Vitamin D Status in Relation to Incident Type 2 Diabetes and Cardiometabolic Risk

描述(由申请人提供)： 迫切需要确定不依赖于重量的环境和易于修改的风险因素 预防2型糖尿病(T2 DM)和心脏代谢性疾病(CMD)的发展，定义为代谢综合征/大血管疾病。根据我们小组和其他人最近的工作，维生素D已经成为T2 DM风险的潜在修饰物。然而，我们对维生素D状态对T2 DM/CMD风险的临床影响(包括与体重变化、种族、体力活动、钙摄入量和肾功能的重要相互作用)的认识存在严重差距，并且对其在人类中与T2 DM/CMD相关的潜在生理作用机制也存在不确定性，这限制了维生素D作为预防T2 DM/CMD的可行营养干预的价值。我们提出的研究的中心假设是，维生素D缺乏是T2 DM/CMD发生的危险因素，与体重减轻无关，并且这种风险是由胰岛β细胞功能、胰岛素敏感性和全身炎症的变化介导的。我们计划根据PAR-07-024对糖尿病预防计划结果研究(DPP/OS)进行以下辅助调查，以检验我们的主要假设并实现这项应用的目标：(1)在DPP/OS的生活方式和安慰剂使用药物的成年人中，采用病例队列研究设计，测量维生素D状态与T2 DM发病之间的关联[前瞻性分析](共2,161名成年糖耐量减低患者和379例新的T2 DM病例)。我们将根据重要的潜在混杂因素进行调整，如体重变化、季节、种族/民族、体力活动、钙摄入量、肾功能和甲状旁腺激素。(2)。衡量维生素D状态与代谢综合征(及其个体成分)和大血管疾病的发展之间的联系[前瞻性分析]。在同一队列中，我们将测量25OHD与复合性大血管疾病(如DPP/OS中定义的)之间的关联。在那些没有代谢的人中 综合征在基线时，我们将测量25OHD与以下结果之间的关联： 代谢综合征(ATP-III定义)及其个别组成部分(中心性肥胖、高血压、低高密度脂蛋白-胆固醇、高甘油三酯血症和血糖)。(3)。测量维生素D状态与胰岛素分泌、胰岛素敏感性和全身炎症之间的关系[横断面分析]。在同一队列中，在基线(T2 DM/心脏病发生之前)，我们将研究25OHD与胰岛素分泌的可用指标(胰岛素：葡萄糖比率、校正的胰岛素反应)、胰岛素抵抗(HOMA-IR)和全身炎症(C-反应蛋白[CRP])之间的关系。维生素D的使用有可能对T2 DM和CMD的预防产生重大影响，特别是考虑到这种干预措施在临床实践中可以轻松且廉价地实施。

DESCRIPTION (provided by applicant): Identification of weight-independent environmental and easily modified risk factors is urgently needed to prevent the development of type 2 diabetes (t2DM) and cardiometabolic disease (CMD), defined as metabolic syndrome/macrovascular disease. Based on recent work from our group and others, vitamin D has emerged as a potential modifier of t2DM risk. However, there are critical gaps in our knowledge about the magnitude of the clinical effect of vitamin D status on t2DM/CMD risk (including important interactions with weight change, race, physical activity, calcium intake and kidney function) and there is also uncertainty about its potential physiologic mechanisms of action in humans in relation to t2DM/CMD, which limits the value of vitamin D as a feasible nutritional intervention for prevention of t2DM/CMD. The central hypothesis of our proposed study is that, vitamin D insufficiency is a risk factor for the development of t2DM/CMD, independent of weight loss, and that the risk is mediated by changes in pancreatic beta-cell function, insulin sensitivity, and systemic inflammation. We plan to test our main hypothesis and accomplish the objectives of this application by pursuing the following ancillary investigations to Diabetes Prevention Program Outcomes Study (DPP/OS), under PAR- 07-024: (1) Measure the association between vitamin D status and incident t2DM [prospective analyses] in a case-cohort study design in adults within the Lifestyle and Placebo arms of the DPP/OS (total of 2,161 adults with glucose intolerance at baseline and 379 new cases of t2DM). We will adjust for important potential confounders, such as weight change, season, race/ethnicity, physical activity, calcium intake, kidney function and parathyroid hormone. (2). Measure the association between vitamin D status and development of metabolic syndrome (and its individual components) and macrovascular disease [prospective analyses]. In the same cohort, we will measure the association between 25OHD and composite macrovascular disease (as defined in the DPP/OS). Among those without the metabolic syndrome at baseline, we will measure the association between 25OHD and the following outcomes: metabolic syndrome (ATP-III definition) and its individual components (central adiposity, hypertension, low HDL-cholesterol, hypertriglyceridemia and glycemia). (3). Measure the association between vitamin D status and insulin secretion, insulin sensitivity and systemic inflammation [cross-sectional analyses]. In the same cohort, at baseline (before t2DM/cardiac disease is developed), we will examine the association between 25OHD and available measures of insulin secretion (Insulin:Glucose ratio, Corrected Insulin Response), insulin resistance (HOMA-IR) and systemic inflammation (C-reactive protein [CRP]). The use of vitamin D has the potential to have a significant impact on prevention of t2DM and CMD especially given that the intervention can be implemented easily and inexpensively in clinical practice.