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Original Research
Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes
Ravi Shah, Venkatesh Murthy, Michael Pacold, Kirsty Danielson, Kahraman Tanriverdi, Martin G. Larson, Kristina Hanspers, Alexander Pico, Eric Mick, Jared Reis, Sarah de Ferranti, Elizaveta Freinkman, Daniel Levy, Udo Hoffmann, Stavroula Osganian, Saumya Das, Jane E. Freedman
Diabetes Care 2017 Feb; dc161354. https://doi.org/10.2337/dc16-1354
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Abstract

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.

Footnotes

  • This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc16-1354/-/DC1.

  • Received June 23, 2016.
  • Accepted January 7, 2017.
  • © 2017 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes
Ravi Shah, Venkatesh Murthy, Michael Pacold, Kirsty Danielson, Kahraman Tanriverdi, Martin G. Larson, Kristina Hanspers, Alexander Pico, Eric Mick, Jared Reis, Sarah de Ferranti, Elizaveta Freinkman, Daniel Levy, Udo Hoffmann, Stavroula Osganian, Saumya Das, Jane E. Freedman
Diabetes Care Feb 2017, dc161354; DOI: 10.2337/dc16-1354

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Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes
Ravi Shah, Venkatesh Murthy, Michael Pacold, Kirsty Danielson, Kahraman Tanriverdi, Martin G. Larson, Kristina Hanspers, Alexander Pico, Eric Mick, Jared Reis, Sarah de Ferranti, Elizaveta Freinkman, Daniel Levy, Udo Hoffmann, Stavroula Osganian, Saumya Das, Jane E. Freedman
Diabetes Care Feb 2017, dc161354; DOI: 10.2337/dc16-1354
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