The Role of Vitamin D in Established Type 2 Diabetes

描述(申请人提供)：糖尿病的发病率在全国和世界范围内以惊人的速度增长，仅在美国每年就有大约200万新确诊病例，近9/10的新病例是由2型糖尿病(T2 DM)引起的。随着8000多万美国人面临患T2 DM的风险，预计未来25年，糖尿病人口和相关成本将至少翻一番。在临床试验中，作为一种适应生活方式变化的药物疗法在治疗T2 DM方面取得了成功，但依从性往往很差，药物相关成本正在上升；因此，迫切需要寻找可应用于公共卫生水平的替代治疗方案，以减轻T2 DM相关的负担。根据我们小组和其他人由NIH资助的研究，次优维生素D状态已成为T2 DM病理生理学的潜在贡献者。然而，由于观察性研究中潜在的混淆，以及缺乏针对血糖和其他代谢结果而设计的充足动力试验的数据，目前尚不清楚维生素D是否在已确定的T2 DM患者中具有临床作用。这次续签申请新的调查者R01，直接扩展了我们在第一个资金周期中进行的这一领域的工作，目的是评估维生素D是否 有效的非药物营养干预治疗2型糖尿病。中心假设是，次优维生素D状态会恶化T2 DM患者的血糖，补充维生素D可通过改善胰岛素分泌和敏感性，改善已确诊的T2 DM患者的血糖和其他代谢结果。第二个假设是维生素D的作用被特定的维生素D受体(VDR)多态所改变。我们计划进行一项为期一年的随机、双盲、安慰剂对照试验，对已确诊的轻度/中度T2 DM患者补充维生素D3，以检验我们的中心假设，并实现这一应用的目标。维生素D水平的下降是我们生活方式改变的结果，在调整了其他生活方式因素(体重、饮食)后，它与T2 DM的密切关联使拟议的研究非常重要和及时，也符合国家研究的优先事项，因为这项研究有望填补一个基本的知识空白，这一空白加剧了目前关于制定针对非骨骼疾病的维生素D补充建议的激烈争议。 公共卫生相关性：拟议的项目与公共健康的相关性：拟议的研究针对一种重要的公共卫生问题--2型糖尿病--提出了替代治疗方案。如果观察性研究中报告的维生素D状态与2型糖尿病之间的有利联系在临床相关试验中得到证实，我们建议，维生素D可以与现有的治疗2型糖尿病的方法一起在2600多万美国患者中发挥其适当的作用。拟议项目与NIH任务的相关性(NIDDK和膳食补充剂办公室[ods])：这项研究涉及与NIDDK和ods都相关的重要健康问题。营养和2型糖尿病是NIDDK感兴趣的两个明显领域，而维生素D是ods感兴趣的一种营养物质。事实上，正如其2010-14年的战略规划所述，TE ods正在领导一项维生素D倡议，这是与美国国立卫生研究院研究所和中心以及其他联邦机构的不断发展的伙伴关系，以资助解决2011年医学研究所关于钙和维生素D饮食参考摄入量报告中指出的知识差距的研究。

DESCRIPTION (provided by applicant): The incidence of diabetes is increasing at an alarming rate both nationally and worldwide with approximately two million new cases diagnosed every year in the US alone, with nearly 9 out of 10 new cases due to type 2 diabetes melitus (t2DM). Diabetes population and related costs are expected to at least double in the next quarter century, as more than 80 million Americans are at risk of developing t2DM. In clinical trials, pharmacotherapy as an adjust to lifestyle changes has been successful for treating t2DM, nonetheless adherence is often poor and drug-related costs are escalating; therefore, identification of alternative therapeutic options that can be applied at the public healh level is urgently needed to decrease t2DM-related burden. Based on NIH-funded research from our group and others, suboptimal vitamin D status has emerged as a potential contributor to the pathophysiology of t2DM. However, because of potential confounding in observational studies and lack of data from adequately powered trials designed for glycemic and other metabolic outcomes, it remains unclear whether vitamin D has a clinical role in patients with established t2DM. The goal of this renewal application for a New Investigator R01, which directly extends our work in this area conducted during the first funding cycle, is to evaluate whether vitamin D is an effective non-pharmacologic nutritional intervention for t2DM. The central hypothesis is that suboptimal vitamin D status worsens glycemia in t2DM and that raising one's 25OHD concentration with vitamin D supplementation improves glycemia and other metabolic outcomes in patients with established t2DM, through improvements in insulin secretion and sensitivity. A secondary hypothesis is that the effect of vitamin D is modified by specific Vitamin D Receptor (VDR) polymorphisms. We plan to test our central hypothesis and accomplish the goals of this application by conducting a 1-year long randomized, double-masked, placebo-controlled trial of vitamin D3 supplementation in persons with established t2DM of mild/moderate severity. Declining vitamin D status is a consequence of our altered lifestyle and its strong association with t2DM, after adjusting for other lifestyle factors (weight, diet), makes the proposed study very important and timely and also consistent with national research priorities as the study is expected to fill a fundamental knowledge gap which fuels the current intense controversy in relation to the development of recommendations for vitamin D supplementation for non-skeletal medical conditions. PUBLIC HEALTH RELEVANCE: Relevance of the proposed project to public health: The proposed study addresses alternative therapeutic options for an important public health problem, type 2 diabetes. If the favorable association between vitamin D status and type 2 diabetes that have been reported in observational studies is confirmed in the clinically relevant trial, we propose, vitamin D can assume its proper role alongside established therapies to treat type 2 diabetes in the more than 26 million Americans with the disease. Relevance of the proposed project to the mission of the NIH (NIDDK and the Office of Dietary Supplements [ODS]): The research addresses important health issues of relevance to both NIDDK and ODS. Nutrition and type 2 diabetes are two obvious areas of interest to NIDDK while vitamin D is a nutrient of significant interest to ODS. Indeed, as stated in its strategic planning for 2010-14, te ODS is leading a Vitamin D Initiative, which is an evolving partnership with NIH institutes and centers and other federal agencies to fund research that address gaps in knowledge, as identified by the 2011 Institute of Medicine report on Dietary Reference Intakes for calcium and vitamin D.