Pathobiology of Prediabetes in A Bi-Racial Cohort

描述（由申请人提供）：此申请是为了响应项目公告编号PA-04-074，“NIDDK疾病的健康差异”。与广泛报道的种族患病率差异相反，在糖尿病预防计划（DPP）中，美国不同种族的个体中，2型糖尿病的发病率惊人地相似（~11%）。由于DPP参与者在基线时葡萄糖耐量（IGT）受损，相似的糖尿病发生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认识到的要早得多。因此，我们建议研究接近糖尿病前期（IGT和空腹血糖受损{IFG}）的种族差异。我们将比较200名患有2型糖尿病父母的非裔美国人和200名白人后代从正常葡萄糖耐量（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）发生致命性心血管疾病（CVD）的风险增加了两倍。然而，在任何人群中，很少有关于NGT向糖尿病前期进展的自然史、预测因素、机制和介质的前瞻性研究，而在非洲裔美国人中则没有。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，无法完全逆转代谢和心血管后遗症。在我们提出的研究中，最初具有2型糖尿病高风险的NGT受试者将接受5年的重复代谢评估，包括葡萄糖耐量、胰岛素敏感性、β细胞功能、脂肪细胞因子、心血管疾病风险标志物、社会经济和其他相关终点。DNA样本将被保存以供将来的基因分析。主要终点是从NGT进展到前驱糖尿病。次要终点包括热量摄入、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测的血糖失调预测因子的变化。通过比较进展者与非进展者、非裔美国人与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到糖尿病前期的过渡过程中被程序化。加深对触发从正常血糖到前驱糖尿病变化的各种因素的了解，将有助于在糖尿病及其相关并发症形成之前发现早期预防干预措施。此外，了解这些因素在不同种族群体之间的差异将提高我们在不同社区更好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.