Shah, RaviMurthy, VenkateshPacold, MichaelDanielson, KirstyTanriverdi, KahramanLarson, Martin G.Hanspers, KristinaPico, AlexanderMick, EricReis, Jaredde Ferranti, SarahFreinkman, ElizavetaLevy, DanielHoffmann, UdoOsganian, StavroulaDas, SaumyaFreedman, Jane E.2018-05-302017Shah, R., V. Murthy, M. Pacold, K. Danielson, K. Tanriverdi, M. G. Larson, K. Hanspers, et al. 2017. “Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes.” Diabetes Care 40 (4): 546-553. doi:10.2337/dc16-1354. http://dx.doi.org/10.2337/dc16-1354.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37068108OBJECTIVE Insulin resistance (IR) is a hallmark of obesity and metabolic disease. Circulating extracellular RNAs (ex-RNAs), stable RNA molecules in plasma, may play a role in IR, though most studies on ex-RNAs in IR are small. We sought to characterize the relationship between ex-RNAs and metabolic phenotypes in a large community-based human cohort. RESEARCH DESIGN AND METHODS We measured circulating plasma ex-RNAs in 2,317 participants without diabetes in the Framingham Heart Study (FHS) Offspring Cohort at cycle 8 and defined associations between ex-RNAs and IR (measured by circulating insulin level). We measured association between candidate ex-RNAs and markers of adiposity. Sensitivity analyses included individuals with diabetes. In a separate cohort of 90 overweight/obese youth, we measured selected ex-RNAs and metabolites. Biology of candidate microRNAs was investigated in silico. RESULTS The mean age of FHS participants was 65.8 years (56% female), with average BMI 27.7 kg/m2; participants in the youth cohort had a mean age of 15.5 years (60% female), with mean BMI 33.8 kg/m2. In age-, sex-, and BMI-adjusted models across 391 ex-RNAs in FHS, 18 ex-RNAs were associated with IR (of which 16 were microRNAs). miR-122 was associated with IR and regional adiposity in adults and IR in children (independent of metabolites). Pathway analysis revealed metabolic regulatory roles for miR-122, including regulation of IR pathways (AMPK, target of rapamycin signaling, and mitogen-activated protein kinase). CONCLUSIONS These results provide translational evidence in support of an important role of ex-RNAs as novel circulating factors implicated in IR.en-USJournal Article2018-05-3010.2337/dc16-1354