Ji Cheol Bae

Exendin-4 Improves Steatohepatitis by Increasing Sirt1 Expression in High-Fat Diet-Induced Obese C57BL/6J Mice

The effects of exendin-4 on Sirt1 expression as a mechanism of reducing fatty liver have not been previously reported. Therefore, we investigated whether the beneficial effects of exendin-4 treatment on fatty liver are mediated via Sirt1 in high-fat (HF) diet-induced obese C57BL/6J mice and related cell culture models. Exendin-4 treatment decreased body weight, serum free fatty acid (FA), and triglyceride levels in HF-induced obese C57BL/6J mice. Histological analysis showed that exendin-4 reversed HF-induced hepatic accumulation of lipids and inflammation. Exendin-4 treatment increased mRNA and protein expression of Sirt1 and its downstream factor, AMPK, in vivo and also induced genes associated with FA oxidation and glucose metabolism. In addition, a significant increase in the hepatic expression of Lkb1 and Nampt mRNA was observed in exendin-4-treated groups. We also observed increased expression of phospho-Foxo1 and GLUT2, which are involved in hepatic glucose metabolism. In HepG2 and Huh7 cells, mRNA and protein expressions of GLP-1R were increased by exendin-4 treatment in a dose-dependent manner. Exendin-4 enhanced protein expression of Sirt1 and phospho-AMPKα in HepG2 cells treated with 0.4 mM palmitic acid. We also found that Sirt1 was an upstream regulator of AMPK in hepatocytes. A novel finding of this study was the observation that expression of GLP-1R is proportional to exendin-4 concentration and exendin-4 could attenuate fatty liver through activation of Sirt1.

Combined Effect of Nonalcoholic Fatty Liver Disease and Impaired Fasting Glucose on the Development of Type 2 Diabetes: A 4-year retrospective longitudinal study

OBJECTIVE To evaluate whether there is a difference in the association between nonalcoholic fatty liver disease (NAFLD) and incident diabetes based on the presence of impaired fasting glucose. RESEARCH DESIGN AND METHODS A total of 7,849 individuals (5,409 men and 2,440 women) without diabetes, who underwent comprehensive health check-ups annually for 5 years, were categorized into four groups by the presence of impaired fasting glucose and NAFLD at baseline. The association between NAFLD and incident diabetes was evaluated separately in groups with normal and impaired fasting glucose. RESULTS For 4 years, the incidence of diabetes in the NAFLD group was 9.9% compared with 3.7% in the non-NAFLD group, with multivariable-adjusted hazard ratio of 1.33 (95% CI 1.07–1.66). However, this higher risk for diabetes only existed in the impaired fasting glucose group. CONCLUSIONS Our study suggests that NAFLD has an independent and additive effect on the development of diabetes under conditions of impaired insulin secretion.

Impact of Nonalcoholic Fatty Liver Disease on Insulin Resistance in Relation to HbA1c Levels in Nondiabetic Subjects

OBJECTIVES:A cross-sectional analysis was conducted in healthy, nondiabetic Korean adults to assess the prevalence of nonalcoholic fatty liver disease (NAFLD), to compare the prevalence of NAFLD across different glycemic ranges as assessed by glycosylated hemoglobin (HbA1c), and to examine the impact of NAFLD on insulin resistance in relation to HbA1c levels.METHODS:After rigorous exclusion criteria, the final number of subjects who participated in a comprehensive health status checkup program was 99,969. All subjects were classified into four categories with respect to HbA1c level (≤4.9, 5.0–5.4, 5.5–5.9, and 6.0–6.4%). We estimated the odds ratio (OR) for prevalence of NAFLD according to the categorized level of HbA1C and evaluated the association of NAFLD with the homeostatic model assessment of insulin resistance (HOMA-IR) in relation to the HbA1c level.RESULTS:Twenty-eight percent (n=28,130, 40.2% of the men, 10.3% of the women) of the study subjects had NAFLD. Men had a 5.83-fold (95% confidence interval 5.63–6.05) increased risk for having NAFLD than did women. The risk for NAFLD increased with increasing level of HbA1c (OR 1.44, 2.62, and 7.18) when compared with the lowest quartile (HbA1C≤4.9%). HOMA-IR increased in the NAFLD subjects as the level of HbA1c increased. The magnitude of association of HOMA-IR with HbA1c level was greater in NAFLD subjects than in non-NAFLD subjects (P<0.001 for interaction). These associations were consistent even after adjustment for body mass index and other metabolic components.CONCLUSIONS:NAFLD had an association with HbA1c level and insulin resistance in nondiabetic individuals, and these associations were independent of obesity and other metabolic components.

Regular Exercise Is Associated with a Reduction in the Risk of NAFLD and Decreased Liver Enzymes in Individuals with NAFLD Independent of Obesity in Korean Adults

Background We evaluated the association of regular physical exercise with the presence of non-alcoholic fatty liver disease (NAFLD) and liver enzymes in relation to obesity and insulin resistance. Methodology/Principal Findings A cross-sectional analysis was conducted in 72,359 healthy Korean adults without diabetes who participated in a comprehensive health check-up. Subjects who have been exercising regularly (more than 3 times per week, at least for 30 minutes each time and for consecutive 3 month) were categorized into exercise group. All subjects were categorized into deciles based on their body mass index (BMI) and we estimated the odds ratios (ORs) for having NAFLD according to exercise regularity in each decile. The diagnosis of NAFLD was based on ultrasonography findings. Individuals with NAFLD (n = 19,921) were analyzed separately to evaluate ORs for having elevated liver enzymes based on regularity of exercise. The risk for NAFLD was significantly reduced in exercise group with age- and sex-adjusted ORs of 0.53–0.72 for all BMI deciles except at BMI categories of <19.6 and 20.7–21.6 kg/m2. While no difference was seen in BMI between subjects in exercise and non-exercise group across the BMI deciles, the values of body fat percentage and metabolic risk factors differed. Among NAFLD patients, subjects in exercise group had a lower risk for having elevated liver enzymes with multivariable adjusted OR of 0.85 (95% CI 0.74–0.99, for AST) and 0.74 (95% CI 0.67–0.81, for ALT) than did subjects in non-exercise group. Conclusions/Significance Regular exercise was associated with a reduced risk for having NAFLD and decreased liver enzymes in patients with NAFLD, and this relationship was also independent of obesity.

Increased Risk of Type 2 Diabetes in Subjects with Both Elevated Liver Enzymes and Ultrasonographically Diagnosed Nonalcoholic Fatty Liver Disease: A 4-year Longitudinal Study

BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is reported to contribute to the development of type 2 diabetes (T2DM). We aimed to compare the risk for development of T2DM among the four groups of NAFLD status divided by the combined assessment of liver enzyme and ultrasonographic steatosis in a retrospective cohort of Korean subjects. METHODS This study included 7,849 individuals without diabetes who underwent annual health check-ups for 5 consecutive years. Based on the presence or absence of fatty liver on ultrasound and serum alanine aminotransferase (ALT) values at baseline, subjects were classified into controls, an increased ALT group without steatosis, a steatosis group with normal ALT, and a group with both steatosis and elevated ALT (combined abnormality). RESULTS During a 4-year period, the incidence of diabetes was 3.5% in the control group, 4.6% in the increased ALT group, 7.3% in the steatosis group, and 11.8% in the combined abnormality group. The hazard ratio (HR) (95% confidence interval [CI]) of incident diabetes was increased in the elevated ALT group, the steatosis group, and the combined abnormality group in a stepwise fashion. Subjects with combined abnormality group had a significantly increased HR of 1.64 (1.27-2.13) even after multivariate adjustment. CONCLUSIONS NAFLD subjects with both elevated ALT and ultrasonographic steatosis have significantly increased risk for future diabetes development.

Metabolic Health Is a More Important Determinant for Diabetes Development than Simple Obesity: A 4-Year Retrospective Longitudinal Study

Background Recent studies report the importance of metabolic health beyond obesity. The aim of this study is to compare the risk for diabetes development according to different status of metabolic health and obesity over a median follow-up of 48.7 months. Methods 6,748 non-diabetic subjects (mean age 43 years) were divided into four groups according to the baseline metabolic health and obesity status: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUHNO) and metabolically unhealthy obese (MUHO). Being metabolically healthy was defined by having less than 2 components among the 5 components, that is, high blood pressure, high fasting blood glucose, high triglyceride, low high-density lipoprotein cholesterol and being in the highest decile of homeostasis model assessment-insulin resistance (HOMA-IR) index. Obesity status was assessed by body mass index (BMI) higher than 25 kg/m2. The development of diabetes was assessed annually from self-questionnaire, fasting glucose and HbA1c. Results At baseline, 45.3% of the subjects were MHNO, 11.3% were MHO, 21.7% were MUHNO, and 21.7% were MUHO. During a median follow-up of 48.7 months, 277 subject (4.1%) developed diabetes. The hazard ratio for diabetes development was 1.338 in MHO group (95% CI 0.67–2.672), 4.321 in MUHNO group (95% CI 2.702–6.910) and 5.994 in MUHO group (95% CI 3.561–10.085) when MHNO group was considered as the reference group. These results were similar after adjustment for the changes of the risk factors during the follow-up period. Conclusion The risk for future diabetes development was higher in metabolically unhealthy subgroups compared with those of metabolically healthy subjects regardless of obesity status.

Co‐Transplantation of Bone Marrow‐Derived Endothelial Progenitor Cells Improves Revascularization and Organization in Islet Grafts

Bone marrow‐derived early endothelial progenitor cells (BM‐EPCs) are a clinical tool for enhancing revascularization. However, the therapeutic efficacy of co‐transplantation of BM‐EPC with islets has not been investigated. In this study, marginal mass islets were co‐transplanted with or without BM‐EPCs under the kidney capsules of syngeneic streptozotocin‐induced diabetic mice. Using green fluorescent protein transgenic (GFP‐Tg) mice as BM‐EPC and islet donors or recipients, the role of EPCs in revascularization was assessed for graft morphology, vascular density and fate of EPCs by immunohistochemistry. Islet‐EPC co‐transplantation improved the outcome of islet transplantation as measured by glucose tolerance, serum insulin level and diabetes reversal rate, compared with transplantation of islets alone. Between groups, the morphology of islet grafts showed significant differences in size and composition of grafted endocrine tissues. Significantly more vessel density derived from donors and recipients was detected with islet‐EPC co‐transplantation. Abundant GFP‐Tg mice‐derived BM‐EPCs (GFP‐EPCs) were observed in or around islet grafts and incorporated into CD31‐positive capillaries. Remaining GFP‐EPCs expressed VEGF. In conclusion, co‐transplantation of islets with BM‐EPCs could improve the outcome of marginal mass islet transplantation by promoting revascularization and preserving islet morphology.

Non-HDL-cholesterol/HDL-cholesterol is a better predictor of metabolic syndrome and insulin resistance than apolipoprotein B/apolipoprotein A1

BACKGROUND The ratio of apolipoprotein B (apoB) to apolipoprotein A1 (apoA1) has been reported to be associated with metabolic syndrome (MetS) and insulin resistance (IR). Non-HDL-C is regarded as a surrogate marker for apoB in routine clinical practice. However, it is unclear whether the ratio of non-HDL-C to HDL-C is an equal or a better predictor than the apoB/apoA1 ratio for the identification of MetS and IR. METHODS We performed a retrospective study of 41,821 Korean adults who participated in a routine health screening examination. Anthropometry, fasting glucose, fasting insulin, HOMA-IR, CRP, lipid profiles, apoB, and apoA1 were measured. RESULTS To compare the predictive value for MetS between different lipid ratios, we analyzed the ROC curves of apoB/apoA1 and non-HDL-C/HDL-C ratios. ROC analysis showed that the AUCs of non-HDL-C/HDL-C (0.75 [95% CI=0.74-0.76] in men and 0.84 [95% CI=0.83-0.85] in women) were significantly higher than those of apoB/apoA1 (0.66 [95% CI=0.65-0.67] in men and 0.77 [95% CI=0.76-0.78] in women). The non-HDL-C/HDL-C ratio also showed a significantly stronger association with HOMA-IR than the apoB/apoA1 ratio. The optimal cutoff value of the non-HDL-C/HDL-C ratio for detection of MetS in men was 3.39, with a sensitivity of 66.7% and a specificity of 71.8%, whereas the optimal ratio cutoff value in women was 2.89, with a sensitivity of 75.7% and a specificity of 78.1%. CONCLUSIONS Our findings indicate that the non-HDL-C/HDL-C ratio is a better marker than the apoB/apoA1 ratio for identifying IR and MetS in Koreans.

Serum uric acid: A strong and independent predictor of metabolic syndrome after adjusting for body composition

BACKGROUND Some observational studies have suggested that serum uric acid (SUA) levels are one of the determinants of the metabolic syndrome (MetS). However, previous studies reported combined results for men and women after adjusting for sex and few studies take body composition into consideration. Therefore, we performed this sex-specific longitudinal study to investigate how baseline SUA levels influence incident MetS, including body composition as an adjusting factor in a large number of subjects. METHODS A total of 14,442 participants (8715 men and 5727 women) participating in a medical health check-up program without diagnosed MetS at baseline were enrolled. Separate analyses were performed for men and women including body composition as a confounding factor. Cox proportional hazards models were used to quantify independent associations between SUA levels and incident MetS. RESULTS During 63,940person-years of follow-up, there were 4215 (2974 men, 1241 women) incident cases of MetS between 2006 and 2012. After adjustments for age, systolic BP, diastolic BP, BMI, eGFR, smoking status, TG, LDL-C, HDL-C, fasting glucose, and proportion of fat-free mass (100-fat mass, %), the hazard ratios (HR) [95% confidence interval (CI)] for incident MetS comparing the second, the third, and the fourth quartiles to the first quartile of SUA levels were 0.862 (0.770-0.965), 1.102 (0.991-1.225), and 1.246 (1.121-1.385) in men (p for trend<0.001), and 1.045 (0.862-1.266), 1.251 (1.050-1.490), and 1.321 (1.109-1.574) in women (p for trend<0.001), respectively. As a continuous variable, in fully-adjusted models, the HRs (95% CI) for incident MetS associated with each increase of 1mg/dl of SUA levels were 1.094 (1.060-1.130) in men (p<0.001) and 1.148 (1.072-1.228) in women (p<0.001), respectively. CONCLUSION We demonstrated that SUA levels are strong and independent predictors of MetS. This relationship remained significant after full adjustments for multiple associated confounders including body composition in both men and women.

Association of Lipid and Lipoprotein Profiles with Future Development of Type 2 Diabetes in Nondiabetic Korean Subjects: A 4-Year Retrospective, Longitudinal Study

CONTEXT Traditional lipid measures are known to be associated with incident type 2 diabetes. OBJECTIVE Our objective was to assess the independent association between lipid profiles and the development of type 2 diabetes in nondiabetic Korean subjects over a 4-yr period. DESIGN AND METHODS A total of 5577 Koreans without diabetes who underwent consecutive comprehensive health check-ups annually for 5 yr were enrolled. We measured concentrations of total cholesterol (TC), triglyceride (TG), apolipoprotein B (apoB), apolipoprotein A-I, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) and calculated lipid ratios. The association between incident type 2 diabetes and the initial values for lipid ratios and other lipoprotein components was examined. RESULTS Over the course of 4 yr, 330 subjects (5.9%) developed type 2 diabetes. TC, LDL-C, TG, non-HDL, apoB, apoB to apolipoprotein A-I ratio, TC to HDL ratio, TG to HDL ratio, LDL to HDL ratio and apoB to HDL ratio were associated with incident type 2 diabetes in multivariate analysis after adjustment for age and gender. Of these, the ratio of TC to HDL and apoB to HDL showed a significant association with increased risk of type 2 diabetes, compared with other lipoprotein parameters: odds ratio (1.340, 95% confidence interval 1.166-1.538; and 1.338, 95% confidence interval 1.162-1.540), respectively. The odds ratio for the development of type 2 diabetes increased significantly as the tertiles of the baseline ratio of TC to HDL and apoB to HDL increased from the first to the third tertile. CONCLUSIONS This study suggests that lipid and lipoprotein profiles can be independently associated with later development of type 2 diabetes in nondiabetic Korean adults in a longitudinal analysis.