? ? 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. ? ? ? ?
RESEARCH &RELATED Other Project Information ITEM 7. Project Narrative Relevance of the Project The research addresses important health issues, since type 2 diabetes and cardiometabolic disease (defined as metabolic syndrome and macrovascular disease) are highly prevalent in the U.S., and therefore it is of potential high impact given its broad applicability, especially given that the cost of supplemental or fortification with vitamin D is relatively inexpensive compared to treating the chronic disease and its complications. Our expectation is that, at the completion of these studies, the magnitude (after adjustments for important covariates) of the clinical risk of progression from glucose intolerance to clinical diabetes and risk of metabolic syndrome/macrovascular disease associated with vitamin D status will have been characterized, including potential interactions with weight change and calcium intake, and insights into mechanisms in relation to glucose metabolism, insulin dynamics and systemic inflammation will be available. Our results will provide novel and important new data that will complement our ongoing mechanistic human studies and will serve as the foundation for the rational design of a randomized trial of a vitamin D/calcium- based nutritional intervention that aim at preventing cardiometabolic disease with the future goal of integrating these therapies into conventional medical care to ameliorate type 2 diabetes and cardiometabolic burden.
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