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

糖尿病患者强化生活方式干预与二甲双胍相关的循环microRNA 预防计划队列 项目总结 2型糖尿病是公共卫生和精准医学的优先事项。2型糖尿病的病因是 复杂的遗传和生活方式/环境因素都会导致风险。当前的风险应对方法 预测和风险降低是有限的，因为它们没有考虑到生物和生物之间的相互作用 生活方式危险因素。MicroRNAs调节基因的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。细胞外循环中的microRNA，它们是 在血液中很容易检测到，它们是疾病病因的有用指标，并显示出反应的变化 对环境和行为的影响。我们自己之前的研究和其他人已经提供了关于 作为2型糖尿病事件和降低风险干预反应的预测生物标记物的microRNAs。 我们发现循环中的microRNA与2型糖尿病的风险有关，即对胰岛素的反应。 致敏药剂和生活方式干预(如瑜伽、体力活动)。此前的研究表明， 主要是横截面性质的，没有能力评估microRNA簇作为预测性的 记号笔。这项研究将确定microRNAs是否预测2型糖尿病的发生，以及是否存在 与降低风险干预措施的互动。我们将测量储存的一组血浆样本中的microRNA 在NIDDK生物资源库，来自完成的NIH资助的糖尿病预防计划(DPP)的参与者 这项试验测试了二甲双胍、强化生活方式干预和安慰剂对2型糖尿病风险的影响。 这项试验显示，强化的生活方式干预使2型糖尿病的发病率降低了58%，而二甲双胍 与安慰剂相比减少了31%。来自DPP试验的现有表型数据和生物标本提供了 这是一个难得的机会来评估microRNA和 接受干预的极具特征的个体样本中患2型糖尿病的风险 这降低了2型糖尿病的发病率。循环中的microRNA将使用流式细胞仪进行测量- 基于与肝素兼容的直接检测方法，肝素是一种用于样品采集的抗凝剂 民进党庭审。这项研究将是第一次在大规模、严格进行的临床试验中评估microRNAs， 作为2型糖尿病的预测指标和与降低风险干预措施的相互作用，单独和AS集群。这 这也将是第一个对microRNAs和空腹血糖随时间变化的纵向轨迹进行建模的研究。 这些知识将提高我们对风险预测、风险优化中个体间变异性的理解 减少干预措施、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.