Journal
DIABETES CARE
Volume 37, Issue 5, Pages 1375-1383Publisher
AMER DIABETES ASSOC
DOI: 10.2337/dc13-1847
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Funding
- Programme Innovative Economy [UDA-POIG.01.03.01-00-128/08]
- European Union within the European Regional Development Fund
- Spanish Ministry of Science and Innovation [FIS 2011-00214]
- CIBER de la Fisiopatologia de la Obesidad y la Nutricion (CIBERobn)
- Associacio Catalana de Diabetis
- Sara Borrell fellowship
- ISCIII
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OBJECTIVEThis study sought to identify the profile of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity.RESEARCH DESIGN AND METHODSThe circulating miRNA profile was assessed in a pilot study of 12 men: 6 with normal glucose tolerance (NGT) and 6 T2D patients. The association of 10 circulating miRNAs with T2D was cross-sectionally validated in an extended sample of 45 NGT vs. 48 T2D subjects (65 nonobese and 28 obese men) and longitudinally in 35 T2D patients who were recruited in a randomized, double-blinded, and placebo-controlled 3-month trial of metformin treatment. Circulating miRNAs were also measured in seven healthy volunteers before and after a 6-h hyperinsulinemic-euglycemic clamp and insulin plus intralipid/heparin infusion.RESULTSCross-sectional studies disclosed a marked increase of miR-140-5p, miR-142-3p, and miR-222 and decreased miR-423-5p, miR-125b, miR-192, miR-195, miR-130b, miR-532-5p, and miR-126 in T2D patients. Multiple linear regression analyses revealed that miR-140-5p and miR-423-5p contributed independently to explain 49.5% (P < 0.0001) of fasting glucose variance after controlling for confounders. A discriminant function of four miRNAs (miR-140-5p, miR-423-5p, miR-195, and miR-126) was specific for T2D with an accuracy of 89.2% (P < 0.0001). Metformin (but not placebo) led to significant changes in circulating miR-192 (49.5%; P = 0.022), miR-140-5p (-15.8%; P = 0.004), and miR-222 (-47.2%; P = 0.03), in parallel to decreased fasting glucose and HbA(1c). Furthermore, while insulin infusion during clamp decreased miR-222 (-62%; P = 0.002), the intralipid/heparin mixture increased circulating miR-222 (163%; P = 0.015) and miR-140-5p (67.5%; P = 0.05).CONCLUSIONSThis study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity.
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