Sunghwan Suh

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.

Glycemic Variability: How Do We Measure It and Why Is It Important?

Chronic hyperglycemia is the primary risk factor for the development of complications in diabetes mellitus (DM); however, it is believed that frequent or large glucose fluctuations may independently contribute to diabetes-related complications. Postprandial spikes in blood glucose, as well as hypoglycemic events, are blamed for increased cardiovascular events in DM. Glycemic variability (GV) includes both of these events; hence, minimizing GV can prevent future cardiovascular events. Correcting GV emerges as a target to be pursued in clinical practice to safely reduce the mean blood glucose and to determine its direct effects on vascular complications in diabetes. Modern diabetes management modalities, including glucagon-related peptide-1-based therapy, newer insulins, modern insulin pumps and bariatric surgery, significantly reduce GV. However, defining GV remains a challenge primarily due to the difficulty of measuring it and the lack of consensus regarding the optimal approach for its management. The purpose of this manuscript was not only to review the most recent evidence on GV but also to help readers better understand the available measurement options and how the various definitions relate differently to the development of diabetic complications.

Diabetes and Cancer: Is Diabetes Causally Related to Cancer?

Diabetes mellitus is a serious and growing health problem worldwide and is associated with severe acute and chronic complications. Moreover, epidemiologic evidence suggests that people with diabetes are at significantly higher risk for many forms of cancer. Several studies indicate an association between diabetes and the risk of liver, pancreas, endometrium, colon/rectum, breast, and bladder cancer. Mortality is also moderately increased in subjects with diabetes. Common risk factors such as age, obesity, physical inactivity and smoking may contribute to increased cancer risk in diabetic patients. Hyperinsulinemia most likely favors cancer in diabetic patients as insulin is a growth factor with pre-eminent metabolic as well as mitogenic effects, and its action in malignant cells is favored by mechanisms acting at both the receptor and post-receptor level. The effect of diabetes treatment drugs, aside from metformin, on cancer is not conclusive. In order to fight the perfect storm of diabetes and cancer, strategies to promote primary prevention and early detection of these conditions are urgently needed.

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.

Clinical characteristics and follow-up of Korean patients with adrenal incidentalomas.

Background/Aims We investigated the clinical characteristics and follow-up findings of subjects with adrenal incidentalomas in a single, tertiary-care hospital in South Korea. Methods The study consisted of a retrospective analysis of 282 adrenal incidentaloma patients who underwent radiographic and endocrinological evaluations at Samsung Medical Center in Seoul, South Korea, between January 2004 and July 2011. Results Most (86.2%) of the subjects were found to have nonfunctioning tumors. Functioning tumors were seen in 39 patients (13.8%). Among them, 28 (9.9%) had subclinical Cushing syndrome (SCS), six (2.1%) had pheochromocytoma, and five (1.8%) had primary hyperaldosteronism. Malignant adrenal tumors were discovered in three cases: two (0.7%) were primary adrenal cancers, and one (0.4%) was a secondary metastasis from a lung cancer. Significant risk factors for functional tumors were female gender (odds ratio [OR], 3.386; 95% confidence interval [CI], 1.611 to 7.117; p = 0.0013) and a noncontrast attenuation value of > 10 Hounsfield units (OR, 2.806; 95% CI, 1.231 to 6.397; p = 0.0141). During follow-up (mean, 22.5 months) of 72 of the patients, three (4.2%) developed hormonal changes due to functional tumors. One was confirmed as pheochromocytoma by histopathology, and the others were diagnosed with SCS and followed routinely without surgical intervention. No malignant transformation was found in these patients. Conclusions Based on these findings, initial hormonal and radiographic evaluations for adrenal incidentalomas appear to be more important than follow-up tests because functional or malignant changes are rare.

Effects of resistance training and aerobic exercise on insulin sensitivity in overweight korean adolescents: a controlled randomized trial.

Background Data on the impact of resistance training on insulin resistance in overweight or obese children are inconclusive. Methods Thirty overweight South Korean adolescents (mean age of 13.10 years) were divided by sex, and then randomly assigned to one of three treatment groups, which were the diet only (DO), diet with aerobic exercise (AE), or diet with resistance training (RT) group. Physiologic and metabolic parameters were assessed at baseline and after 12 weeks of exercise training and diet modification. Results Both exercise groups (aerobic and resistance) showed significant improvements in their insulin area under the curve and insulin sensitivity index values when compared to their baseline values while the DO group showed no significant changes in these variables. Age-, sex-, and body mass index (BMI)-adjusted intergroup comparison analyses showed a marked reduction in BMI and a significant reduction in muscle mass in the AE group when compared to the RT group and the DO group, respectively. Conclusion A 12-week exercise training program of either resistance or aerobic activity improved insulin sensitivity in overweight adolescents, although it failed to show superiority over a DO program. Aerobic exercise decreased both body weight and BMI, and it was noted that this group also had a significant reduction in muscle mass when compared to the DO group.

Risk of Bladder Cancer among Patients with Diabetes Treated with a 15 mg Pioglitazone Dose in Korea: A Multi-Center Retrospective Cohort Study

It has not yet been determined whether chronic exposure to relatively low doses of pioglitazone increases risk of bladder cancer. We aimed to assess the risk of bladder cancer associated with pioglitazone in Korean patients. This was a retrospective cohort study of diabetic patients who had ≥ 2 clinic visits between November 2005 and June 2011 at one of four tertiary referral hospitals in Korea. A prevalent case-control analysis nested within the cohort was conducted to further adjust confounders. A total of 101,953 control patients and 11,240 pioglitazone-treated patients were included, in which there were 237 and 30 cases of incidental bladder cancer (64.9 and 54.9 per 100,000 person-years; age, sex-adjusted HR 1.135, 95% confidence interval [CI] 0.769-1.677), respectively. In the prevalent case-control analysis nested within the cohort, use of pioglitazone for a duration of > 6 months, but not ever use of pioglitazone, was associated with an increased rate of bladder cancer as compared to never use of pioglitazone. In conclusion, we failed to exclude the possible association between use of pioglitazone for a duration of > 6 months and bladder cancer. Graphical Abstract

Strong correlation between glycaemic variability and total glucose exposure in type 2 diabetes is limited to subjects with satisfactory glycaemic control

AIMS This study investigated the relationship between markers of overall glucose exposure, postprandial glucose excursions and glycaemic variability in patients with type 2 diabetes mellitus (T2DM). METHODS A total of 63 patients with T2DM (mean age 56 years) were enrolled. All wore a continuous glucose monitoring system (CGMS) device for 72 h to collect data on markers of overall glucose exposure, postprandial glucose excursions and glycaemic variability parameters. RESULTS Spearmans correlation analysis revealed significant correlations between all markers of overall glucose exposure and various parameters related to glucose excursions. The percent coefficient of variation (CV) showed the strongest correlation with glycated albumin (r=0.470, P<0.01). In participants with HbA1c levels < 7.5% (n=33), almost all glycaemic markers and glycaemic variability parameters were significantly correlated with each other. Also, all postprandial glucose excursion parameters showed significant correlation with other glycaemic markers, and all markers of overall glucose exposure were significantly related to mean glucose, postprandial glucose excursions and glycaemic variability parameters (except CV). In contrast, in participants with HbA1c levels ≥ 7.5% (n=30), no parameters of postprandial glucose excursions and glycaemic variability were related to any markers of chronic glycaemia. CONCLUSION Postprandial glucose excursions may explain glycaemic variability and total glucose exposures in well-controlled T2DM patients.

Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance

BACKGROUND & AIMS Most studies on the role of STAMP2 in metabolism have used adipose tissue. Little knowledge exists concerning the role of STAMP2 in the liver, which is a metabolically central target. We hypothesized that STAMP2 is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. METHODS We examined our hypothesis using human NAFLD patient pathology samples and a high-fat diet (HFD)-induced NAFLD mouse model. The molecular mechanism underlying hepatic STAMP2-mediated lipid imbalance was explored using an oleic acid (OA)-induced NAFLD in vitro model. RESULTS Noticeably, the expression level of STAMP2 protein was reduced in the livers obtained from NAFLD patients and HFD-induced NAFLD mice. In vivo knockdown of hepatic STAMP2 by siRNA accelerated hepatic steatosis and insulin resistance in mice fed a HFD. Conversely, the delivery of adenoviral STAMP2 (Ad-STAMP2) improved hepatic steatosis in HFD-induced NAFLD mice. The expression of lipogenic or adipogenic factors was increased in both in vitro and in vivo NAFLD models but was reversed by Ad-STAMP2. Adenoviral overexpression of STAMP2 improved insulin resistance in the HFD-induced NAFLD mice. In vivo and in vitro assays demonstrated that STAMP2 modulates insulin sensitivity and glucose metabolism and that STAMP2 counteracts OA-induced insulin resistance by modulating insulin receptor substrate-1 stability. CONCLUSIONS The present study revealed that hepatic STAMP2 plays a pivotal role in preventing HFD-induced NAFLD and that STAMP2 overexpression improves hepatic steatosis and insulin resistance in NAFLD. Our findings indicate that STAMP2 may represent a suitable target for interventions targeting NAFLD.