Urinary exosomal microRNAs in incipient diabetic nephropathy.

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.

NH2-terminal probrain natriuretic peptide is associated with diabetes complications in the EURODIAB Prospective Complications Study: the role of tumor necrosis factor-α.

OBJECTIVE: Circulating levels of NH(2)-terminal probrain natriuretic peptide (NT-proBNP), a marker of acute heart failure, are associated with increased risk of cardiovascular disease (CVD) in the general population. However, there is little information on the potential role of NT-proBNP as a biomarker of vascular complications in type 1 diabetic patients. We investigated whether serum NT-proBNP levels were associated with micro- and macrovascular disease in type 1 diabetic subjects. RESEARCH DESIGN AND METHODS: A cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 507 type 1 diabetic patients was performed. Case subjects (n = 345) were defined as those with one or more complications of diabetes; control subjects (n = 162) were those with no evidence of any complication. We measured NT-proBNP levels by a two-site sandwich electrochemiluminescence immunoassay and investigated their associations with complications. RESULTS: Mean NT-proBNP levels were significantly higher in case than in control subjects. In logistic regression analyses, NT-proBNP values >26.46 pg/mL were independently associated with a 2.56-fold increased risk of all complications. Odds ratios of CVD (3.95 [95% CI 1.26-12.35]), nephropathy (4.38 [1.30-14.76]), and distal symmetrical polyneuropathy (4.32 [1.41-13.23]) were significantly increased in patients with NT-proBNP values in the highest quartile (>84.71 pg/mL), independently of renal function and known risk factors. These associations were no longer significant after inclusion of TNF-α into the model. CONCLUSIONS: In this large cohort of type 1 diabetic subjects, we found an association between NT-proBNP and diabetic micro- and macrovascular complications. Our results suggest that the inflammatory cytokine TNF-α may be involved in this association.

QTc interval prolongation is independently associated with severe hypoglycemic attacks in type 1 diabetes from the EURODIAB IDDM complications study.

OBJECTIVE: Our aim was to assess whether severe hypoglycemic attacks were cross-sectionally associated with abnormalities of the QTc interval in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: The study included 3,248 type 1 diabetic patients from the EURODIAB IDDM Complications Study. Severe hypoglycemia was defined as an attack serious enough to require the help of another person. A corrected QTc interval (QTc) >0.44 s was considered abnormally prolonged. RESULTS: Nineteen percent of patients declared one to two attacks, and 13.2% of patients had three or more attacks. Prevalence of QTc prolongation was greater in patients who experienced three or more hypoglycemic attacks. Logistic regression analysis showed that the frequency of severe hypoglycemia was independently associated with QTc prolongation, even after adjustment for diabetes complications, including autonomic neuropathy (odds ratio 1.27, 95% CI 1.02-1.58). CONCLUSIONS: We have provided evidence that severe hypoglycemic attacks are independently associated with a prolonged QTc interval in type 1 diabetic patients from the EURODIAB IDDM Complications Study.