Pathobiology of Prediabetes in A Bi-Racial Cohort

描述(由申请人提供)：本申请是对PA-04-074号计划公告的回应，“NIDDK疾病中的健康差异”。与广泛报道的发病率种族差异相反，在糖尿病预防计划(DPP)中，来自不同种族的美国人的2型糖尿病发病率惊人地相似(~11%)。由于DPP参与者在基线时有糖耐量受损(IGT)，相似的糖尿病发病率的发现使我们假设种族差异在2型糖尿病发病过程中比通常意识到的更早开始。因此，我们建议研究糖尿病前期阶段(IGT和空腹血糖受损{IFG})的种族差异。我们将比较200名非裔美国人和200名高加索人的2型糖尿病父母的后代从正常糖耐量(NGT)到糖尿病前期的进展率。与NGT受试者相比，糖尿病前期患者(如IGT)患致命心血管疾病(CVD)的风险增加一倍。然而，几乎没有关于任何人群从NGT进展到糖尿病前期的自然病史、预测因素、机制和中介因素的前瞻性研究，在非裔美国人中也没有。我们认为，关注这一早期阶段具有公共卫生意义，因为IGT阶段可能已经太晚了，无法完全逆转代谢和心血管后遗症。在我们建议的研究中，最初，2型糖尿病高风险的NGT受试者将接受重复的代谢评估，包括葡萄糖耐量、胰岛素敏感性、β细胞功能、脂肪细胞因子、心血管风险标记物以及社会经济和其他相关终点。DNA样本将被储存起来，以供将来进行遗传分析。主要终点是从NGT进展到糖尿病前期。次要终点包括热量摄入、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、促炎标志物和其他已知或推测的血糖失调预测指标的变化。通过比较进展者和非进展者以及非裔美国人和高加索人之间的这些终点，我们希望提供关于糖尿病前期自然历史的新数据，并确定种族差异是否在从NGT向糖尿病前期的过渡过程中被编程。增加对触发从正常血糖转变为糖尿病前期的各种因素的了解，将能够在全面发展的糖尿病及其相关并发症确立之前发现早期预防干预措施。此外，了解这些因素在不同族裔群体中的差异将提高我们在不同社区更有针对性地采取预防措施的能力。

DESCRIPTION (provided by applicant): This application is in response to Program Announcement Number PA-04-074, "Health Disparities in NIDDK 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 in the Diabetes Prevention Program (DPP). Because DPP participants had impaired glucose tolerance (IGT) at baseline, the finding of similar incident diabetes rates led us to hypothesize that 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 fasting glucose {IFG}). We will compare the rates of progression from normal glucose tolerance (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 cardiovascular disease (CVD). Yet, few prospective studies exist on the natural history, predictors, mechanisms, and mediators of progression from NGT to prediabetes in any population, and none in African-Americans. We argue that focusing on this early period is of public health significance, because the IGT stage may already be too late for complete reversal of metabolic and cardiovascular sequelae. In our proposed study, initially NGT subjects at high risk for type 2 diabetes will undergo repeated metabolic assessments, including glucose tolerance, insulin sensitivity, beta cell function, adipocytokines, CVD risk markers, and socioeconomic and other pertinent endpoints for 5 years. DNA specimens will be stored for future genetic analysis. The primary endpoint is progression from NGT to prediabetes. Secondary endpoints include changes in caloric intake, physical activity, body composition, insulin sensitivity, insulin secretion, lipoproteins, adipocytokines, proinflammatory markers and other known or putative predictors of glycemic dysregulation. By comparing these endpoints between Progressors and Nonprogressors and African-Americans vs. Caucasians we 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 various factors that trigger the change from normal glucose to prediabetes would enable the discovery of early preventive interventions before full blown diabetes and its related complications become established. Furthermore, understanding how these factors differ across ethnic groups will improve our ability to better target preventive measures in different communities.