Adaptations of Human Islets to Insulin Resistance

描述（由申请人提供）： 2型糖尿病的病理生理学中的一个主要因素是响应于胰岛素抵抗的胰岛素分泌不足。由于实验的局限性，确定人类β细胞对胰岛素抵抗的反应受损的分子机制以及胰岛存活和功能的最佳治疗方法的工作进展缓慢。大多数关于胰岛对胰岛素抵抗的反应的研究都是用啮齿类动物的胰岛进行的，但是人类和啮齿类动物的胰岛在结构、细胞组成、增殖能力、对损伤的敏感性和形成胰岛淀粉样蛋白的能力方面有很大的不同。大多数人β细胞的实验研究旨在模拟胰岛素抵抗（体外暴露于脂肪、葡萄糖、氧化应激等）。由于缺乏原位研究人β细胞的方法，我们的研究团队提出研究，以直接解决这些差距，在我们的科学知识，使用新的模型和方法，研究人体胰岛的反应，在体内胰岛素抵抗，通过测试两个假设：1）胰岛素抵抗促进多层次的反应，在人类胰岛（基因表达、ER应激、血管分布的变化）;和2）目前用于2型糖尿病的一些疗法在促进胰岛功能和在胰岛素抵抗情况下的存活方面是有利的。这些研究将利用新的模型，使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（GLUT 4敲除，ob/ob小鼠和高脂肪喂养）后进行研究。我们提出三个目标：1）定义当人β细胞在体内受到胰岛素抵抗攻击时，它们的分子、细胞和血管变化。2)研究当人体胰岛在体内受到胰岛素抵抗的挑战时，目前2型糖尿病的哪些疗法可以保护和/或增强人体β细胞功能或存活。3)确定当胰岛素抵抗挑战消除时，人体β细胞响应胰岛素抵抗的体内变化是否消退。通过评估β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深入了解和理解，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。 公共卫生相关性： 2型糖尿病是VA系统中的主要健康问题（多达20%的VA人群患有糖尿病），因此，糖尿病是发病率和死亡率的主要来源。目前的治疗是不够的，拟议的研究将提高我们对胰岛素分泌如何受损以及2型糖尿病的最佳治疗方法的理解。

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. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a major health problem in the VA system (as many as 20% of the VA population are afflicted with diabetes) and thus, diabetes is a major source of morbidity and mortality. Current treatment is inadequate and the proposed studies will improve our understanding of how insulin secretion becomes impaired and what are the optimal therapies for type 2 diabetes.