Association between central obesity and total mortality and CVD mortality in the Casale Monferrato Study.

<p>*adjusted for age, sex, diabetes duration.</p><p>**adjusted also for systolic blood pressure, HbA1c, LDL-cholesterol, smoking, CVD, logCRP, logAER.</p><p>***adjusted also for logNT-proBNP.</p

NT-proBNP Linking Low-Moderately Impaired Renal Function and Cardiovascular Mortality in Diabetic Patients: The Population-Based Casale Monferrato Study

<div><p>Background</p><p>Few data are available to assess whether a low-moderate reduction in estimated glomerular filtration rates (eGFR) has a role per se on cardiovascular (CV) mortality or other biomarkers such as NT-proBNP allow to explain such association.</p><p>Methods and Findings</p><p>In a prospective study including 1,645 type 2 diabetic subjects of the population-based Casale Monferrato Study, who had no clinical evidence of heart failure and eGFR >45 ml/min/1.73 m², we examined 6 years CV mortality. Multivariate Cox proportional hazards modeling were used to estimate the effect of NT-proBNP on the association between eGFR and mortality, independently of baseline CV risk factors, albumin excretion rate (AER) and C-reactive protein (CRP). During follow-up, 327 people died (149 of CV diseases) out of 8334.5 person-years. Compared to eGFR≥90 ml/min/1.73 m², values of 60–89 and 45–59 ml/min/1.73 m² conferred a fully adjusted hazard ratios (HRs) of CV mortality of 1.74 (1.08–2.82) and 1.95 (1.03–3.68), respectively. After further adjustment for NT-proBNP, however, HRs were no longer significant (HRs 1.42, 0.83–2.42 and 1.22, 0.59–2.51). In this model, HR for logNT-proBNP was 1.84 (1.52–2.22). Adding NT-proBNP to the model improved the C-statistic of CV mortality from 0.79 (0.76–0.83) to 0.84 (0.81–0.87), yielded an IDI of 0.03 (p = 0.02), and a NRI of 0.44 (p = 0.016).</p><p>Conclusions</p><p>In diabetic people a modest reduction in renal function increased 6-year CV mortality independently of albuminuria. This association, however, was mainly explained by the effect of NT-proBNP, that remained the strongest prognostic marker for a worse CV outcome, even after adjustment for other CV risk factors and pre-existing CVD.</p></div

Results of Cox-regression analysis of variables associated with 6-years all-cause and cardiovascular mortality in people with type 2 diabetes of the Casale Monferrato Study.

<p>Results of Cox-regression analysis of variables associated with 6-years all-cause and cardiovascular mortality in people with type 2 diabetes of the Casale Monferrato Study.</p

Urinary Exosomal MicroRNAs in Incipient Diabetic Nephropathy

<div><p>MicroRNAs (miRNAs), a class of small non-protein-encoding RNAs, regulate gene expression via suppression of target mRNAs. MiRNAs are present in body fluids in a remarkable stable form as packaged in microvesicles of endocytic origin, named exosomes. In the present study, we have assessed miRNA expression in urinary exosomes from type 1 diabetic patients with and without incipient diabetic nephropathy. Results showed that miR-130a and miR-145 were enriched, while miR-155 and miR-424 reduced in urinary exosomes from patients with microalbuminuria. Similarly, in an animal model of early experimental diabetic nephropathy, urinary exosomal miR-145 levels were increased and this was paralleled by miR-145 overexpression within the glomeruli. Exposure of cultured mesangial cells to high glucose increased miR-145 content in both mesangial cells and mesangial cells-derived exosomes, providing a potential mechanism for diabetes-induced miR-145 overexpression. In conclusion, urinary exosomal miRNA content is altered in type 1 diabetic patients with incipient diabetic nephropathy and miR-145 may represent a novel candidate biomarker/player in the complication. </p> </div

Expression of miR-145 in experimental diabetes.

<p>MiR-145 levels were measured by qRT-PCR in both urinary exosomes (<b>A</b>) and isolated glomeruli (<b>B</b>) from diabetic (DM) and control (ND) mice as described in the Methods. Results, corrected for the expression of housekeeping U6 snRNA, are shown in the graphs (*p<0.001 DM vs ND). </p

Expression of miR-145 in human mesangial cells.

<p>(<b>A</b>) Expression of STAT-1, a known miR-145 target, was assessed by immunoblotting in total protein extracts from mesangial cells transfected with either miR-145 mimic or scramble oligonucleotides. Tubulin was used as loading control. Results are depicted in the graph (*p<0.05) and a representative immunoblot is shown. (<b>B</b>) Human mesangial cells were exposed to increasing (6.8, 15, and 25 mM) glucose concentrations for 4,6,12 and 24 hours. Total RNA was extracted and levels of miR-145 measured by qRT-PCR (*p<0.01) 15 and 25 mM glucose vs. 6.8 mM glucose at all time points). (<b>C</b>) Human mesangial cells were exposed to either normal (6.8 mM-NG) or high (25 mM-HG) glucose concentrations for 24 hours. Exosomes were isolated from the supernatants by ultracentrifugation as described in the Methods. Total RNA was extracted and levels of miR-145 measured by qRT-PCR (*p<0.001 HG vs. NG).</p