Pathobiology and Reversibility of Prediabetes in a Biracial Cohort

描述(由申请人提供)：双相队列中糖尿病前期的病理生物学和可逆性研究(PROP-ABC)建议对现有的队列进行研究，该队列包括大约400名患有2型糖尿病父母的正常血糖的非裔美国人和高加索人后代，再研究5年。这些受试者是在2006年至2009年间登记的，并一直被跟踪到2012年，在此期间，11人患上了糖尿病，100人患上了糖尿病前期，没有种族差异的证据。本建议的目的是通过评估RACE在第二波血糖进展中的作用以及糖尿病前期可逆性的时间依赖性，更全面地了解早期血糖异常的自然病史和代谢预测因素。这项研究测试了4个假设：1)在患有2型糖尿病的父母的子女中，早期从正常发展到糖调节受损(在5年内)。发生在高危人群中，与种族无关，而进展较晚(5-10岁)表现出种族差异，并由生理、生化和行为标记物预测；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血糖调节正常到受损的转变过程中出现，表现出种族差异，并由血糖和非血糖因素预测；3)“代谢健康的”胰岛素敏感型肥胖(ISO)表型在与心脏代谢危险因素和2型糖尿病父母的非裔美国人和高加索人后代中发生的血糖异常相关方面显示种族差异；以及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，并与之成反比。 干预以诱导糖尿病前期表型的消退和正常血糖调节的恢复。100名患有糖尿病前期的参与者将接受强化生活方式干预(ILI)，以逆转糖尿病前期并恢复正常血糖。血糖维持正常的~260名参与者将继续随访5年；出现糖尿病前期的患者将立即接受ILI。了解脱离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是至关重要的，因为发现逆转前期糖尿病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年内糖尿病前期发病率和预测因素的数据，以及 第二波进展，以及糖尿病前期的时间依赖性可逆性。关注糖尿病前期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及其相关并发症。

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.