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。以前的研究主要是横断面研究，而不是 有能力评估作为预测性标记的microRNA簇。我们目前资助的R01研究将确定 MicroRNAs是否可以预测2型糖尿病的发生以及与降低风险是否存在相互作用 干预措施。我们测量了NIDDK生物资源库中储存的一部分血浆样本中的microRNA 来自完成的NIH资助的糖尿病预防计划(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。这场试验显示出密集的 与安慰剂相比，生活方式干预使2型糖尿病的发病率降低了58%，二甲双胍降低了31%。 来自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 评估人群中microRNAs的纵向变化与2型糖尿病风险之间的关系 接受干预的个体样本特征非常好，减少了 2型糖尿病。母公司的研究是第一次在大规模、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 也是第一个对microRNA和空腹血糖随时间变化的纵向轨迹进行建模的研究。建房 在母项目中，本附录建议确定预测的基因和生物途径 父母研究中确定的microRNAs的靶标。增刊的潜在影响是发现了 可能导致2型糖尿病风险的特定机制在具有未来潜在的 优化治疗和发现新的治疗方法。这一知识将提高我们对 风险预测、减少风险干预措施的优化和类型机制的个体间变异性 2糖尿病和对降低风险干预措施的反应。此外，这一副刊将提供一个未来 来自种族代表性不足的少数群体的科学家，接受过临床和生物医学研究方面的培训 以便为候选人在学术医学领域的成功生涯做好准备。

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.