Ethnic Differences in Mechanisms of Pancreatic Beta Cell Failure

胰腺β细胞衰竭机制的种族差异

• 批准号: 7989276
• 负责人: LIDIA S SZCZEPANIAK
• 金额: $ 54.15万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989276
• 关键词: 2,4-thiazolidinedione; Adipose tissue; Affect; African; African American; American; Apoptosis; Body mass index; Cell physiology; Cells; Clinical; Coupled; Data; Diabetes Mellitus; Diagnostic; Employee Strikes; Epidemic; Failure; Fatty acid glycerol esters; Glucose tolerance test; Human; Incidence; Individual; Insulin; Insulin Resistance; Intervention; Islets of Langerhans; Lead; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Mexican; Mexican Americans; Minority; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pathogenesis; Patients; Persons; Pioglitazone; Play; Population; Production; Protons; Rattus; Risk Factors; Role; Sampling; Structure of beta Cell of islet; Techniques; Thiazolidinediones; Tissues; Triglycerides; Visceral; diabetes risk; diabetic; ethnic difference; high risk; human subject; impaired glucose tolerance; improved; insight; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; islet; macrovascular disease; prevent; subcutaneous; therapeutic target; tool

DESCRIPTION (provided by applicant): The unrelenting obesity epidemic has led to a dramatic increase in the incidence of type 2 diabetes and its associated microvascular and macrovascular complications. Minorities - African Americans, and Mexican Americans are affected disproportionately by type 2 diabetes, but the reasons are incompletely understood. Like Zucker Diabetic Fatty (ZDF) rat model, human type 2 diabetes is characterized by progressive inability of pancreatic islet beta cell to compensate for tissue insulin demands due to insulin resistance. In ZDF rats, a major mechanism of progressive islet beta cell failure is excessive accumulation of triglyceride in the pancreas, leading to production of toxic intermediates that cause beta cell apoptosis. In ZDF rat model, the beta cell failure can be prevented by the treatment with thiazolidinedione agents. We recently have had a major technological breakthrough in which 1H MRS allows precise measurement of pancreatic triglyceride content in humans. Having now validated the technique in ZDF rat model and human subjects, our new human pilot data lead us to hypothesize that profound ethnic differences in a regional fat distribution are such that pancreatic steatosis plays much more important role in the pathogenesis of beta cell failure and type 2 diabetes in Mexican Americans than in African Americans. Such striking ethnic differences should provide new insights into mechanisms and therapeutic targets for preserving beta cell function in high risk human populations. We hypothesize that pancreatic steatosis constitutes a major mechanism leading to beta cell failure in persons with an inadequate subcutaneous fat storage pool. We further hypothesize that regression of pancreatic steatosis is an important mechanism by which thiazolidinedione rescue beta cell function in human diabetes. Our specific aims are as follows: Aim 1: Understanding ethnic differences in the mechanisms underlying beta cell failure in Mexican Americans, African Americans and Whites; Aim 2: Reversing pancreatic steatosis and protecting 2 cell function with pioglitazone treatment in Mexican Americans, and African Americans. To achieve our aims we will study 210 individuals in Aim 1 and 80 in Aim 2. We will use MRS to measure levels of fat within pancreas, MRI to measure fat mass, and frequently sampled iv glucose tolerance test (FSivGTT) to access beta cell function. PUBLIC HEALTH RELEVANCE: Although obesity is a major risk factor for diabetes, many obese individuals never become diabetic. Furthermore, type 2 diabetes certainly can develop in lean persons. We hypothesize, that pancreatic steatosis constitutes a major mechanism leading to beta cell failure and that regression of pancreatic steatosis is an important mechanism by which thiazolidinedione rescue beta cell function in human diabetes. If we confirm this hypothesis, pancreatic TG content could be used to enhance diabetes risk prediction and to identify individuals who would benefit from early targeted interventions to prevent type 2 diabetes. With further technological refinements regarding the ease of the pancreatic TG levels measurement, pancreatic MRS could become broadly applied clinical diagnostic tool.

描述（由申请人提供）：持续的肥胖流行导致2型糖尿病及其相关微血管和大血管并发症的发病率急剧增加。少数族裔——非裔美国人和墨西哥裔美国人患2型糖尿病的比例过高，但原因尚不完全清楚。与Zucker糖尿病脂肪（ZDF）大鼠模型一样，人类2型糖尿病的特征是胰岛β细胞由于胰岛素抵抗而无法补偿组织胰岛素需求。在ZDF大鼠中，进行性胰岛β细胞衰竭的主要机制是胰腺中甘油三酯的过度积累，导致产生导致β细胞凋亡的有毒中间体。在ZDF大鼠模型中，噻唑烷二酮类药物可以预防β细胞衰竭。我们最近取得了一项重大技术突破，其中1H MRS可以精确测量人类胰腺甘油三酯含量。现在已经在ZDF大鼠模型和人类受试者中验证了该技术，我们新的人类先导数据使我们假设，区域脂肪分布的深刻种族差异使得胰腺脂肪变性在墨西哥裔美国人的β细胞衰竭和2型糖尿病的发病机制中比在非洲裔美国人中发挥更重要的作用。这种显著的种族差异应该为在高危人群中保护β细胞功能的机制和治疗靶点提供新的见解。我们假设胰腺脂肪变性是导致皮下脂肪储存池不足的人β细胞衰竭的主要机制。我们进一步假设胰腺脂肪变性的消退是噻唑烷二酮拯救糖尿病患者β细胞功能的重要机制。我们的具体目标如下：目标1：了解墨西哥裔美国人、非洲裔美国人和白人中β细胞衰竭机制的种族差异；目的2：用吡格列酮治疗墨西哥裔美国人和非洲裔美国人逆转胰腺脂肪变性和保护细胞功能。为了实现我们的目标，我们将在目标1中研究210个人，在目标2中研究80个人。我们将使用MRS来测量胰腺内的脂肪水平，MRI来测量脂肪量，并经常采样静脉葡萄糖耐量试验（FSivGTT）来获取β细胞功能。公共卫生相关性：虽然肥胖是糖尿病的主要危险因素，但许多肥胖者从未成为糖尿病患者。此外，2型糖尿病肯定会发生在瘦人身上。我们推测，胰腺脂肪变性是导致β细胞衰竭的主要机制，而胰腺脂肪变性的恢复是噻唑烷二酮在人类糖尿病中恢复β细胞功能的重要机制。如果我们证实了这一假设，胰腺TG含量可以用来增强糖尿病风险预测，并确定哪些人可以从早期有针对性的干预措施中受益，以预防2型糖尿病。随着胰腺TG水平测量技术的进一步完善，胰腺MRS可能成为广泛应用的临床诊断工具。