Epidemiologic Studies of Type 2 Diabetes in Normal Weight Adults

描述（由主要研究者提供）：代谢肥胖正常体重（MONW）表型是体重指数（BMI）正常的人群中与肥胖相关的代谢疾病（如2型糖尿病[T2DM]、高甘油三酯血症、高血压）的聚类。正常体重人群的T2DM是MONW表型的一个有趣且未充分研究的代表，影响5- 15%的T2DM患者。为了响应PA-06-151（肥胖、糖尿病、消化和肾脏疾病的二次分析），我们建议汇集多个现有纵向队列研究的数据，对正常体重参与者中与T2DM发展相关的人口统计学和临床特征、行为因素和候选基因进行流行病学研究。通过对每项研究的临床事件进行纵向随访，我们将比较正常体重和超重/肥胖的T2DM患者心血管并发症的发生率。本应用程序中包含的队列研究包括社区动脉粥样硬化风险、心血管健康研究、年轻人冠状动脉风险发展、弗雷明汉后代研究、杰克逊心脏研究、动脉粥样硬化多种族研究和候选基因协会资源项目的遗传数据。由此产生的汇总数据集将包括一个大的、多样化的（例如，种族/民族、性别和年龄）样本，这些人在发生T2DM时可以被分类为正常体重（BMI<25 kg/m2）或超重/肥胖（BMI>25 kg/m2）。初步研究和已发表的报告表明，超过2600例T2DM病例和迄今为止最大的正常体重T2DM患者样本（约占T2DM患者总数的10%）将可用于以下目的：1)比较正常体重和超重/肥胖T2DM患者的患病率或基线人口统计学和临床特征的平均水平；2)检验基因型与T2DM发病的关系是否受T2DM确诊时体重状况的影响；3)比较正常体重与超重/肥胖合并t2dm的心血管发病率和死亡率。这些研究的成功完成有望确定与正常体重的T2DM较高可能性相关的人口统计学和临床特征，并确定三个先前确定的T2DM新危险因素（即炎症、自主神经系统功能和抑郁症状）是否在没有肥胖的情况下是疾病的预测因素。通过研究肥胖与T2DM相关基因（PPARG、KCNJ11和TCF7L2）之间的相互作用，我们可以开始揭示这些候选基因与T2DM相关的机制。这项研究的结果将超越正常体重T2DM患者的一小部分，更好地了解T2DM的新危险因素和遗传多态性，以及肥胖在T2DM临床心血管后果中的作用。2型糖尿病（T2DM）是一种严重的慢性疾病。根据体重指数（BMI< 25kg /m2）测量，大约15%的T2DM患者体重正常。由于在任何一项研究中，正常体重的人患T2DM的人数都很少，我们建议将6项现有流行病学研究的数据汇总起来，以组建一个T2DM患者队列。根据已发表的估计和初步研究，我们预计将有2600多例2型糖尿病病例。使用研究间的共同测量和对疾病和死亡的长期随访，我们将测试既定的基线临床和人口学特征和候选基因在发生T2DM时体重正常与超重/肥胖的参与者中是否更常见，以及两组之间心血管疾病的发病率和死亡率是否存在差异。这项研究的结果超出了正常体重的T2DM患者的一小部分，为更好地了解超重以外的T2DM风险因素和T2DM的心血管后果提供了帮助。

DESCRIPTION (provided by principal investigator): The metabolically obese normal weight (MONW) phenotype is a clustering of obesity-related metabolic disorders (e.g., type 2 diabetes [T2DM], hypertriglyceridemia, hypertension) in persons with normal body mass index (BMI). T2DM in normal weight persons is an intriguing and understudied representation of the MONW phenotype that affects between 5-15 percent of persons with T2DM. In response to PA-06-151 (Secondary Analyses in Obesity, Diabetes, Digestive and Kidney Disease), we propose to pool together data from multiple existing longitudinal cohort studies to conduct an epidemiologic study of demographic and clinical characteristics, behavioral factors, and candidate genes associated with the development of T2DM in normal weight participants. Using longitudinal follow-up for clinical events in each of the studies, we will compare the rates of cardiovascular complications between normal weight and overweight/ obese persons who experienced incident T2DM. The cohort studies included in this application are the Atherosclerosis Risk in Communities, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults, Framingham Offspring Study, Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis and genetic data from the Candidate Gene Association Resource project. The resulting pooled dataset will include a large, diverse (e.g., race/ethnic, gender, and age) sample of persons who can be classified at the time of incident T2DM as normal weight (BMI<25 kg/m2) or overweight/obese (BMI>25 kg/m2). Preliminary studies and published reports suggest that over 2600 cases of incident T2DM, and the largest sample of normal weight persons with incident T2DM to date (~10 percent of total with T2DM), will be available to carry out the following aims: 1) compare the prevalence or mean levels of baseline demographic and clinical characteristics between normal weight and overweight/obese participants with incident T2DM; 2) test whether the relation between genotype and incident T2DM is modified by weight status at the time T2DM is identified; 3) compare the cardiovascular morbidity and mortality rates between normal weight and overweight/obese persons with incidentT2DM. The successful completion of these studies can be expected to identify demographic and clinical characteristics associated with a higher likelihood of having T2DM despite being normal weight, and to determine whether three previously-identified novel risk factors for T2DM (i.e., inflammation, autonomic nervous system function, and depressive symptoms) are predictors of disease in the absence of obesity. By investigating the presence of an interaction between obesity and established genes for T2DM (PPARG, KCNJ11 and TCF7L2) in association with T2DM, we can begin to unravel the mechanisms by which these candidate genes are associated with T2DM. Findings from this study will extend beyond the small proportion of normal weight persons with T2DM to provide a better understanding of novel risk factors and genetic polymorphisms for T2DM and the role of obesity in clinical cardiovascular consequences of T2DM. PUBLIC HEALTH RELEVANCE: Type 2 diabetes (T2DM) is a serious chronic medical condition. Approximately 15 percent of persons with T2DM are normal weight according to body mass index measurements (BMI<25 kg/m2). Because of the small number of normal weight persons who have T2DM in any single study, we propose to pool together data from 6 existing epidemiologic studies to assemble a cohort of persons with incident T2DM. According to published estimates and preliminary studies, we expect to have over 2600 incident cases of T2DM. Using common measurements across studies and long-term follow up for illness and death, we will test whether established baseline clinical and demographic characteristics and candidate genes are more common in participants who are normal weight versus overweight/obese at the time of incident T2DM and whether rates of illness and death from cardiovascular diseases differ between the two groups. Findings from this study extend beyond the small proportion of normal weight persons with T2DM to provide a better understanding of risk factors other than overweight for T2DM and the cardiovascular consequences of T2DM.