Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization
Résumé
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. RESEARCH DESIGN AND 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 \textless 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 \textless 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.
Mots clés
blood
Adolescent"*"Adult"*"Aged"*"Biological Markers/metabolism"*"Cross-Sectional Studies"*"Diabetes Mellitus
Type 2/blood/drug therapy/*genetics"*"Double-Blind Method"*"Female"*"Humans"*"Hypoglycemic Agents/administration & dosage/pharmacology"*"Insulin/administration & dosage/pharmacology"*"Insulin Resistance/*genetics"*"Male"*"Metformin/therapeutic use"*"MicroRNAs/*metabolism"*"Middle Aged"*"Pilot Projects"*"Young Adult
administration & dosage
drug therapy
*genetics"*"Double-Blind Method"*"Female"*"Humans"*"Hypoglycemic Agents
*genetics"*"Male"*"Metformin
*metabolism"*"Middle Aged"*"Pilot Projects"*"Young Adult
pharmacology"*"Insulin
pharmacology"*"Insulin Resistance
therapeutic use"*"MicroRNAs
Type 2