钳以确定是否 肌肉中支链氨基酸氧化的增加可抑制脂肪氧化并促进全身胰岛素抵抗。和 这些技术和小鼠模型可供我使用，我将描述支链氨基酸的具体机制 有助于胰岛素抵抗和 2 型糖尿病的发展，这可能会带来更好、更多的结果 对本病患者进行针对性治疗。