Vitamin D metabolism and type 1 diabetes complications

描述(申请人提供)：1型糖尿病并发症会导致相当大的发病率和死亡率。特别是，肾脏疾病很常见，可能发展为终末期肾脏疾病，并极大地放大了心血管疾病的风险，心血管疾病是该人群的主要死亡原因。维生素D代谢受损可能通过对1型糖尿病具有特殊重要性的机制导致肾脏和心血管疾病。然而，维生素D代谢受损与1型糖尿病并发症的临床相关性仍有待确定。这项应用的总体目标是评估维生素D代谢受损在临床上重要的1型糖尿病并发症发病机制中的潜在作用。我们建议在糖尿病控制和并发症试验/糖尿病干预和并发症流行病学研究(DCCT/EDIC)中，使用采用新颖、精确和准确的质谱学方法测量的关键维生素D代谢物的组合，对1,093名参与者的维生素D代谢进行全面表征。具体地说，我们建议分别测量25-羟基维生素D、24，25-二羟基维生素D和1，25-二羟基维生素D来确定维生素D的摄入量、周转和活动。我们将把这些测量与DCCT/EDIC在长期随访中收集的大量适合路径的临床微血管和大血管疾病结果联系起来。我们将验证维生素D代谢受损(较低的25-羟基维生素D、24，25-二羟基维生素D和1，25-二羟基维生素D浓度)与糖尿病肾病和亚临床心血管疾病的发展相关的假设。为了成功实现拟议的目标，我们组建了一支长期直接参与DCCT/EDIC的多学科研究团队，他们在1型糖尿病及其并发症、维生素D代谢、实验室科学、流行病学和生物统计学方面拥有丰富的专业知识。 公共卫生相关性：需要叙事新颖的治疗目标来预防1型糖尿病并发症的发展，尽管应用了现有的治疗方法，但1型糖尿病并发症的发生率仍然很高。拟议的研究将有助于确定维生素D代谢受损在多大程度上是预防1型糖尿病患者肾脏和心血管疾病的治疗目标。这些研究将侧重于1型糖尿病的高危人群；通过使用新的和精确的生物标记物的组合，更好地确定维生素D代谢受损的成分与不良健康结果最密切的关系；建立维生素D代谢受损与肾脏疾病的时间关系以及维生素D代谢受损可能增加心血管风险的机制；并为设计针对维生素D代谢受损的临床试验建立关键的知识基础。

DESCRIPTION (provided by applicant): Abstract Type 1 diabetes complications cause substantial morbidity and mortality. In particular, kidney disease is common, may progress to end stage renal disease, and potently amplifies the risk of cardiovascular disease, the major cause of death in this population. Impaired vitamin D metabolism may contribute to kidney and cardiovascular disease through mechanisms of specific importance to type 1 diabetes. However, the clinical relevance of impaired vitamin D metabolism in type 1 diabetes complications remains to be determined. The overall goal of this application is to assess the potential role of impaired vitamin D metabolism in the pathogenesis of clinically important type 1 diabetes complications. We propose to comprehensively characterize vitamin D metabolism in 1,093 participants in the Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) using a combination of key vitamin D metabolites measured using novel, precise, and accurate mass spectrometry methods. Specifically, we propose to measure 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25- dihydroxyvitamin D to ascertain vitamin D intake, turnover, and activity, respectively. We will relate these measurements to an extensive collection of pathway-appropriate clinical microvascular and macrovascular disease outcomes collected by DCCT/EDIC over long-term follow-up. We will test the hypotheses that impaired vitamin D metabolism (lower 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D concentrations) is associated with the development of diabetic kidney disease and subclinical cardiovascular disease. To successfully complete the proposed aims, we have assembled a multidisciplinary team of investigators with long-standing direct involvement in DCCT/EDIC who have substantial expertise in type 1 diabetes and its complications, vitamin D metabolism, laboratory science, epidemiology, and biostatistics. PUBLIC HEALTH RELEVANCE: Narrative Novel therapeutic targets are needed to prevent the development of type 1 diabetes complications, which continue to occur at high rates despite the application of existing therapies. The proposed studies will help determine the extent to which impaired vitamin D metabolism is a therapeutic target for the prevention of kidney and cardiovascular disease in type 1 diabetes. These studies will focus on the high-risk type 1 diabetes population; better define the components of impaired vitamin D metabolism most strongly related to adverse health outcomes by using a combination of novel and precise biomarkers; establish temporal relationships of impaired vitamin D metabolism with kidney disease and mechanisms through which impaired vitamin D metabolism may increase cardiovascular risk; and build a critical foundation of knowledge for the design of clinical trials targeting impaired vitamin D metabolism.