Adaptations of Human Islets to Insulin Resistance

人类胰岛对胰岛素抵抗的适应

基本信息

批准号：
8262637
负责人：
ALVIN C POWERS
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

项目摘要

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.

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抵抗导致的胰岛素分泌不足。由于这两个实验限制，识别导致人类β细胞对胰岛素抵抗反应受损的分子机制以及对胰岛存活和功能最佳的治疗方法已被放慢。大多数关于胰岛对胰岛素抵抗的反应的研究都是在啮齿动物胰岛中进行的，但人类和啮齿动物胰岛在结构、细胞组成、增殖能力、损伤易感性和形成胰岛淀粉样蛋白的能力方面存在显着差异。大多数旨在模拟胰岛素抵抗（体外暴露于脂肪、葡萄糖、氧化应激等）的实验中对人类β细胞的研究都是在体外进行的，因为缺乏原位研究人类β细胞的方法。我们的研究团队提出研究，通过测试两个假设来直接解决我们科学知识中的这些差距，使用新的模型和方法来研究人类胰岛对体内胰岛素抵抗的反应：1）胰岛素抵抗促进多级反应人类胰岛（基因表达、内质网应激、血管分布的变化）； 2) 目前使用的一些 2 型糖尿病疗法有利于在胰岛素抵抗的情况下促进胰岛功能和存活。这些研究将利用新模型，将人类胰岛移植到具有遗传或饮食形式胰岛素抵抗的免疫缺陷小鼠（GLUT4 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）定义人类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) 研究当人类胰岛受到体内胰岛素抵抗的挑战时，目前哪些 2 型糖尿病疗法可以保留和/或增强人类 β 细胞功能或存活率。 3) 确定当胰岛素抵抗的挑战消除时，人β细胞响应胰岛素抵抗的体内变化是否消失。通过评估 β 细胞功能、基因表达、功能和存活率，这些研究应该可以深入了解和理解 2 型糖尿病的胰岛功能障碍，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 系统中的一个主要健康问题（多达 20% 的 VA 人口患有糖尿病），因此，糖尿病是发病率和死亡率的主要来源。目前的治疗方法还不够充分，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。