Gallic Acid Improves Diabetic Steatosis by Downregulating MicroRNA-34a-5p through Targeting NFE2L2 Expression in High-Fat Diet-Fed db/db Mice.

Type 2 diabetes mellitus (T2DM) has become epidemic worldwide and is strongly associated with nonalcoholic fatty liver disease (NAFLD). The molecular mechanisms of microRNAs in NAFLD and T2DM development and the corresponding therapies remain unclear. We performed microRNA microarray validation to determine whether hepatic miR-34a-5p was significantly upregulated in db/db mice fed with a high-fat diet (HFD), a mouse model of T2DM with steatohepatitis. The potential role of miR-34a-5p and gallic acid (GA) in regulating hepatic lipid metabolism and diabetic steatosis was explored. GA improved the activities of antioxidant enzymes and suppressed lipid accumulation in the HFD-induced steatotic liver of db/db mice. In vitro, the silencing of miR-34a-5p in hepatocyte HepG2 cells ameliorated high glucose + oleic acid/palmitic acid mixture-induced accumulation of cellular triglycerides. We identified nuclear factor erythroid-derived 2-like 2 (NFE2L2) as a direct target of miR-34a-5p. Reduction in intracellular triglyceride and the expression levels of sterol regulatory element-binding protein 1 and fatty acid synthase by GA were mediated by the inhibition of miR-34a-5p expression in HepG2 cells. The findings suggest that GA improves hepatic lipogenesis by downregulating miR-34a-5p by suppressing NFE2L2 expression, indicating the potential therapeutic role of GA or an NFE2L2-activating agent in diabetic fatty liver disease.

Effects of statins on all-cause mortality at different low-density-lipoprotein cholesterol levels in Asian patients with type 2 diabetes.

OBJECTIVE: To investigate the effects of statins on all-cause mortality risk at different low-density lipoprotein cholesterol (LDL-C) levels, and to compare the mortality risk between statin users and non-users with identical LDL-C levels in a type 2 diabetes cohort. METHODS: In total, 10,582 outpatients aged ≥18 years with type 2 diabetes mellitus (T2DM) between 2009 and 2012 were enrolled in this retrospective cohort study in central Taiwan. All-cause mortality events were followed up until the end of 2014. According to the medical records during the follow-up period, the patients were classified into statin (+) and statin (-) groups. Patients were categorized into different LDL-C segments based on their mean LDL-C levels during the 2.8-year follow-up. RESULTS: Non-cardiovascular mortality accounted for more than half the deaths. Overall, statin therapy significantly reduced the all-cause mortality risk in both univariable and multivariable models (hazard ratios = 0.39 and 0.38, respectively). Sub-group analyses showed that the lowest mortality risk occurred in the 80-89 mg/dL segment in the statin (-) group and in the 90-99 mg/dL segment in the statin (+) group. Statin therapy significantly reduced the mortality risk at all LDL-C levels except for low LDL-C (<60 mg/dL). CONCLUSIONS: In addition to reducing LDL-C levels, statin therapy reduced all-cause mortality risk in Taiwanese patients with T2DM. Statins further reduced the mortality risk at most LDL levels. However, at low LDL-C levels, the positive effects of statins may have been nullified.

Higher serum total bilirubin concentration is associated with lower risk of renal insufficiency in an adult population.

BACKGROUND: Chronic inflammation is proposed to play a central role in the pathogenesis of chronic kidney disease (CKD), and serum bilirubin has antioxidant and anti-inflammatory effects. We investigated the association between serum total bilirubin (Tb) concentration and renal function in an adult population. METHODS: We conducted a cross-sectional study and collected anthropometric measurements, fasting blood tests, lifestyle habits and medical history of 3876 subjects attending a health examination. Renal insufficiency was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) calculated by using the CKD-EPI equation. RESULTS: Serum Tb concentrations were higher in subjects without renal insufficiency than in those with renal insufficiency. Multivariable linear regression analysis showed that Tb concentration was positively associated with eGFR after adjusting for important CKD risk factors (P=0.04). Multivariable logistic regression analysis also revealed that higher Tb concentration (each increment of 1.71 µmol/L) (0.1 mg/dL) was associated with a reduced risk of renal insufficiency: odds ratios were 0.94 (P=0.005) for men and 0.90 (P=0.015) for women, respectively. When subjects were divided into quartiles of serum Tb, multivariable-adjusted odds ratios for renal insufficiency comparing the fourth to the first Tb quartile were 0.49 (P=0.001) for men and 0.35 (P=0.003) for women. A stepwise exclusion of subjects, first those with possible liver disease and second, those with CKD stage 4 and 5, showed consistent results. CONCLUSION: Higher serum Tb concentration was associated with lower risk of renal insufficiency, regardless of other conventional CKD risk factors.