Regulation of Skeletal Muscle Metabolism by Insulin Signaling

项目摘要 患有2型糖尿病(T2 DM)的人数保持在历史最高水平，预计 在接下来的十年里增加。因此，定义潜在的机制具有重大的医学意义。 推动T2 DM提高治疗效果。胰岛素抵抗，一种被称为治疗效果降低的情况 胰岛素荷尔蒙与葡萄糖稳态改变和肌肉功能障碍有关。尽管几十年来 在研究中，关键的知识缺口仍然存在于导致 胰岛素抵抗的启动和传播。骨骼肌在葡萄糖中起着重要作用。 动态平衡，是餐后葡萄糖消耗的主要来源。胰岛素信号转导的缺陷 骨骼肌中的通路被认为是导致胰岛素抵抗的主要原因 高血糖、蛋白质代谢改变和心血管疾病。越来越多的证据表明 丝氨酸/苏氨酸激酶Akt(蛋白激酶B)作为胰岛素作用的关键调节因子。要直接测试 假设通过AKT减少胰岛素信号会导致胰岛素抵抗并改变肌肉功能，我们 产生的小鼠在骨骼肌中缺乏AKT信号，并令人惊讶地发现胰岛素可以 在没有AKT的情况下，刺激骨骼肌对葡萄糖的摄取和利用。这些数据与以下数据不一致 胰岛素抵抗的典型分子模型，并提示AKT在对照中不是必需的中间体 在所有条件下，胰岛素对骨骼肌葡萄糖代谢的影响。AKT不依赖于AKT 途径及其作用碳水化合物动态平衡将是本提案目标1的重点。虽然小鼠缺乏 骨骼肌中的AKT具有正常的葡萄糖摄取和胰岛素敏感性，但我们发现它们 表现出明显的肌肉萎缩和线粒体功能障碍，并伴有相应的肌肉缺陷 表现，证实AKT是肌肉生长和体内功能所必需的。下游 AKT控制肌肉生长和功能的机制将在目标2中定义。总的来说， 这一建议将建立在这些重要观察的基础上，并阐明Akt依赖和独立的 体内控制胰岛素代谢作用的途径。这些实验有可能深刻地 影响我们对胰岛素抵抗潜在途径的机械性理解，并将导致 确定治疗2型糖尿病、心血管和骨骼肌疾病的新靶点。

Project Summary The number of individuals with type 2 diabetes mellitus (T2DM) remains at an all-time high and is predicted to increase over the next decade. Therefore, it is of significant medical interest to define the underlying mechanisms driving T2DM to improve therapeutic efficacy. Insulin resistance, a condition known as reduced effectiveness to the hormone insulin, is associated with altered glucose homeostasis and muscle dysfunction. Despite decades of investigation, critical knowledge gaps remain in the molecular mechanisms that are responsible for the initiation and propagation of insulin resistance. The skeletal muscle plays a significant role in glucose homeostasis and accounts for a majority of glucose disposal following a meal. Defects in the insulin signaling pathway in the skeletal muscle have been hypothesized to be the primary cause of insulin resistance leading to hyperglycemia, altered protein metabolism and cardiovascular disease. Accumulating evidence has implicated the serine/threonine kinase Akt (protein kinase B) as a critical regulator of insulin action. To directly test the hypothesis that reduced insulin signaling via AKT causes insulin resistance and alters muscle function, we generated mice that lack AKT signaling specifically in skeletal muscle and surprisingly found that insulin can stimulate skeletal muscle glucose uptake and utilization in the absence of AKT. These data are inconsistent with the canonical molecular model of insulin resistance and suggest AKT is not an obligate intermediate in the control of skeletal muscle glucose metabolism by insulin in all conditions. The identification of this AKT-independent pathway and its role carbohydrate homeostasis will be the focus of Aim 1 of this proposal. Although mice lacking AKT in skeletal muscle have normal glucose uptake and insulin sensitivity, we found that they nevertheless exhibit significant muscle atrophy and mitochondrial dysfunction with a corresponding defect in muscle performance, confirming that AKT is required for muscle growth and function in vivo. The downstream mechanisms responsible for AKT’s control of muscle growth and function will be defined in Aim 2. Collectively, this proposal will build upon these important observations and elucidate the Akt-dependent and independent pathways that control the metabolic actions of insulin in vivo. These experiments have the potential to profoundly affect our mechanistic understanding of the pathways underlying insulin resistance and will lead to the identification of new therapeutic targets for T2DM, cardiovascular and skeletomuscular diseases.