Jang Yel Shin

Serum adipocyte fatty acid-binding protein levels are associated with nonalcoholic fatty liver disease in type 2 diabetic patients.

OBJECTIVE Adipocyte fatty acid-binding protein (A-FABP) is a major cytoplasmic protein in adipocytes and macrophages and is closely associated with metabolic syndrome, type 2 diabetes, and atherosclerosis. Here, we investigated whether A-FABP was associated with nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes. RESEARCH DESIGN AND METHODS We enrolled 181 type 2 diabetic patients. Clinical and biochemical metabolic parameters were measured. The severity of NAFLD was measured by ultrasound. A-FABP, adiponectin, and retinol-binding protein-4 (RBP-4) were determined by enzyme-linked immunosorbent assay. RESULTS A-FABP levels, defined as more than a moderate degree of fatty liver compared with men, those without metabolic syndrome, and those without NAFLD, were higher in women, patients with metabolic syndrome, and patients with overt NAFLD, respectively. Adiponectin was decreased according to the severity of NAFLD, but RBP-4 showed no difference. Age- and sex-adjusted A-FABP showed positive correlations with BMI, waist-to-hip ratio, waist circumference, triglycerides, gamma-glutamyltransferase, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), A1C, and C-reactive protein (CRP) but showed negative correlation with HDL cholesterol. The odds ratio (OR) for the risk of overt NAFLD with increasing levels of sex-specific A-FABP was significantly increased (OR 2.90 [95% CI 1.15-7.29] vs. 7.87 [3.20-19.38]). The OR in the highest tertile of A-FABP remained significant after adjustments for BMI, waist circumference, A1C, HDL cholesterol, triglycerides, HOMA-IR, CRP, and hepatic enzymes. CONCLUSIONS Our study demonstrates that serum A-FABP is significantly associated with NAFLD in type 2 diabetes, independent of BMI, waist circumference, HOMA-IR, A1C, triglycerides, HDL cholesterol, and CRP.

Serum sex hormone-binding globulin levels are independently associated with nonalcoholic fatty liver disease in people with type 2 diabetes

AIM To clarify the association between serum sex hormone-binding globulin (SHBG) levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes. METHODS Two hundred seventy nine patients with type 2 diabetes were consecutively enrolled and metabolic parameters were checked. High-grade NAFLD was defined as moderate or severe fatty liver disease, measured using liver ultrasound. SHBG, testosterone, and estradiol levels were measured. RESULTS SHBG levels were lower in patients with high-grade NAFLD than in those with normal ultrasound and decreased significantly based on the severity of fatty liver disease. SHBG levels were negatively correlated with hypertension, body mass index (BMI), waist circumference, high-grade NAFLD, triglycerides, alanine aminotransferase (ALT), γ-glutamyltransferase (γGT), homeostasis model assessment-estimated insulin resistance (HOMA-IR), and C-reactive protein (CRP) and were positively correlated with testosterone and estradiol levels. The odds ratios (ORs) predicting the presence of high-grade NAFLD in men and women decreased significantly with increasing SHBG tertile. The ORs remained significant even after further adjusting for BMI, waist circumference, hypertension, triglycerides, γGT, ALT, CRP, HOMA-IR, testosterone, estradiol, and anti-diabetic medications. CONCLUSIONS Serum SHBG levels were independently associated with the high-grade NAFLD in patients with type 2 diabetes.

Elevated serum γ-glutamyltransferase levels are independently associated with insulin resistance in non-diabetic subjects

We investigated the associations of gamma-glutamyltransferase (GGT) with visceral obesity, adiponectin and retinol binding protein 4 (RBP4), and insulin resistance (IR) and compared these associations with other liver enzymes in non-diabetes. We enrolled 94 healthy subjects 30-69 years old. Clinical and biochemical metabolic parameters were measured. Adiponectin and RBP4 were determined by ELISA. IR was examined by HOMA-IR. Visceral fat was determined by computed tomography scan. GGT and alanine aminotransferase (ALT) were positively correlated with waist circumference (WC), waist-to-hip ratio (WHR), visceral fat area (VFA), visceral-to-subcutaneous fat area ratio (VSR), HOMA-IR, and RBP4, but was negatively correlated with adiponectin (p<0.05). In multivariate regression, GGT was associated with male sex, HOMA-IR, and RBP4 (R(2)=0.48, p<0.05) and ALT was associated with HOMA-IR (R(2)=0.22, p<0.05). By logistic regression after adjusted for age and sex, the odds ratio (OR) for IR in the highest tertile of sex-specific GGT and ALT were significantly increased compared to those in the lowest [OR (95% CI); 6.90 (2.08-22.82), 3.38 (1.08-10.57), respectively]. However, these relationships after further adjustments for RBP4, adiponectin, VFA, VSR, WHR, WC, TG, and HDL remained significant in only GGT. In conclusions, GGT may be a useful marker of IR in non-diabetes.

Peroxisome proliferator-activated receptor δ agonist attenuates hepatic steatosis by anti-inflammatory mechanism

Although peroxisome proliferator receptor (PPAR)-α and PPAR-γ agonist have been developed as chemical tools to uncover biological roles for the PPARs such as lipid and carbohydrate metabolism, PPAR-δ has not been fully investigated. In this study, we examined the effects of the PPAR-δ agonist GW0742 on fatty liver changes and inflammatory markers. We investigated the effects of PPAR-δ agonist GW0742 on fatty liver changes in OLETF rats. Intrahepatic triglyceride contents and expression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1) and also, PPAR-γ coactivator (PGC)-1α gene were evaluated in liver tissues of OLETF rats and HepG2 cells after GW0742 treatment. The level of TNF-α and MCP-1 was also examined in supernatant of Raw264. 7 cell culture. To address the effects of GW0742 on insulin signaling, we performed in vitro study with AML12 mouse hepatocytes. Rats treated with GW0742 (10 mg/kg/day) from 26 to 36 weeks showed improvement in fatty infiltration of the liver. In liver tissues, mRNA expressions of TNF-α, MCP-1, and PGC-1α were significantly decreased in diabetic rats treated with GW0742 compared to diabetic control rats. We also observed that GW0742 had inhibitory effects on palmitic acid-induced fatty accumulation and inflammatory markers in HepG2 and Raw264.7 cells. The expression level of Akt and IRS-1 was significantly increased by treatment with GW0742. The PPAR-δ agonist may attenuate hepatic fat accumulation through anti-inflammatory mechanism, reducing hepatic PGC-1α gene expression, and improvement of insulin signaling.

Association between alcohol intake amount and prevalence of metabolic syndrome in Korean rural male population.

Moderate alcohol consumption is known to be associated with a reduced risk of cardiovascular disease and mortality. However, few studies reported that long-term alcohol drinking may increase the prevalence of central obesity, and cardiovascular disease. We examined the association between metabolic syndrome, nutritional factors and alcohol intake amount in Korean male rural population. We performed a cross-sectional analysis on data from Korean Rural Genomic Cohort (KRGC) study. We used multiple logistic regression analysis to estimate the adjusted odds ratio of metabolic syndrome according to alcohol intake amount categories (never, 0-16 g/day, 16-40 g/day, and >40 g/day). The age adjusted odds ratio for the prevalence of metabolic syndrome was significantly increased in the quartile with the highest alcohol consumption compared to the non-alcohol drinking group (1.33; C.I., 1.11-1.59). These results were similar in the high energy intake group, but not in the low energy intake group. Waist circumference, blood pressure, and serum triglyceride levels were significantly higher in the quartile with the highest alcohol consumption compared to the non-alcohol drinking group. These results suggest that large alcohol consumption is associated with metabolic syndrome and may be a modifiable risk factor of metabolic syndrome especially in subjects with high calorie intake.

Bone mineral density and bone turnover markers in patients on long-term suppressive levothyroxine therapy for differentiated thyroid cancer

Purpose Current management for patients with differentiated thyroid cancer includes near total thyroidectomy and radioactive iodine therapy followed by administration of supraphysiological doses of levothyroxine (L-T4). Although hyperthyroidism is a well known risk factor for osteoporosis, the effects of L-T4 treatment on bone mineral density (BMD) in patients with thyroid cancer do not appear to be as significant as with endogenous hyperthyroidism. In this study, we evaluated the impact of long-term suppressive therapy with L-T4 on BMD and bone turn over markers in Korean female patients receiving L-T4 suppressive therapy. Methods We enrolled 94 female subjects (mean age, 50.84 ± 11.43 years) receiving L-T4 after total or near total thyroidectomy and radioactive iodine therapy for thyroid cancer (mean follow-up period, 12.17 ± 4.27 years). The subjects were divided into three groups by thyroid stimulating hormone (TSH) level (group 1 with TSH level ≤0.001 µIU/mL, group 2 with TSH level between 0.001 and 0.17 µIU/mL, group 3 with TSH level >0.17 µIU/mL) and four groups by quartile of free T4 level. L-T4 dosage, BMD (examined by dual-energy x-ray absorptiometry), and bone turnover markers were evaluated according to TSH and free T4 levels. Results No significant decrease was detected in BMD or bone turnover markers according to TSH level or free T4 level. Also, the prevalence of osteoporosis and osteopenia was not different among groups. Conclusion Long-term L-T4 suppressive therapy after thyroid cancer management did not affect bone density or increase the prevalence of osteoporosis even though TSH levels were supraphysiologically suppressed.

Gender-specific association between urinary sodium excretion and body composition: Analysis of the 2008-2010 Korean National Health and Nutrition Examination Surveys

OBJECTIVE Few studies have reported the relationship between sarcopenia and the estimated amount of sodium excreted in 24 h, as measured by the spot urine test (E24UNA), in a community-dwelling cohort. We investigated the gender specific association between E24UNA values and body composition indices. MATERIALS AND METHODS Data from a total of 7162 participants (3545 men and 3617 postmenopausal women) aged 45 years or older were obtained from multiple Korea National Health and Nutrition Examination Surveys (2008-2010) and analyzed. The total amount of sodium excreted in the urine in a 24-h period was estimated with spot urine specimens. Sarcopenia was defined as an appendicular skeletal muscle mass divided by body weight (ASM/Wt) that was less than 1 standard deviation below the sex-specific mean for young adults. RESULTS E24UNA values were positively correlated with body mass index, waist circumference, total fat mass, and blood pressure; in contrast, E24UNA values were negatively correlated with ASM/Wt in both sexes. Compared with those in the lowest E24UNA tertile, participants in the highest E24UNA tertile were at higher risk for sarcopenia (men: odds ratio (OR)=1.3 [95% confidence interval (CI)=1.07-1.59]; women: OR=1.41 [95% CI=1.16-1.73]). Further classification of subjects with sarcopenia into sarcopenic obese and sarcopenic nonobese groups revealed that the highest E24UNA values were found in the sarcopenic obese group; this difference was statistically significant. The next highest levels were found in the sarcopenic nonobese group, followed by the nonsarcopenic group. This trend was observed in both sexes. CONCLUSION High E24UNA values were independently associated with both sarcopenia and obesity in Korean individuals older than 45 years. These results suggest that high salt intake may have a deleterious effect on body composition.

Optimal Waist Circumference Cutoff Values for Metabolic Syndrome Diagnostic Criteria in a Korean Rural Population

The Korean Society for the Study of Obesity (KSSO) has defined the waist circumference cutoff value of central obesity as 90 cm for men and 85 cm for women. The purpose of this investigation was to determine the corresponding waist circumference values. A total of 3,508 persons in the Korean Rural Genomic Cohort Study were enrolled in this survey. Receiver operating characteristic (ROC) curve analysis was used to find appropriate waist circumference cutoff values in relation to insulin resistance determined by homeostasis model assessment for insulin resistance (HOMA-IR), body mass index (BMI), and components of metabolic syndrome. The optimal waist circumference cutoff values were 87 cm for men and 83 cm for women by ROC analysis to HOMA-IR and 86 cm for men and 83 cm for women by ROC analysis to value with more than two components of metaobolic syndrome. By using a BMI ≥25 kg/m2, 86 cm for men and 82 cm for women were optimal waist circumference cutoff values. In this study, we suggest that the most reasonable waist circumference cutoff values are 86-87 cm for men and 82-83 cm for women.

Role of HbA1c in the Screening of Diabetes Mellitus in a Korean Rural Community

Background Recently, the measurement of glycated hemoglobin (HbA1c) was recommended as an alternative to fasting plasma glucose or oral glucose tolerance tests for diagnosing diabetes mellitus (DM). In this study, we analyzed HbA1c levels for diabetes mellitus screening in a Korean rural population. Methods We analyzed data from 10,111 subjects from a Korean Rural Genomic Cohort study and generated a receiver operating characteristic curve to determine an appropriate HbA1c cutoff value for diabetes. Results The mean age of the subjects was 56.3±8.1 years. Fasting plasma glucose and 2-hour plasma glucose after 75 g oral glucose tolerance tests were 97.5±25.6 and 138.3±67.1 mg/dL, respectively. The mean HbA1c level of the subjects was 5.7±0.9%. There were 8,809 non-DM patients (87.1%) and 1,302 DM patients (12.9%). A positive relationship between HbA1c and plasma glucose levels and between HbA1c and 2-hour plasma glucose levels after oral glucose tolerance tests was found in a scatter plot of the data. Using Youdens index, the proper cutoff level of HbA1c for diabetes mellitus screening was 5.95% (sensitivity, 77%; specificity, 89.4%). Conclusion Our results suggest that the optimal HbA1c level for DM screening is 5.95%.

Effects of spironolactone and losartan on diabetic nephropathy in a type 2 diabetic rat model.

Background While there is an evidence that the anti-inflammatory properties of spironolactone can attenuate proteinuria in type 2 diabetes, its effects on vascular endothelial growth factor (VEGF) expression in diabetic nephropathy have not been clearly defined. In this study, we examined the effects of spironolactone, losartan, and a combination of these two drugs on albuminuria, renal VEGF expression, and inflammatory and oxidative stress markers in a type 2 diabetic rat model. Methods Thirty-three Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats were divided into four groups and treated with different medication regimens from weeks 25 to 50; OLETF diabetic controls (n=5), spironolactone-treated (n=10), losartan-treated (n=9), and combination of spironolactone- and losartan-treated (n=9). Results At week 50, the albumin-to-creatinine ratio was significantly decreased in the losartan and combination groups compared to the control OLETF group. No decrease was detected in the spironolactone group. There was a significant reduction in renal VEGF, transforming growth factor (TGF)-β, and type IV collagen mRNA levels in the spironolactone- and combination regimen-treated groups. Twenty-four hour urine monocyte chemotactic protein-1 levels were comparable in all four groups but did show a decreasing trend in the losartan and combination regimen groups. Twenty-four hour urine malondialdehyde levels were significantly decreased in the spironolactone- and combination regimen-treated groups. Conclusion These results suggest that losartan alone and a combined regimen of spironolactone and losartan could ameliorate albuninuria by reducing renal VEGF expression. Also, simultaneous treatment with spironolactone and losartan may have protective effects against diabetic nephropathy by decreasing TGF-β and type IV collagen expression and by reducing oxidative stress in a type 2 diabetic rat model.