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

描述（由申请人提供）： 迫切需要确定与权重无关的环境和容易修改的风险因素， 预防2型糖尿病（t2 DM）和心脏代谢疾病（CMD）（定义为代谢综合征/大血管疾病）的发展。根据我们小组和其他人最近的工作，维生素D已成为2型糖尿病风险的潜在调节剂。然而，关于维生素D状态对t2 DM/CMD风险的临床影响程度，我们的知识存在重大差距（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），并且其在人体中与t2 DM/CMD相关的潜在生理作用机制也不确定，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不足是2型糖尿病/CMD发展的风险因素，与体重减轻无关，并且该风险由胰腺β细胞功能、胰岛素敏感性和全身炎症的变化介导。我们计划根据PAR- 07-024，通过对糖尿病预防项目结局研究（DPP/OS）进行以下辅助研究，检验我们的主要假设并实现本申请的目的：（1）在DPP/OS的生活方式组和安慰剂组的成人病例队列研究设计中，测量维生素D状态与2型糖尿病事件之间的关联[前瞻性分析]（共有2，161例基线葡萄糖耐受不良的成人和379例新发2型糖尿病病例）。我们将调整重要的潜在混杂因素，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。（二）、测量维生素D状态与代谢综合征（及其单个组分）和大血管疾病发展之间的相关性[前瞻性分析]。在同一队列中，我们将测量25 OHD与复合大血管疾病（如DPP/OS中定义）之间的相关性。在那些没有新陈代谢的人中， 在基线时，我们将测量25 OHD与以下结局之间的相关性： 代谢综合征（ATP-III定义）及其单个组分（中心性肥胖、高血压、低HDL-胆固醇、高脂血症和高胆固醇血症）。（三）、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联[横断面分析]。在同一队列中，在基线时（发生t2 DM/心脏病之前），我们将检查25 OHD与胰岛素分泌（胰岛素：葡萄糖比，校正胰岛素反应）、胰岛素抵抗（HOMA-IR）和全身炎症（C-反应蛋白[CRP]）的可用指标之间的相关性。使用维生素D有可能对预防2型糖尿病和CMD产生重大影响，特别是考虑到在临床实践中可以轻松且廉价地实施干预。

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.