Pathobiology of Prediabetes in A Bi-Racial Cohort

这项提案是对项目公告编号PA-04-074的回应，项目公告编号PA-04-074《NIDDK的健康差距 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 在美国不同种族的人中，糖尿病的发病率惊人地相似(约11% 糖尿病预防计划(DPP)。因为DPP参与者的糖耐量受损(IGT)在 基线，相似糖尿病发病率的发现使我们假设种族差异是 在2型糖尿病的发病过程中发生的时间比人们通常所认识的要早得多。因此，我们， 建议研究糖尿病前期阶段(糖耐量低减和空腹血糖受损)的种族差异 {IFG})。我们将比较200名患者从正常糖耐量(NGT)到糖尿病前期的进展率 患有2型糖尿病父母的非裔美国人和200名高加索人后代。与NGT相比 受试者，糖尿病前期患者(如糖耐量低减)患致命心血管疾病的风险增加两倍 (CVD)。然而，很少有前瞻性的研究是关于糖尿病的自然历史、预测因素、机制和调节因素的。 在任何人群中，从NGT进展到糖尿病前期，在非裔美国人中都没有。我们争辩说 关注这一早期阶段具有公共卫生意义，因为IGT阶段可能已经为时已晚 用于完全逆转代谢和心血管后遗症。在我们提议的研究中，最初的NGT受试者 2型糖尿病的高危人群将接受反复的代谢评估，包括糖耐量， 胰岛素敏感性、β细胞功能、脂肪细胞因子、心血管疾病危险标记物和社会经济及其他 相关终点为5年。DNA样本将被储存起来，以供将来进行遗传分析。初级阶段 终点是从NGT进展到糖尿病前期。次要终点包括卡路里摄入量的变化， 体力活动，身体成分，胰岛素敏感性，胰岛素分泌，脂蛋白，脂肪细胞因子， 促炎症标志物和其他已知或推测的血糖失调预测因子。通过比较 我们希望进步者和非进步者以及非裔美国人和高加索人之间的这些终点 提供有关糖尿病前期自然病史的新数据，并确定种族差异是否 在从NGT过渡到糖尿病前期的过程中编程。 增加对引发从正常血糖到糖尿病前期变化的各种因素的了解 将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 并发症已成定局。此外，了解这些因素在不同领域的差异 小组将提高我们更有针对性地针对不同社区的预防措施的能力。

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.