Free Fatty Acids, p16 and Pancreatic Beta Cell Proliferation

描述(申请人提供)：糖尿病患者的β细胞质量减少；开发增加β细胞质量的治疗方法，以增加胰岛素分泌能力，是糖尿病研究的主要目标。在人类尸检研究中，β细胞的增殖率很低，这表明β细胞的内在或外在因素抑制了β细胞的增殖。支持这一假说的是，全基因组关联研究一致地将2型糖尿病的风险与编码细胞周期抑制物p16的遗传位点联系在一起，p16是一种强大的β细胞抗增殖信号。通过p16作用抑制β细胞增殖的因素尚不清楚。肥胖和代谢综合征的特征之一是循环中游离脂肪酸(FFAs)升高。使用静脉输注脂质进入 在小鼠的实验中，我们发现游离脂肪酸可以阻断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FFA处理原代胰岛细胞或INS-1细胞也可以消除葡萄糖刺激的增殖。有趣的是，游离脂肪酸可在体内诱导胰岛p16的表达。此外，在INS-1细胞中，FFAs也能诱导p16的表达，而p16基因的敲除可消除FFAs的抗增殖作用。我们建议通过以下特定目的来剖析这些发现的机制和人类相关性：目的1：确定p16是否是FFA抑制小鼠β细胞增殖所必需的；目的2：探讨衰老相关的p16诱导对葡萄糖的影响以及FFA对β细胞增殖的影响；目的3：确定FFA是否限制人β细胞的增殖。为了解决这些问题，我们将使用我们最近开发的新的和强大的技术的组合，包括向转基因小鼠、老龄小鼠和植入人类胰岛的小鼠持续静脉注射葡萄糖和/或脂类。这些研究有可能阐明p16基因如何导致糖尿病风险，探索一种新形式的脂毒性(抗增殖)，并定义一个新的治疗领域。 目标：通过阻断限制人类β细胞增殖的因子来增加β细胞质量。

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.