PT  - JOURNAL ARTICLE
AU  - Shah, Ravi
AU  - Murthy, Venkatesh
AU  - Pacold, Michael
AU  - Danielson, Kirsty
AU  - Tanriverdi, Kahraman
AU  - Larson, Martin G.
AU  - Hanspers, Kristina
AU  - Pico, Alexander
AU  - Mick, Eric
AU  - Reis, Jared
AU  - de Ferranti, Sarah
AU  - Freinkman, Elizaveta
AU  - Levy, Daniel
AU  - Hoffmann, Udo
AU  - Osganian, Stavroula
AU  - Das, Saumya
AU  - Freedman, Jane E.
TI  - Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes
AID  - 10.2337/dc16-1354
DP  - 2017 Feb 09
TA  - Diabetes Care
PG  - dc161354
4099  - http://care.diabetesjournals.org/content/early/2017/02/08/dc16-1354.short
4100  - http://care.diabetesjournals.org/content/early/2017/02/08/dc16-1354.full
AB  - OBJECTIVE 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.