Beta Cell Adaptation in HF Diet-Induced Obesity

2型糖尿病在美国构成了巨大的健康负担，尽管 这种疾病的流行越来越普遍，在了解根本原因方面仍然存在重大差距。 越来越多的证据表明，当β细胞分泌的胰岛素不足时，2型糖尿病就会发生。 胰岛素抵抗的发展加速了这一过程。肥胖是一种常见的 胰岛素抵抗和这种联系在一定程度上是通过循环中脂肪酸水平的增加来调节的 超重的人。最近对培养细胞的研究表明，脂肪酸的升高也可能是 不利于胰岛素分泌和胰岛生长。此外，这些研究表明， 脂肪酸，饱和的但不是单不饱和的脂肪酸会导致β细胞损伤。这些有趣的东西 这些发现还没有在体内得到证实。因此，循环中的高水平脂肪酸可能会导致 胰岛素的需求增加和供应减少是导致糖尿病的核心问题。在……里面 在这个计划项目的第一个周期，我们证明了随意摄入含有20%的 作为黄油脂肪的卡路里--一种高饱和脂肪饮食--会导致大鼠肥胖、胰岛素抵抗和 高胰岛素血症。他们还出现了葡萄糖不耐受，这表明他们的β细胞反应是 不足以补偿他们增加的胰岛素需求。此应用程序的总体目标是 确定饮食中脂肪含量增加是否会导致β细胞功能障碍，以及特定类型的 在这一过程中，消耗的脂肪酸的数量是重要的。指导这一应用程序的中心假设是 饮食中摄入大量饱和脂肪会损害胰岛功能和补偿能力 胰岛素抵抗。我们将通过完成三个具体目标来验证这一假设：i)确定影响 短期和长期接触高饱和或单不饱和脂肪酸饮食对葡萄糖的影响 代谢；2)确定饮食饱和脂肪酸对β细胞适应增加的影响 需求；3)确定不同环境中单一脂肪酸和饱和脂肪酸浓度的影响 对胰岛/P细胞功能和脂质含量的影响。该项目的完成将在体外扩展令人信服的 对完整的动物进行研究，并提供有关饮食对β细胞功能影响的重要新信息 和葡萄糖耐量。这些翻译研究与人类疾病高度相关，并可能形成 旨在降低糖尿病风险的临床研究的基础。

Type 2 diabetes mellitus constitutes an enormous health burden in the United States, and despite the increasing prevalence of this disease there are still major gaps in understanding the underlying causes. Increasing evidence indicates that type 2 diabetes ensues when beta-cell secretion is insufficient for insulin needs, and that the development of insulin resistance accelerates this process. Obesity is a common cause of insulin resistance and this connection is mediated in part by increased levels of fatty acids in the circulation of overweight individuals. Recent studies of cultured cells suggest that elevations of fatty acids may also be detrimental to insulin secretion and islet growth. Moreover, these studies suggest a differential effect among fatty acids, with saturated but not monounsaturated fatty acids leading to beta-cell damage. These interesting findings have not been confirmed in vivo. Thus, high circulating levels of fatty acids could contribute to the increased demand for, and decreased supply of, insulin that are the core problems leading to diabetes. In the first cycle of this program project we demonstrated that ad libitum intake of a diet containing 20% of calories as butter fat- a high saturated fat diet- caused rats to get obese, insulin resistant, and hyperinsulinemic. They also developed glucose intolerance indicating that their beta-cell response was inadequate to compensate for their increased insulin requirements. The overall goal of this application is to determine whether increased fat content in the diet leads to beta-cell dysfunction and whether the specific types of fatty acids consumed are important in this process. The central hypothesis guiding this application is that the intake of high amounts of saturated fat in the diet impairs islet function and the ability to compensate for insulin resistance. We will test this hypothesis by completing three specific aims: i) To determine the effects of short- and long-term exposure to diets high in saturated or monounsaturated fatty acids on glucose metabolism; 2) To determine the effects of dietary saturated fatty acids on beta-cell adaptation to increased demand; 3) To determine the effects of varying ambient concentrations of mono- and saturated-fatty acids on islet/p-cell function and lipid content. Completion of this project will extend a body of compelling in vitro work to intact animals and provide important new information regarding the effect of diet on beta-cell function and glucose tolerance. These translational studies are highly relevant to human disease and could form the basis for clinical studies aimed at modifying diabetes risk.