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.

Circulating long-non coding RNAs as biomarkers of left ventricular diastolic function and remodelling in patients with well-controlled type 2 diabetes.

Contractile dysfunction is underdiagnosed in early stages of diabetic cardiomyopathy. We evaluated the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers of subclinical cardiac abnormalities in type 2 diabetes. Forty-eight men with well-controlled type 2 diabetes and 12 healthy age-matched volunteers were enrolled in the study. Left ventricular (LV) parameters were measured by magnetic resonance imaging. A panel of lncRNAs was quantified in serum by RT-qPCR. No differences in expression levels of lncRNAs were observed between type 2 diabetes patients and healthy volunteers. In patients with type 2 diabetes, long intergenic non-coding RNA predicting cardiac remodeling (LIPCAR) was inversely associated with diastolic function, measured as E/A peak flow (P < 0.050 for all linear models). LIPCAR was positively associated with grade I diastolic dysfunction (P < 0.050 for all logistic models). Myocardial infarction-associated transcript (MIAT) and smooth muscle and endothelial cell-enriched migration/differentiation-associated long noncoding RNA (SENCR) were directly associated with LV mass to LV end-diastolic volume ratio, a marker of cardiac remodelling (P < 0.050 for all linear models). These findings were validated in a sample of 30 patients with well-controlled type 2 diabetes. LncRNAs are independent predictors of diastolic function and remodelling in patients with type 2 diabetes.

Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with type 2 diabetes mellitus.

OBJECTIVE: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures and thiazolidinediones (TZDs) increase this risk. TZDs stimulate the expression of sclerostin, a negative regulator of bone formation, in vitro. Abnormal sclerostin production may, therefore, be involved in the pathogenesis of increased bone fragility in patients with T2DM treated with TZDs. METHODS: We measured serum sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and carboxy-terminal cross-linking telopeptide of type I collagen (CTX) in 71 men with T2DM treated with either pioglitazone (PIO) (30 mg once daily) or metformin (MET) (1000 mg twice daily). Baseline values of sclerostin and P1NP were compared with those of 30 healthy male controls. RESULTS: Compared with healthy controls, patients with T2DM had significantly higher serum sclerostin levels (59.9 vs 45.2 pg/ml, P<0.001) but similar serum P1NP levels (33.6 vs 36.0 ng /ml, P=0.39). After 24 weeks of treatment, serum sclerostin levels increased by 11% in PIO-treated patients and decreased by 1.8% in MET-treated patients (P=0.018). Changes in serum sclerostin were significantly correlated with changes in serum CTX in all patients (r=0.36, P=0.002) and in PIO-treated patients (r=0.39, P=0.020), but not in MET-treated patients (r=0.17, P=0.31). CONCLUSIONS: Men with T2DM have higher serum sclerostin levels than healthy controls, and these levels further increase after treatment with PIO, which is also associated with increased serum CTX. These findings suggest that increased sclerostin production may be involved in the pathogenesis of increased skeletal fragility in patients with T2DM in general and may specifically contribute to the detrimental effect of TZDs on bone.

Pioglitazone compared with metformin increases pericardial fat volume in patients with type 2 diabetes mellitus.

CONTEXT: Peroxisome proliferator-activated receptor-gamma agonists are involved in fat cell differentiation. OBJECTIVE: The objective of the study was to investigate the effect of pioglitazone vs. metformin on pericardial fat volume in type 2 diabetic (T2DM) patients. Furthermore, we aimed to assess the relationship between pericardial fat volume, other fat compartments, and myocardial function at baseline and after treatment. DESIGN: This was a prospective, randomized, double-blind, intervention study. SETTING: The study was conducted at a university hospital. PATIENTS: Patients included 78 men with T2DM (aged 56.5 +/- 0.6 yr; glycosylated hemoglobin 7.1 +/- 0.1%) without structural heart disease. INTERVENTION: Patients were randomly assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo during 24 wk. MAIN OUTCOME MEASURES: Pericardial and abdominal fat volumes and myocardial left ventricular function were measured by magnetic resonance imaging and hepatic and myocardial triglyceride content by proton magnetic resonance spectroscopy. RESULTS: Pioglitazone increased pericardial fat volume [30.5 +/- 1.7 ml (baseline) vs. 33.1 +/- 1.8 ml], whereas metformin did not affect pericardial fat volume (29.2 +/- 1.5 ml vs. 29.6 +/- 1.6 ml, between groups P = 0.02). After correction for body mass index and age, only visceral fat volume correlated with pericardial fat volume at baseline (r = 0.55, P < 0.001). The increase in pericardial fat volume induced by pioglitazone was not associated with a decrease in left ventricular diastolic function. CONCLUSION: In T2DM patients, pioglitazone increases pericardial fat volume. This increase in pericardial fat volume did not negatively affect myocardial function after 24 wk. These observations question the notion of an inverse causal relationship between pericardial fat volume and myocardial function.