Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes
Department of Medicine, Division of Cardiovascular Medicine; Department of Quantitative Health Sciences; UMass Metabolic Network
Cellular and Molecular Physiology | Endocrinology | Endocrinology, Diabetes, and Metabolism | Nutritional and Metabolic Diseases
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.
DOI of Published Version
Diabetes Care. 2017 Apr;40(4):546-553. doi: 10.2337/dc16-1354. Epub 2017 Feb 9. Link to article on publisher's site
Shah R, Murthy V, Pacold M, Danielson K, Tanriverdi K, Larson MG, Hanspers K, Pico A, Mick EO, Reis J, de Ferranti S, Freinkman E, Levy D, Hoffmann U, Osganian S, Das S, Freedman JE. (2017). Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.2337/dc16-1354. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1395