The Impact of Interventions to Treat Incident Diabetes on Circulating microRNAs in the Diabetes Prevention Program

糖尿病患者中与强化生活方式干预和代谢相关的循环microRNA 预防方案队列 项目摘要 2型糖尿病是公共卫生和精准医疗的优先事项。2型糖尿病的病因是 复杂的遗传和生活方式/环境因素都有助于风险。目前应对风险的办法 预测和风险降低是有限的，因为它们不能解释生物和 生活方式风险因素。microRNA调节基因表达，以响应生活方式因素，并捕获 遗传易感性和环境的综合影响。细胞外循环microRNA， 在血液中容易检测到，正在成为疾病病因学的有用指标，并显示反应的变化， 对环境和行为的影响。我们自己先前的研究和其他人已经提供了关于以下方面的初步信息： microRNA作为2型糖尿病发病的预测生物标志物和对降低风险干预措施的反应。 我们发现，循环中的microRNA与2型糖尿病的风险有关， 致敏药物和生活方式干预（例如，瑜伽、体育活动）。先前的研究已经 本质上主要是横截面的，并且没有能力评估microRNA簇作为预测 标记。这项研究将确定微小RNA是否可以预测2型糖尿病的发生以及是否存在 与减少风险干预措施的互动。我们将测量一部分血浆样本中的microRNA， 来自完成NIH资助的糖尿病预防计划（DPP）的参与者的NIDDK生物储存库 二甲双胍、强化生活方式干预和安慰剂对2型糖尿病风险的影响试验。 这项试验表明，强化生活方式干预可使2型糖尿病的发病率降低58%，二甲双胍可使2型糖尿病的发病率降低58%。 与安慰剂相比下降了31%。DPP试验的现有表型数据和生物标本提供了 这是一个评估microRNA纵向变化与 在接受干预的个体样本中，2型糖尿病的风险非常明确 降低了2型糖尿病的发病率。将使用流式细胞术测量循环microRNA- 基于直接检测的检测试剂盒，与肝素兼容，肝素是用于样本采集的抗凝剂， 民进党审判。这项研究将是第一个评估，在一个大的，严格进行的临床试验，微RNA， 单独和集群，作为2型糖尿病的预测因子和与风险降低干预措施的相互作用。这 这也将是第一个研究microRNA和空腹血糖随时间的纵向轨迹模型。 这些知识将提高我们对风险预测中个体间变异性的理解， 减少干预措施和2型糖尿病的机制以及对减少风险干预措施的反应。

Circulating MicroRNAs Associated with Intensive Lifestyle Intervention and Metformin in the Diabetes Prevention Program Cohort Project summary Type 2 diabetes is priority for both public health and precision medicine. The etiology of type 2 diabetes is complex and both genetic and lifestyle/environmental factors contribute to risk. Current approaches to risk prediction and risk reduction are limited because they fail to account for the interactions between biological and lifestyle risk factors. MicroRNAs regulate expression of genes in response to lifestyle factors and capture the combined effects of genetic predisposition and the environment. Extracellular circulating microRNAs, which are readily detectable in blood, are emerging as useful indicators of disease etiology and show changes in response to the environment and behaviors. Our own prior studies and others have provided preliminary information about microRNAs as predictive biomarkers for incident type 2 diabetes and responses to risk reduction interventions. We showed that circulating microRNAs are associated with risk for type 2 diabetes, response to an insulin sensitizing pharmacologic agent, and lifestyle interventions (e.g., yoga, physical activity). Prior studies have been primarily cross-sectional in nature and were not powered to evaluate clusters of microRNAs as predictive markers. This study will determine whether microRNAs predict incident type 2 diabetes and whether there are interactions with risk reduction interventions. We will measure microRNAs in a subset of plasma samples banked at the NIDDK biorespository from participants in the completed NIH-funded Diabetes Prevention Program (DPP) trial that tested the effect of metformin, intensive lifestyle intervention, and placebo on risk for type 2 diabetes. This trial showed intensive lifestyle intervention decreased incidence of type 2 diabetes by 58% and metformin by 31% compared to placebo. The existing phenotypic data and biologic specimens from the DPP trial provide an exceptional opportunity to evaluate the relationships between longitudinal changes in both microRNAs and risk for type 2 diabetes in an extremely well characterized sample of individuals who underwent interventions that decreased incidence of type 2 diabetes. Circulating microRNAs will be measured using a flow cytometry- based direct detection assay that is compatible with heparin, the anticoagulant used for sample collection in the DPP trial. This study will be the first to evaluate, in a large, rigorously conducted clinical trial, microRNAs, singularly and as clusters, as predictors of type 2 diabetes and interactions with risk reduction interventions. This will also be the first study to model longitudinal trajectories of microRNAs and fasting blood glucose over time. This knowledge will improve our understanding of inter-individual variability in risk prediction, optimization of risk reduction interventions, and mechanisms for type 2 diabetes and responses to risk reduction interventions.