Free Fatty Acids, p16 and Pancreatic Beta Cell Proliferation

描述（由申请人提供）：糖尿病患者的β细胞质量减少;开发增加β细胞质量的疗法，以增加胰岛素分泌能力，是糖尿病研究的主要目标。在人体尸检研究中，β细胞增殖率较低，表明β细胞的内在或外在因素抑制了β细胞增殖。支持这一假设的是观察到全基因组关联研究一致地将2型糖尿病风险与编码细胞周期抑制剂p16的遗传位点联系起来，p16是一种强β细胞抗增殖信号。通过p16作用抑制β细胞增殖的因素仍然未知。肥胖和代谢综合征的标志之一是循环游离脂肪酸（FFA）升高。通过静脉输注脂质 在小鼠中，我们已经发现FFA阻断由高血糖诱导的代偿性β细胞增殖。FFA直接作用于β细胞，因为原代胰岛细胞或INS-1细胞的FFA处理也消除了葡萄糖刺激的增殖。有趣的是，FFA在体内诱导胰岛中的p16表达。此外，INS-1细胞中的p16也被FFA诱导，并且p16的敲低消除了FFA的抗增殖作用。我们建议通过以下具体目标来剖析这些发现的机制和人类相关性：目标1：确定p16是否是FFA抑制小鼠β细胞增殖所必需的，目标2：探索衰老相关的p16诱导对葡萄糖和FFA对β细胞增殖的影响，目标3：确定FFA是否限制人类β细胞增殖。为了解决这些问题，我们将使用我们最近开发的新颖而强大的技术组合，包括将葡萄糖和/或脂质连续静脉输注到转基因小鼠，老龄小鼠和移植人类胰岛的小鼠中。这些研究有可能阐明p16基因位点如何导致糖尿病风险，探索一种新的脂毒性（抗增殖）形式，并定义一个新的治疗竞技场。 目标：通过阻断限制人类β细胞增殖的因子来增加β细胞群。

DESCRIPTION (provided by applicant): People with diabetes have reduced beta cell mass; developing therapies that increase beta cell mass, to increase insulin secretory capacity, is a primary goal in diabetes research. Beta cell proliferation rates are low in human autopsy studies, suggesting that factors either intrinsic or extrinsic to the beta cell restrain beta cell proliferation. Supporting this hypothesis is the observation that genome-wide association studies consistently link type 2 diabetes risks with the genetic locus encoding the cell cycle inhibitor p16, a strong beta cell anti- proliferative signal. Factors that restrain beta cell proliferation via p16 action remain unknown. One of the hallmarks of obesity and the metabolic syndrome is elevated circulating free fatty acids (FFAs). Using intravenous infusion of lipids into mice, we have discovered that FFAs block the compensatory beta cell proliferation induced by hyperglycemia. FFAs act directly on the beta cell, as FFA treatment of either primary islet cells or INS-1 cells also eliminates glucose-stimulated proliferation. Intriguingly, FFAs induce p16 expression in islets in vivo. Furthermore, p16 is also induced by FFAs in INS-1 cells, and knockdown of p16 eliminates the anti-proliferative effects of FFAs. We propose to dissect the mechanism and human relevance of these findings through the following specific aims: Aim 1: Establish whether p16 is required for FFA-inhibition of beta cell proliferation in mice, Aim 2: Explore the impact of aging-related p16 induction on glucose and FFA effects on beta cell proliferation, and Aim 3: Determine whether FFAs restrict human beta cell proliferation. To address these questions we will use a combination of novel and powerful techniques we have recently developed, including continuous intravenous infusion of glucose and/or lipids into genetically modified mice, into aging mice, and into mice engrafted with human islets. These studies have the potential to shed light on how the p16 locus contributes to diabetes risk, to explore a novel form of lipotoxicity (anti-proliferative), and to define a new arena of therapeutic targets: enhancing beta cell mass by blocking factors that restrict human beta cell proliferation.