Pathobiology of Prediabetes in A Bi-Racial Cohort

本提案是对PA-04-074号计划公告“NIDDK中的健康差异”的回应 疾病“与广泛报道的患病率的种族差异相反，2型糖尿病的发病率 糖尿病在美国不同种族人群中惊人地相似（~11%）。 糖尿病预防计划（DPP）。由于DPP参与者在以下时间点葡萄糖耐量受损（IGT）， 基线，发现类似的糖尿病发病率使我们假设种族差异是 在2型糖尿病的发病过程中比通常认识到的更早开始。因此， 我建议研究接近糖尿病前期阶段（IGT和空腹血糖受损）的种族差异 {IFG}）。我们将比较200例正常葡萄糖耐量（NGT）患者进展为糖尿病前期的速度， 非裔美国人和200名白人后代的父母患有2型糖尿病。与NGT相比 受试者，患有前驱糖尿病的人（例如，IGT）患致命性心血管疾病的风险增加两倍 （CVD）。然而，很少有前瞻性的研究存在的自然历史，预测，机制，和介导的 在任何人群中从NGT进展为糖尿病前期，在非洲裔美国人中没有。我们感谢 关注这一早期阶段具有公共卫生意义，因为IGT阶段可能已经太晚 完全逆转代谢和心血管后遗症。在我们提出的研究中，最初NGT受试者 2型糖尿病高危人群将接受反复的代谢评估，包括葡萄糖耐量， 胰岛素敏感性、β细胞功能、脂肪细胞因子、CVD风险标志物以及社会经济和其他因素 5年的相关终点。DNA样本将被储存用于未来的遗传分析。主 终点是从NGT进展为前驱糖尿病。次要终点包括热量摄入的变化， 身体活动、身体组成、胰岛素敏感性、胰岛素分泌、脂蛋白、脂肪细胞因子， 促炎标志物和其他已知或推定的血糖失调的预测因子。通过对比 我们希望这些进展者和非进展者以及非洲裔美国人和白人之间的终点 提供关于糖尿病前期自然史的新数据，并确定种族差异是否 在从NGT到前驱糖尿病的过渡期间编程。 增加对触发从正常血糖到糖尿病前期变化的各种因素的理解 能够在糖尿病及其相关疾病全面爆发之前发现早期预防干预措施， 并发症已经形成。此外，了解这些因素在不同种族之间的差异， 团体将提高我们在不同社区更好地采取预防措施的能力。

This proposal is in response to ProgramAnnouncement Number PA-04-074, "Health Disparities inNIDDK Disease." In contrast to the widely reported ethnic differences in prevalence, the incidence of type 2 diabetes was surprisingly similar (~11%) among individuals from the different U.S. ethnic groups inthe Diabetes Prevention Program(DPP). Because DPP participants had impaired glucose tolerance (IGT) at baseline, the finding of similar incident diabetes rates led us to hypothesizethat ethnic disparities are initiated much earlier during the pathogenesis of type 2 diabetes than is commonly realized. We,therefore, propose to study ethnic disparities proximal to the stage of prediabetes (IGT and impaired fastingglucose {IFG}). We will compare the rates of progression from normal glucosetolerance (NGT) to prediabetes in 200 African-American and 200 Caucasian offspring of parents with type 2 diabetes. Compared with NGT subjects, persons with prediabetes (e.g., IGT) have a two-fold increased risk of fatal cardiovasculardisease (CVD). Yet, few prospective studies exist on the natural history, predictors, mechanisms, and mediatorsof progression from NGT to prediabetes in any population, and none in African-Americans. We arguethat focusing on this early period is of public health significance, because the IGT stage may already betoo late for complete reversal of metabolic and cardiovascular sequelae. In our proposed study, initially NGTsubjects at high risk for type 2 diabetes will undergo repeated metabolic assessments, including glucosetolerance, insulin sensitivity, beta cell function, adipocytokines, CVD risk markers,and socioeconomic and other pertinent endpoints for 5 years. DNAspecimens will be stored for future genetic analysis. The primary endpoint is progression from NGTto prediabetes. Secondaryendpoints include changes in caloricintake, physical activity, body composition, insulin sensitivity, insulin secretion, lipoproteins, adipocytokines, proinflammatory markers and other known or putative predictors of glycemic dysregulation. Bycomparing these endpoints between Progressorsand Nonprogressors and African-Americans vs. Caucasianswe hope to provide novel data on the natural history of prediabetes, and determine whether ethnic disparities are programmed during the transition from NGT to prediabetes. Increased understanding of the variousfactors that trigger the changefrom normal glucose to prediabetes would enable the discovery of early preventive interventions beforefull blown diabetes and its related complications become established. Furthermore, understanding howthese factors differ acrossethnic groups will improve our ability to better target preventive measuresin different communities.