Adaptations of Human Islets to Insulin Resistance

描述(由申请人提供)： 2型糖尿病病理生理学的一个主要因素是胰岛素分泌不足，以应对胰岛素抵抗。由于这两个实验的限制，确定人类β细胞对胰岛素抵抗的反应受损的分子机制和优化胰岛存活和功能的治疗方法的速度都很慢。大多数关于胰岛对胰岛素抵抗反应的研究都是在啮齿动物胰岛上进行的，但人类和啮齿动物胰岛在结构、细胞组成、增殖能力、对损伤的敏感性以及形成胰岛淀粉样蛋白的能力上存在本质上的差异。大多数对人类β细胞的研究旨在模拟胰岛素抵抗(在体外暴露于脂肪、葡萄糖、氧化应激等)。由于缺乏原位研究人类β细胞的方法学，已经在体外进行了研究。我们的研究团队建议进行研究，直接解决我们科学知识中的这些空白，使用新的模型和方法通过测试两个假设来研究体内人类胰岛对胰岛素抵抗的反应：1)胰岛素抵抗促进人类胰岛的多水平反应(基因表达、内质网应激、血管的变化)；2)目前使用的一些治疗2型糖尿病的方法在胰岛素抵抗的背景下有利于促进胰岛功能和生存。这些研究将利用新的模型，允许将人类胰岛移植到具有遗传或饮食形式的胰岛素抵抗的免疫缺陷小鼠(GLUT4基因敲除、ob/ob小鼠和高脂肪喂养)中进行研究。我们提出了三个目标：1)确定人β细胞在体内受到胰岛素抵抗挑战时的分子、细胞和血管变化。2)研究当人的胰岛在体内受到胰岛素抵抗的挑战时，目前治疗2型糖尿病的方法是保留和/或提高人类β细胞的功能或存活率。3)确定当胰岛素抵抗的挑战被消除时，人体β细胞对胰岛素抵抗的体内变化是否得到解决。通过评估胰岛细胞功能、基因表达、功能和存活率，这些研究应该提供对2型糖尿病胰岛功能障碍的洞察和理解，以及哪些治疗药物在改善人类胰岛功能和存活率方面最有效。

DESCRIPTION (provided by applicant): A major element in the pathophysiology of type 2 diabetes is inadequate insulin secretion in response to insulin resistance. Identifying the molecular mechanisms responsible for the impaired human beta cell response to insulin resistance and therapies optimal for islet survival and function has been slowed by both experimental limitations. Most studies of the islet response to insulin resistance have been performed with rodent islets, but human and rodent islets differ substantially in architecture, cell composition, proliferative capacity, susceptibility to injury, and ability to form islet amyloid. Most studies of human beta cells in experiments intended to mimic insulin resistance (in vitro exposure to fat, glucose, oxidative stress, etc.) have been conducted in vitro because there has been a lack of methodology to study human beta cells in situ. Our team of investigators proposes studies to directly address these gaps in our scientific knowledge using new models and approaches to study the response of human islets in response to insulin resistance in vivo by testing two hypotheses: 1) insulin resistance promotes a multi-level response in human islets (changes in gene expression, ER stress, vascularity); and 2) some currently used therapies for type 2 diabetes are advantageous in promoting islet function and survival in the setting of insulin resistance. The studies will utilize new models that allow human islets to be studied after transplantation into immunodeficient mice that have genetic or dietary forms of insulin resistance (GLUT4 knockout, ob/ob mice, and high fat feeding). We propose three aims: 1) Define the molecular, cellular and vascular changes in human beta cells when they are challenged with insulin resistance in vivo. 2) Investigate which current therapies for type 2 diabetes preserve and/or enhance human beta cell function or survival when human islets are challenged with insulin resistance in vivo. 3) Determine if the in vivo changes in human beta cells in response to insulin resistance resolve when the challenge of insulin resistance is removed. By assessing beta cell function, gene expression, function, and survival, these studies should provide insight and understanding into the islet dysfunction of type 2 diabetes and into which therapeutic agents are most effective in improving human islet function and survival.