Free Fatty Acids, p16 and Pancreatic Beta Cell Proliferation

游离脂肪酸、p16 和胰腺 β 细胞增殖

• 批准号: 8271681
• 负责人: Laura C Alonso
• 金额: $ 32.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271681
• 关键词: Ablation; Address; Adenoviruses; Adult; Aging; Agreement; Area; Attention; Autopsy; Beta Cell; CDKN2A gene; Cell Culture Techniques; Cell Cycle; Cell Proliferation; Cells; Ceramides; Continuous Intravenous Infusion; Cyclin-Dependent Kinase 4 Inhibitor B; Diabetes Mellitus; Dose; Drug Delivery Systems; Failure; Fatty Acids; Future; Genetic; Genetic Risk; Glucose; Goals; Human; Hyperglycemia; In Vitro; Infusion procedures; Insulin; Insulin Resistance; Intravenous infusion procedures; Islet Cell; Lead; Light; Link; Lipids; Mediating; Messenger RNA; Metabolic Pathway; Metabolic syndrome; Modeling; Mus; NOD/SCID mouse; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Pancreas; Proteins; Regulation; Relative (related person); Research; Research Personnel; Risk; Rodent; Role; Seminal; Signal Transduction; Small Interfering RNA; Staging; Stimulus; Structure of beta Cell of islet; Sum; Techniques; Technology; Testing; Time; Transplantation; Work; Youth; age related; blocking factor; diabetes risk; genetic variant; genome wide association study; glucose metabolism; human tissue; in vivo; inhibitor/antagonist; islet; knock-down; mouse model; new therapeutic target; novel; prevent; research study; response; senescence; small hairpin RNA; therapeutic target; therapy development; young adult

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. PUBLIC HEALTH RELEVANCE: Diabetes mellitus occurs when pancreatic beta cell mass is insufficient to produce enough insulin to maintain healthy glucose metabolism. We have discovered that free fatty acids (FFAs) block beta cell proliferation by inducing a cell cycle inhibitor, p16. Here we propose to explore the relationship between FFAs, p16, and aging and how they interfere with mouse and human beta cell proliferation; this work has the potential to identify new drug targets to increase insulin secretory capacity in people with diabetes.

描述（由申请人提供）：糖尿病患者的β细胞量减少；开发增加β细胞肿块以增加胰岛素分泌能力的疗法是糖尿病研究的主要目标。在人类尸检研究中，β细胞增殖率很低，这表明因β细胞的内在或外在的因素限制了β细胞的增殖。支持这一假设的是，全基因组关联的研究始终将2型糖尿病风险与编码细胞周期抑制剂p16的遗传基因座的风险联系起来，这是一个强大的β细胞抗增殖信号。通过p16作用来限制β细胞增殖的因素尚不清楚。肥胖和代谢综合征的标志之一是循环自由脂肪酸（FFA）。将脂质静脉输注到 小鼠，我们发现FFA阻断了高血糖诱导的补偿性β细胞增殖。 FFA直接作用于β细胞，因为FFA对原代胰岛细胞或INS-1细胞的处理也消除了葡萄糖刺激的增殖。有趣的是，FFA诱导体内胰岛中的P16表达。此外，p16在INS-1细胞中也是FFA诱导的，p16的敲低消除了FFA的抗增殖作用。我们建议通过以下特定目的剖析这些发现的机制和人类相关性：目标1：确定p16是否需要抑制小鼠β细胞增殖的抑制作用，目标2：探索与衰老相关的p16诱导葡萄糖和FFA对BetA细胞效应对Beta细胞增殖的影响的影响：确定FFAS BETA beta beta beta beta beta beta beta beta beta beta beta beta beta becta beclift infif是否越来越限制。为了解决这些问题，我们将使用我们最近开发的新型和强大的技术的组合，包括连续静脉注射葡萄糖和/或脂质对转基因小鼠，衰老的小鼠，以及植入了人类小岛的小鼠中。这些研究有可能阐明p16基因座如何促进糖尿病风险，探索一种新型的脂肪毒性形式（抗增殖性），并定义了一种新的治疗领域 靶点：通过阻止限制人β细胞增殖的因子来增强β细胞量。 公共卫生相关性：当胰腺β细胞量不足以产生足够的胰岛素以维持健康的葡萄糖代谢时，就会发生糖尿病。我们已经发现，游离脂肪酸（FFA）通过诱导细胞周期抑制剂P16来阻断β细胞的增殖。在这里，我们建议探索FFA，p16和衰老之间的关系，以及它们如何干扰小鼠和人类β细胞增殖。这项工作有可能确定新药靶标，以增加糖尿病患者的胰岛素分泌能力。