Lipid Metabolism in the Etiology of Type 2 Diabetes

描述：(摘自申请者的描述)2型糖尿病具有重大的临床和社会影响，但其潜在的 病理生理学知之甚少。由于这种疾病被诊断为 碳水化合物代谢紊乱，即高血糖，可能 脂代谢异常对其病因的贡献在很大程度上 被忽视了。与肥胖相关的主要形式的糖尿病的特点是 高胰岛素血症，胰岛素介导的葡萄糖处置的抵抗 骨骼肌，血浆游离脂肪酸和甘油三酯水平升高。 有人认为脂代谢紊乱是一种早期事件。 促进高胰岛素血症和胰岛素的发展 抵抗。我们的实验室已经证明了血浆的重要作用 脂肪酸在维持正常的葡萄糖刺激的胰岛素分泌中起作用 禁食受试者，还利用了新的1-H核磁共振波谱技术 为了说明心肌细胞内脂质(IMCL)之间的强相关性 含量与骨骼肌胰岛素抵抗。 在目前的提案中，我们试图通过调查 高脂饮食的影响，药物抑制脂质氧化，以及 瘦素对大鼠胰岛素分泌和胰岛素敏感性的影响 确定这些变化可能如何与肌肉和 胰岛甘油三酯含量。因为瘦素和/或瘦素缺乏 信号可以加速肥胖/糖尿病的发展，它是 可想而知，瘦素的主要功能是控制脂质氧化 并以防止组织脂质堆积的方式进行脂肪分解，因此 维持正常的葡萄糖代谢。我们将使用瘦素 对食用高脂饮食的大鼠进行脑室注射，并确定 这会逆转高胰岛素血症和胰岛素抵抗的发展。 IMCL、肌肉P13-激酶活性和胰岛的平行测量 甘油三酯水平将寻求在脂肪之间建立直接联系 消散和改善这些组织中的功能。未来的研究将探索 瘦素调节脂类代谢的生化途径。

DESCRIPTION: (Scanned from the applicant's description) Type 2 diabetes mellitus has major clinical and social impact, but its underlying pathophysiology is poorly understood. Since the disease is diagnosed as a disorder of carbohydrate metabolism, i.e., hyperglycemia, the possible contribution of abnormal lipid metabolism to its etiology has been largely overlooked. The predominant, obesity-related form of diabetes is characterized by hyperinsulinemia, resistance to insulin-mediated glucose disposal in skeletal muscle, and elevated plasma free fatty acid and triglyceride levels. It has been suggested that a derangement of lipid metabolism is an early event contributing to the development of both hyperinsulinemia and insulin resistance. Our laboratory has demonstrated the essential role that plasma fatty acids play in sustaining normal glucose-stimulated insulin secretion in fasted subjects, and has also utilized novel 1-H NMR spectroscopic techniques to illustrate the strong correlation between intramyocellular lipid (IMCL) content and skeletal muscle insulin resistance. In the current proposal, we seek to expand on this theme by investigating the effects of high-fat feeding, pharmacologic inhibition of lipid oxidation, and leptin administration on insulin secretion and insulin sensitivity in rats and determining how these changes might be linked to alterations in muscle and islet triglyceride content. Because deficiencies of leptin and/or leptin signaling can precipitate the development of obesity/diabetes mellitus, it is conceivable that the primary function of leptin is to control lipid oxidation and lipolysis in a manner that prevents tissue lipid accumulation, thus maintaining normal glucose metabolism. We will administer leptin intracerebroventricularly to rats consuming a high fat diet and determine if this reverses the development of hyperinsulinemia and insulin resistance. Parallel measurements of IMCL, muscle P13-kinase activation and islet triglyceride levels will seek to establish a direct link between fat dissipation and improved function in these tissues. Future studies will explore the biochemical pathways through which leptin regulates lipid metabolism.