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

项目摘要 支链氨基酸(BCAA)是一种必需氨基酸，其分解代谢受其代谢速率的控制。 限制性支链氨基酸脱氢酶复合体(BCKDH)及其抑制激酶BCKDK。升高的血浆水平 自20世纪60年代以来，支链氨基酸一直与2型糖尿病有关。最近的研究表明， 支链氨基酸水平升高会导致胰岛素抵抗和2型糖尿病的发生。然而， 支链氨基酸导致胰岛素抵抗的机制尚不清楚。我们之前已经展示了 通过体内稳态重同位素示踪表明，db/db小鼠模型的胰岛素抵抗和2型 糖尿病增加了骨骼肌中支链氨基酸的氧化，减少了肝脏和脂肪组织中的氧化。 骨骼肌中高水平的支链氨基酸氧化可能通过以下几个潜在机制导致胰岛素抵抗 促进脂肪吸收进入肌肉细胞，以及抑制脂肪分解代谢。这两个都是 据预测，导致骨骼肌脂类积聚的机制会导致胰岛素的产生。 抵抗。基于这些观察，我推测骨骼肌中支链氨基酸的氧化增加 促进胰岛素抵抗的发展。为了验证这一假设，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。我将使用各种技巧，包括 体内稳态输注13C标记的营养素和高胰岛素-正常血糖钳以确定是否 肌肉中支链氨基酸氧化增加抑制脂肪氧化，促进全身性胰岛素抵抗。使用 这些技术和鼠标模型在我的支配下，我将描述BCAA通过哪些具体机制 有助于胰岛素抵抗和2型糖尿病的发展，这可能会导致更好、更多 有针对性地治疗这种疾病的患者。

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.