Vitamin D and Calcium Homeostasis in Relation to Type 2 Diabetes

描述（由申请人提供）：2型糖尿病（t2DM）的发病率正在以惊人的速度增长，无论是在国内还是在世界范围内，仅在美国每年就诊断出超过100万例新病例。虽然减肥已被证明在延缓糖尿病方面是成功的，但它很难实现并长期维持。因此，迫切需要识别与体重无关且易于改变的环境危险因素，以防止t2DM发病率的增加。根据动物和人类研究，包括我们自己的观察数据，维生素D和钙这两种营养因子被怀疑是糖尿病风险的调节剂。然而，我们对维生素D和钙对糖尿病风险的临床影响程度的认识存在重大差距，包括它们与2型糖尿病相关的潜在生理作用机制的不确定性。目前，数据的缺乏限制了维生素D和钙作为预防2型糖尿病的可行营养干预措施的有效性。本研究的中心假设是，维生素D和钙缺乏是t2DM发生的危险因素，这种危险是由胰腺细胞功能、胰岛素敏感性和全身性炎症的改变介导的。我们计划通过采用双重方法（观察性研究和实验性人体试验）来验证我们的主要假设，以实现以下两个具体目标。(1)。在护士健康研究这一大型前瞻性队列中，对女性进行巢式病例对照研究，评估维生素D状态与2型糖尿病风险之间的关联程度。目前的假设是，血清25OHD水平测量的维生素D状态与2型糖尿病风险呈负相关。这种关联将被量化(2)。在一项为期3个月的随机安慰剂对照试验中，确定维生素D和钙补充剂对β细胞功能、胰岛素敏感性、葡萄糖耐量和全身炎症的影响，该试验对有t2DM风险的成年人给予维生素D3和碳酸钙（2x2因子设计）。目前的假设是，补充维生素D和钙可以改善β细胞功能和胰岛素敏感性（主要结果），以及全身炎症和葡萄糖耐量（次要结果）。我们的研究结果将提供新颖而重要的数据，为将这些营养素合理整合到常规医疗保健中以减轻2型糖尿病负担提供基础。

DESCRIPTION (provided by applicant): The incidence of type 2 Diabetes Mellitus (t2DM) is increasing at an alarming rate both nationally and worldwide with more than 1 million new cases per year diagnosed in the US alone. Although weight- loss has been shown to be successful in delaying diabetes, it is difficult to achieve and maintain long- term. Therefore, identification of weight-independent environmental and easily modified risk factors is urgently needed to prevent the increase in the incidence of t2DM. Vitamin D and calcium are two nutritional factors that have been suspected as modifiers of diabetes risk based on animal and human studies including our own observational data. However, there are critical gaps in our knowledge about the magnitude of the clinical effect of vitamin D and calcium on diabetes risk, including uncertainty about their potential physiologic mechanism of action in relation to t2DM. Currently, this lack of data limits the usefulness of vitamin D and calcium as feasible nutritional interventions for prevention of t2DM. The central hypothesis of the proposed study is that, vitamin D and calcium insufficiency are risk factors for the development of t2DM 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 by pursuing a dual approach (observational study and experimental human trial) to achieve the following 2 specific aims. (1). Assess the magnitude of the association between vitamin D status and risk of t2DM in a nested case-control study design in women in a large prospective cohort, the Nurses' Health Study. The working hypothesis is that vitamin D status, as measured by serum 25OHD level, is inversely associated with t2DM risk. The association will be quantified (2). Determine the effects of vitamin D and Calcium supplementation on beta-cell function, insulin sensitivity, glucose tolerance and systemic inflammation in a 3-month randomized placebo-controlled trial of adults at risk for t2DM given vitamin D3 and calcium carbonate (2x2 factorial design). The working hypothesis is that vitamin D and calcium supplementation improves beta-cell function and insulin sensitivity (primary outcomes) and systemic inflammation and glucose tolerance (secondary outcomes). Our results will provide novel and important data that will serve as the foundation for the rational integration of these nutrients into conventional medical care to ameliorate t2DM burden.