miR-25 and miR-92b regulate insulin biosynthesis and pancreatic ß-cell apoptosis.

PURPOSE: Pancreatic ß-cell failure is a central hallmark of the pathogenesis of diabetes mellitus; however, the molecular basis underlying chronic inflammation-caused ß-cell failure remains unclear. This study reported here specifically assessed the association between miR-25/miR-92b family and ß-cell failure in diabetes. METHODS: IL-1ß and two additional ER stress activators, palmitate and tunicamycin were applied to evaluate the expression level miR-25 by Taqman® RT-PCR. Glucose- and potassium-stimulated insulin secretion assays were performed to assess ß-cell function. Dual-luciferase activity, and western blotting assays were utilized for miR-25 target gene verification. CCK-8 and TUNEL staining were used to evaluate ß-cell viability and apoptosis. RESULTS: miRNA ChIP identified the increased level of miR-25 in INS-1 cells by IL-1ß treatment. Expression levels of miR-25 were significantly upregulated with the treatment of IL-1ß, palmitate or tunicamycin in both INS-1 cells and human islets. Ectopic elevation of miR-25 recapitulated most featured ß-cell defects caused by IL-1ß, including inhibition of insulin biosynthesis and increased ß-cell apoptosis. These detrimental effects of miR-25 relied on its seed sequence recognition and repressed expression of its target genes Neurod1 and Mcl1. The miR-25/NEUROD1 axis reduced insulin biosynthesis via transcriptional regulation of ß-cell specific genes. The miR-25/MCL1 axis caused ß-cell apoptosis in a CASPASE-3/PARP1-dependent manner. Comparable impairments were generated by miR-92b and miR-25, emphasizing the redundant biological roles of miRNA family members with the same seed sequence. CONCLUSION: MiR-25/miR-92b family plays a major role in ß-cell failure occurring under inflammation and diabetes states.

Serum uric acid levels and decreased estimated glomerular filtration rate in patients with type 2 diabetes: A cohort study and meta-analysis.

BACKGROUND: Epidemiological studies suggest that elevated serum uric acid (SUA) is associated with heightened incident kidney disease in both the general population and the type 2 diabetes (T2D) cases, although the results were not entirely consistent. METHODS: We investigated prospective association between SUA levels and estimated glomerular filtration (eGFR) decline risk (eGFR <60 mL min-1 1.73 m-2 ) among 3123 T2D in the Dongfeng-Tongji cohort and further examined this association with a meta-analysis. Generalize linear model was used to assess the associations of SUA with eGFR decline in the cohort. In the meta-analysis, we used both fix-effects and random-effects models to calculate the overall effect estimate. RESULTS: During 5-year follow-up, 303 (9.7%) patients developed eGFR decline. After multiple adjustments, the relative risk (RR) (95% CI) of eGFR decline was 1.55 (1.07, 2.26) when comparing the highest with the lowest sex-specific uric acid quartile. A 100 µmol/L increment of SUA level was significantly associated with 21% increased risk of eGFR decline. The SUA-eGFR decline association was more evident in men, but not in women. In meta-analysis, the pooled RR (95% CI) was 2.33 (1.66, 3.25) for developing eGFR decline when comparing the highest with the lowest levels of uric acid. A 100 µmol/L increment of SUA level was significantly associated with a 33% increased risk of eGFR decline. CONCLUSIONS: Our results indicate an independent and significant positive association between higher SUA and increased risk of developing eGFR decline among T2D cases.