Epidemiologic Studies of Type 2 Diabetes in Normal Weight Adults

描述（由主要研究者提供）：代谢性肥胖正常体重（MONW）表型是肥胖相关代谢紊乱（例如，2型糖尿病[T2 DM]、高血糖、高血压）。正常体重人群中的T2 DM是MONW表型的一个有趣且未充分研究的代表，影响5- 15%的T2 DM患者。根据PA-06-151（肥胖、糖尿病、消化系统和肾脏疾病的次要分析），我们建议汇总多项现有纵向队列研究的数据，对正常体重受试者中与T2 DM发生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。在每项研究中使用临床事件的纵向随访，我们将比较发生T2 DM事件的正常体重和超重/肥胖患者之间的心血管并发症发生率。本申请中包括的队列研究是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、弗雷泽后代研究、杰克逊心脏研究、动脉粥样硬化的多种族研究和来自候选基因关联资源项目的遗传数据。所得到的池化数据集将包括大的、多样的（例如，种族/民族、性别和年龄）样本，其在T2 DM事件发生时可被分类为正常体重（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例新发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/肥胖受试者之间的基线人口统计学和临床特征的患病率或平均水平与事件T2 DM; 2）检测T2 DM发生时的体重状况是否改变了基因型与T2 DM发生的关系; 3）比较正常体重与超重/肥胖T2 DM发生者的心血管病发病率和死亡率。这些研究的成功完成有望确定与尽管体重正常但患T2 DM的可能性较高相关的人口统计学和临床特征，并确定是否存在三种先前确定的T2 DM的新风险因素（即，炎症、自主神经系统功能和抑郁症状）在没有肥胖的情况下是疾病的预测因子。通过研究肥胖与T2 DM相关的已建立的基因（PPARG、KCNJ 11和TCF 7 L2）之间的相互作用，我们可以开始阐明这些候选基因与T2 DM相关的机制。本研究的结果将超出正常体重T2 DM患者的小部分，以更好地了解T2 DM的新风险因素和遗传多态性以及肥胖在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，大约15%的T2 DM患者体重正常（BMI<25 kg/m2）。由于在任何一项研究中，正常体重的T2 DM患者数量较少，我们建议将6项现有流行病学研究的数据汇总在一起，以组成一个T2 DM患者队列。根据已发表的估计和初步研究，我们预计将有超过2600例T2 DM病例。使用研究中的常见测量和疾病和死亡的长期随访，我们将测试在发生T2 DM时正常体重与超重/肥胖的受试者中，已确定的基线临床和人口统计学特征以及候选基因是否更常见，以及两组之间心血管疾病的患病率和死亡率是否不同。本研究的结果超出了正常体重的T2 DM患者的小部分，以更好地了解T2 DM的超重以外的风险因素和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.