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

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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.