Serum microRNA-1 and microRNA-133a levels reflect myocardial steatosis in uncomplicated type 2 diabetes

Using in vitro, in vivo and patient-based approaches, we investigated the potential of circulating microRNAs (miRNAs) as surrogate biomarkers of myocardial steatosis, a hallmark of diabetic cardiomyopathy. We analysed the cardiomyocyte-enriched miRNA signature in serum from patients with well-controlled type 2 diabetes and with verified absence of structural heart disease or inducible ischemia, and control volunteers of the same age range and BMI (N = 86), in serum from a high-fat diet-fed murine model, and in exosomes from lipid-loaded HL-1 cardiomyocytes. Circulating miR-1 and miR-133a levels were robustly associated with myocardial steatosis in type 2 diabetes patients, independently of confounding factors in both linear and logistic regression analyses (P < 0.050 for all models). Similar to myocardial steatosis, miR-133a levels were increased in type 2 diabetes patients as compared with healthy subjects (P < 0.050). Circulating miR-1 and miR-133a levels were significantly elevated in high-fat diet-fed mice (P < 0.050), which showed higher myocardial steatosis, as compared with control animals. miR-1 and miR-133a levels were higher in exosomes released from lipid-loaded HL-1 cardiomyocytes (P < 0.050). Circulating miR-1 and miR-133a are independent predictors of myocardial steatosis. Our results highlight the value of circulating miRNAs as diagnostic tools for subclinical diabetic cardiomyopathy.This work was supported by the Spanish Atherosclerosis Foundation/Spanish Atherosclerosis Society (Basic Research Award 2013), Fundación Merck Salud (Merck Serono Research Award in Cardiometabolism 2014), FIS PI14/01729 from the Instituto Salud Carlos III, co-financed by the European Fund for Regional Development (E.F.R.D.) and Fundació Marató TV3 (201521 10). CIBER Cardiovascular (CB16/11/00403) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas are Instituto de Salud Carlos III Projects. DdG-C was a recipient of a Sara Borrell grant from the Instituto de Salud Carlos III (CD14/00109). PIRAMID study was supported by Eli Lilly, the Netherlands, which has a partnership with Takeda, the manufacturer of pioglitazone.Peer reviewe