Free Fatty Acids, p16 and Pancreatic Beta Cell Proliferation

描述（由申请人提供）：糖尿病患者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。在人体解剖研究中，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。支持这一假设的观察结果是，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标志之一是循环游离脂肪酸（FFAs）升高。通过静脉输注脂质

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.