Epidemiologic Studies of Type 2 Diabetes in Normal Weight Adults

描述(由首席研究人员提供)：代谢性肥胖正常体重(MONW)表型是体重指数(BMI)正常者中与肥胖相关的代谢紊乱(例如，2型糖尿病、高甘油三酯血症、高血压)的聚集性。正常体重的T2 DM是一种耐人寻味且未被充分研究的MONW表型，影响5-15%的T2 DM患者。针对PA-06-151(肥胖、糖尿病、消化和肾脏疾病的二次分析)，我们建议汇集现有多项纵向队列研究的数据，对正常体重参与者的人口学和临床特征、行为因素和与T2 DM发生相关的候选基因进行流行病学研究。在每项研究中对临床事件进行纵向随访，我们将比较正常体重和超重/肥胖者中发生T2 DM的心血管并发症的发生率。这项应用中包括的队列研究包括社区动脉粥样硬化风险研究、心血管健康研究、年轻人中的冠状动脉风险发展、弗雷明翰后代研究、杰克逊心脏研究、动脉粥样硬化的多种族研究以及候选基因协会资源项目的遗传数据。合并后的数据集将包括一个大的、不同的样本(例如，种族/民族、性别和年龄)，这些人在发生T2 DM时可以被归类为正常体重(BMI&lt；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T2 DM病例，以及迄今为止最大的正常体重T2 DM患者样本(约占T2 DM患者总数的10%)将可用于实现以下目标：1)比较正常体重和超重/肥胖T2 DM患者的基线人口学和临床特征的患病率或平均水平；2)测试在确认T2 DM时的体重状况是否改变了基因型与T2 DM事件之间的关系；3)比较正常体重和超重/肥胖T2 DM患者之间的心血管发病率和死亡率。这些研究的成功完成有望确定尽管体重正常，但患T2 DM的可能性较高的人口学和临床特征，并确定之前发现的三个T2 DM的新危险因素(即炎症、自主神经系统功能和抑郁症状)是否是在没有肥胖的情况下疾病的预测因素。通过研究肥胖与T2 DM相关基因(PPARG、KCNJ11和TCF7L2)之间相互作用的存在，我们可以开始揭示这些候选基因与T2 DM相关的机制。这项研究的发现将超越正常体重的T2 DM患者的一小部分，以更好地了解T2 DM的新危险因素和基因多态，以及肥胖在T2 DM临床心血管后果中的作用。公共卫生相关性：2型糖尿病(T2 DM)是一种严重的慢性疾病。根据体重指数测量(BMI和lt；25公斤/平方米)，大约15%的T2 DM患者是正常体重。由于在任何一项研究中患有T2 DM的正常体重人群很少，我们建议从现有的6项流行病学研究中收集数据来集合T2 DM发病人群。根据已公布的估计和初步研究，我们预计将有超过2600例T2 DM病例。我们将通过对疾病和死亡的研究和长期随访的共同测量，测试在发生T2 DM时体重正常与超重/肥胖的参与者中，既定的基线临床和人口学特征和候选基因是否更常见，以及两组之间的心血管疾病发病率和死亡率是否不同。这项研究的发现超出了正常体重的T2 DM患者的一小部分，以更好地了解T2 DM超重以外的危险因素以及T2 DM的心血管后果。

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.