Pathobiology and Reversibility of Prediabetes in a Biracial Cohort

描述（由申请方提供）：一项糖尿病前期队列的病理生物学和可逆性（PROP-ABC）研究计划研究一个现有队列，包括约400名血糖正常的非裔美国人和高加索人后代，其父母患有2型糖尿病，为期5年。这些受试者在2006年至2009年期间入组，并随访至2012年，在此期间，11人患上了糖尿病，100人患上了前驱糖尿病，没有种族差异的证据。本提案的目的是通过评估种族在血糖进展第二波中的作用，以及前驱糖尿病可逆性的时间依赖性，更全面地了解早期血糖异常的自然史和代谢预测因子。该研究测试了4个假设：1）在父母患有2型糖尿病的后代中，从正常血糖调节到受损的早期进展（5年内）。发生在最高风险的受试者中，与种族无关，而晚期进展（5-10岁）2）早期微血管并发症、外周血管疾病（PVD）和内皮功能障碍在从正常葡萄糖调节转变为受损葡萄糖调节期间表现出，显示种族差异，并且通过血糖和非血糖因素预测; 3）“代谢健康”的胰岛素敏感性肥胖（ISO）表型在其与心脏代谢危险因素和非洲人中的偶发性精神障碍的相关性方面显示出种族差异。2型糖尿病父母的美国人和高加索人后代;和4）糖尿病前期状态的持续时间是生活方式疗效的主要决定因素，并且与生活方式疗效呈负相关。 干预以诱导糖尿病前期表型的消退和正常葡萄糖调节的恢复。100名患有前驱糖尿病的参与者将接受强化生活方式干预（ILI），以逆转前驱糖尿病并恢复正常。约260名血糖状态保持正常的受试者将继续随访5年;发生前驱糖尿病的人将立即接受ILI。了解逃避正常血糖的预测因素、种族的作用以及新发糖尿病前期的可逆性至关重要，因为发现逆转糖尿病前期的干预措施也将有助于消除下游糖尿病事件中的种族差异。另外5年的随访将提供10年糖尿病前期发病率和预测因素的数据， 第二波进展，以及糖尿病前期的时间依赖性可逆性。关注前驱糖尿病具有巨大的公共卫生意义，因为它的成功逆转可以预防糖尿病和相关并发症。

DESCRIPTION (provided by applicant): The Pathobiology and Reversibility of Prediabetes in a Biracial Cohort (PROP-ABC) study proposes to study an extant cohort, comprising ~400 normoglycemic African American and Caucasian offspring of parents with type 2 diabetes for an additional 5-year. The subjects were enrolled between 2006 and 2009 and have been followed up to 2012, during which 11 have developed diabetes and 100 developed prediabetes, without evidence of racial disparities. The objective of the present proposal is to gain a fuller understanding of the natural history and metabolic predictors of early glucose abnormalities, by assessing the role of race during the second wave of glycemic progression, and the time dependency of reversibility of prediabetes. The study tests 4 hypotheses: 1) Among offspring of parents with type 2 diabetes, early progression from normal to impaired glucose regulation (within 5 yr.) occurs in the highest-risk subjects independently of race, whereas late progression (5-10 yr.) displays racial disparities, and is predicted by physiological, biochemical and behavioral markers; 2) Early microvascular complications, peripheral vascular disease (PVD), and endothelial dysfunction manifest during transition from normal to impaired glucose regulation, display racial disparities, and are predicted by glycemic and nonglycemic factors; 3) The "metabolically healthy" insulin-sensitive obese (ISO) phenotype displays racial disparities in its association with cardiometabolic risk factors and incident dysglycemia among African-Americans and Caucasians offspring of parents with type 2 diabetes; and 4) Duration of the prediabetic state is a major determinant of, and is inversely related to, the efficacy of lifestyle intervention to induce regression of the prediabetic phenotype and restoration of normal glucose regulation. The 100 participants with prediabetes will receive Intensive Lifestyle intervention (ILI), to reverse prediabetes and restore normoglycemia. The ~260 participants who have maintained normal glucose status will continue follow-up for 5 years; persons who develop prediabetes will immediately receive ILI. Understanding the predictors of the escape from normoglycemia, the role of race, and the reversibility of new-onset prediabetes is of utmost importance, because the discovery of interventions for reversal of prediabetes will also help eliminate ethnic disparities in downstream diabetes events. The additional 5 years of follow-up will provide data on 10-yr rates and predictors of incident prediabetes, racial patterns during the second wave of progression, and, time-dependent reversibility of prediabetes. Focusing on prediabetes is of immense public health significance, as its successful reversal prevents diabetes and associated complications.