Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization.
OBJECTIVE
This study sought to identify the profile of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity.


METHODS
The 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.


RESULTS
Cross-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 HbA1c. 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).


CONCLUSIONS
This study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity.
Corresponding author: José Manuel Fernández-Real, jmfreal@idibgi.org.
Francisco J
FJ
Ortega
Josep M
JM
Mercader
José María
JM
Moreno-Navarrete
Oscar
O
Rovira
Ester
E
Guerra
Eduardo
E
Esteve
Gemma
G
Xifra
Cristina
C
Martínez
Wifredo
W
Ricart
Jennifer
J
Rieusset
Sophie
S
Rome
Monika
M
Karczewska-Kupczewska
Marek
M
Straczkowski
José Manuel
JM
Fernández-Real
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D010865:Pilot Projects; D055815:Young Adult
D015415:Biomarkers; D007004:Hypoglycemic Agents; D007328:Insulin; D035683:MicroRNAs; D008687:Metformin