Ethnic Differences in Mechanisms of Pancreatic Beta Cell Failure

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。少数民族-非洲裔美国人和墨西哥裔美国人不成比例地受到2型糖尿病的影响，但原因尚不完全清楚。与Zucker糖尿病脂肪（ZDF）大鼠模型一样，人2型糖尿病的特征在于胰岛β细胞由于胰岛素抵抗而逐渐不能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细胞凋亡的毒性中间体。在ZDF大鼠模型中，β细胞衰竭可以通过噻唑烷二酮类药物治疗来预防。我们最近有一个重大的技术突破，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，我们新的人类试验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起着比非洲裔美国人更重要的作用。这种显著的种族差异应该为保护高危人群中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备不足的人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人类糖尿病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细胞衰竭的潜在机制的种族差异;目标2：在墨西哥裔美国人和非洲裔美国人中使用吡格列酮治疗逆转胰腺脂肪变性并保护2细胞功能。为了实现我们的目标，我们将研究目标1中的210人和目标2中的80人。我们将使用MRS测量胰腺内的脂肪水平，MRI测量脂肪量，并经常进行静脉葡萄糖耐量试验（FSivGTT）以评估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，但许多肥胖者从未患糖尿病。此外，2型糖尿病当然可以在瘦人中发展。我们假设，胰腺脂肪变性是导致β细胞衰竭的主要机制，而胰腺脂肪变性的消退是噻唑烷二酮拯救人类糖尿病β细胞功能的重要机制。如果我们证实了这一假设，胰腺TG含量可用于增强糖尿病风险预测，并确定谁将受益于早期有针对性的干预措施，以预防2型糖尿病的个人。随着胰腺TG水平测量技术的进一步改进，胰腺MRS可能成为广泛应用的临床诊断工具。

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.