DESCRIPTION (provided by applicant): The diabetes population and related costs are expected to double in the next quarter century, as more than 79 million Americans are at risk of developing diabetes. In trials, lifestyle changes aimed at weight loss were successful at reducing risk of type 2 diabetes (t2DM), the most common type of diabetes. However, long-term weight maintenance in the clinical setting has proved elusive. Importantly, even after successful weight loss, substantial residual risk (~40-50%) remains and may be attributable to other modifiable factors. Several medications used to treat established t2DM have also been studied for t2DM prevention and many have been shown to delay incident diabetes; however, the role of pharmacotherapy for diabetes prevention is not clear. Therefore, there is a continued and pressing need for identification of modifiable risk factors and interventions that are safe, inexpensive and acceptable to prevent t2DM and decrease diabetes-related disease burden. Based on a large body of recently published studies, vitamin D has emerged as a potential determinant of type 2 diabetes (t2DM) risk. In longitudinal observational studies, higher vitamin D status was associated with up to 83% reduction in the risk of t2DM. However, the evidence to support vitamin D supplementation for prevention of t2DM remains inconclusive. The favorable association between vitamin D status and t2DM risk in observational studies may be confounded by a variety of factors. Directly extending our prior work, the goal of the research described in this grant application is to address the issue of causality by evaluating whether vitamin D is an effective intervention for prevention of t2DM among high-risk individuals. We propose to conduct the vitamin D and type 2 diabetes (D2d) study, a multicenter, randomized, double-masked, placebo- controlled, parallel-group primary prevention clinical trial to evaluate the safety of vitamin D supplementation and its effect on the time to onset of diabetes in participants with pre-diabetes. The need for a trial such as the D2d study has been recognized in recent editorials and reviews, including the 2011 Institute of Medicine report on dietary reference intakes for vitamin D, which identified diabetes as one of the most promising non-skeletal outcomes with an urgent need for rigorously conducted trials to confirm the promising results seen in observational and mechanistic studies. The proposed trial, therefore, addresses an important and timely question and has the potential for significant impact in the clinically important area of t2DM prevention with direct public health implications. The potential impact of the study is heightened by the assembly of a team of highly qualified investigators with complementary expertise and experience in conducting nutrition-based multicenter trials, many of whom have worked together previously.

The proposed trial addresses an important question and has the potential for significant impact in the clinically important area of type 2 diabetes mellitus (t2DM) prevention. If the trial confirms a favorable benefit/harm ratio of vitamin D supplementation, vitamin D would likely be integrated into contemporary strategies to prevention of t2DM in the more than 79 million Americans at risk of developing diabetes and ameliorate the high personal and societal burden of 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. Consistent with its strategic planning for 2010-14, the ODS is leading a vitamin D Initiative, which is an evolving partnership with NIH and other federal agencies to fund research that address gaps in knowledge, such as those stated by the 2011 Institute of Medicine report on dietary reference intakes for vitamin D. The Institute of Medicine report specifically identified the link between vitamin D and diabetes as one of the most promising non-skeletal outcomes that require further research with rigorously done trials.