Exploratory Analysis of the Functional Implications of MicroRNAs Associated with Incident Type 2 Diabetes and Related Risk Factors.

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。以前的研究主要是横截面性质， 来评估作为预测标志物的microRNA簇。我们目前资助的R 01研究将确定 microRNA是否可以预测2型糖尿病的发生以及是否与风险降低有相互作用 干预措施。我们测量了NIDDK生物储存库中的一部分血浆样本中的microRNA 来自完成的NIH资助的糖尿病预防项目（DPP）试验的参与者，该试验测试了 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。这次审判显示， 与安慰剂相比，生活方式干预使2型糖尿病发病率降低58%，二甲双胍降低31%。 DPP试验的现有表型数据和生物标本提供了一个特殊的机会， 评估两种microRNA的纵向变化与2型糖尿病风险之间的关系， 接受干预措施的个体的特征非常明确的样本，这些干预措施降低了 2型糖尿病这项母体研究是第一个在一项大型的、严格进行的临床试验中评估microRNA的研究， 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 这也是第一个研究模型的纵向轨迹microRNA和空腹血糖随着时间的推移。建筑 在母项目中，本补充建议识别预测的基因和生物途径 在母体研究中鉴定的microRNA的靶点。补充剂的潜在影响是发现 在未来有可能发生2型糖尿病的亚组中， 优化治疗和发现新疗法。这些知识将提高我们对 风险预测中的个体间差异，风险降低干预措施的优化，以及 2型糖尿病和降低风险干预措施的反应。此外，这一补充将为未来 来自种族代表性不足的少数群体的科学家，在临床和生物医学研究方面接受过培训， 为了准备候选人在学术医学事业的成功。

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. Prior studies have been primarily cross-sectional in nature and were not powered to evaluate clusters of microRNAs as predictive markers. Our current funded R01 study will determine whether microRNAs predict incident type 2 diabetes and whether there are interactions with risk reduction interventions. We measured 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 provided 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. The parent study is 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 is also the first study to model longitudinal trajectories of microRNAs and fasting blood glucose over time. Building on the parent project, this supplement proposes to identify the genes and biological pathways that are predicted targets of the microRNAs identified in the parent study. The potential impact of the supplement is discovery of the specific mechanisms that may underlie risk for type 2 diabetes within subgroups with future potential for optimization of treatments and discovery of new therapies. 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. In addition, this supplement will provide a future scientist from a racially under-represented minority group with training in clinical and biomedical research in order to prepare the candidate for a successful career in academic medicine.