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1.  Association between Serum Albumin, Insulin Resistance, and Incident Diabetes in Nondiabetic Subjects 
Endocrinology and Metabolism  2013;28(1):26-32.
Background
Serum albumin has been suggested to be associated with insulin resistance. We evaluated the association between serum albumin concentration and insulin resistance. We also investigated whether serum albumin level has an independent effect on the development of diabetes.
Methods
In our study, 9,029 subjects without diabetes, who underwent comprehensive health check-ups annually for 5 years, were categorized into tertiles based on their serum albumin levels at baseline. The odds ratio (OR) for the prevalence of insulin resistance, defined as the top quartile of homeostasis model assessment of insulin resistance and the presence of impaired fasting glucose and nonalcoholic fatty liver disease, was evaluated cross-sectionally. Also, the hazard ratio (HR) for incident diabetes was estimated longitudinally, according to the baseline albumin tertiles using Cox proportional hazard analysis respectively.
Results
From the lowest to the highest tertile of albumin, the multivariable-adjusted ORs of insulin resistance increased significantly in both men and women. During the mean follow-up period of nearly 4 years, 556 (6.1%) subjects progressed to diabetes. The multivariable-adjusted HR (95% confidence interval [CI]) of diabetes in men were 1, 1.09 (95% CI, 0.86 to 1.40), and 1.10 (95% CI, 0.86 to 1.41), respectively, from the lowest to the highest tertiles of baseline albumin. Corresponding values for women were 1, 1.21 (95% CI, 0.66 to 2.21), and 1.06 (95% CI, 0.56 to 2.02), respectively.
Conclusion
Our study showed that increased serum albumin level was associated with insulin resistance. However, serum albumin did not have an independent effect on the development of diabetes.
doi:10.3803/EnM.2013.28.1.26
PMCID: PMC3811792  PMID: 24396647
Serum albumin; Insulin resistance; Diabetes
2.  Relationship between Vitamin D, Parathyroid Hormone, and Bone Mineral Density in Elderly Koreans 
Journal of Korean Medical Science  2012;27(6):636-643.
There is controversy regarding definition of vitamin D inadequacy. We analyzed threshold 25-hydroxyvitamin D (25[OH]D) below which intact parathyroid hormone (iPTH) increases, and examined age- and sex-specific changes of 25(OH)D and iPTH, and association of 25(OH)D and iPTH with bone mineral density (BMD) in elderly Koreans. Anthropometric parameters, serum 25(OH)D and iPTH, lumbar spine and femur BMD by dual-energy radiography absorptiometry (DXA) were measured in 441 men and 598 postmenopausal women. iPTH increased below serum 25(OH) of 36.7 ng/mL in men, but failed to reach plateau in women. Femur neck BMD above and below threshold differed when threshold 25(OH)D concentrations were set at 15-27.5 ng/mL in men, and 12.5-20 ng/mL in postmenopausal women. Vitamin D-inadequate individuals older than 75 yr had higher iPTH than those aged ≤ 65 yr. In winter, age-associated iPTH increase in women was steeper than in summer. In conclusion, vitamin D inadequacy threshold cannot be estimated based on iPTH alone, and but other factors concerning bone health should also be considered. Older people seemingly need higher 25(OH)D levels to offset age-associated hyperparathyroidism. Elderly vitamin D-inadequate women in the winter are most vulnerable to age-associated hyperparathyroidism.
doi:10.3346/jkms.2012.27.6.636
PMCID: PMC3369450  PMID: 22690095
Vitamin D; Intact Parathyroid Hormone; Bone Density; Age; Sex
3.  Increased Risk of Diabetes Development in Subjects with the Hypertriglyceridemic Waist Phenotype: A 4-Year Longitudinal Study 
Endocrinology and Metabolism  2014;29(4):514-521.
Background
The hypertriglyceridemic waist (HTGW) phenotype is a simple and inexpensive screening parameter to identify people at increased risk of cardiovascular disease. We evaluated whether the HTGW phenotype predicts diabetes in urban Korean adults.
Methods
A total of 2,900 nondiabetic subjects (mean age 44.3 years), comprising 2,078 males (71.7%) and 822 females (28.3%) who underwent annual medical check-ups at our center between January 2005 and December 2009, were recruited. The subjects were divided into four groups according to baseline serum triglyceride (TG) level and waist circumference (WC): normal WC-normal TG (NWNT) level, normal WC-high TG level, enlarged WC-normal TG level, and enlarged WC-high TG (EWHT) level. High serum TG level was defined as ≥150 mg/dL and enlarged WC was defined as ≥90 cm for men and ≥85 cm for women. New cases of diabetes were determined according to questionnaires filled in by participants and the diagnostic criteria of the American Diabetes Association. Cox proportional hazards model analysis was used to assess the association of HTGW phenotype with the incidence of diabetes.
Results
A total of 101 (3.5%) new diabetes cases were diagnosed during the study period. The EWHT group had a higher incidence of diabetes (8.3%) compared with the NWNT group (2.2%). The adjusted hazard ratio for diabetes for subjects with the EWHT phenotype at baseline was 4.113 (95% confidence interval [CI], 2.397 to 7.059) after adjustment for age, and 2.429 (95% CI, 1.370 to 4.307) after adjustment for age, sex, total cholesterol, systolic blood pressure, and alcohol drinking history. It was attenuated by inclusion of baseline fasting glucose level in the model.
Conclusion
Subjects with the HTGW phenotype showed the highest risk of incident diabetes. This tool could be useful for identifying individuals at high risk of diabetes.
doi:10.3803/EnM.2014.29.4.514
PMCID: PMC4285031  PMID: 25325274
Hypertriglyceridemic waist phenotype; Hypertriglyceridemia; Waist circumference; Diabetes; Metabolic syndrome
4.  Activation of AMP-Activated Protein Kinase Attenuates Tumor Necrosis Factor-α-Induced Lipolysis via Protection of Perilipin in 3T3-L1 Adipocytes 
Endocrinology and Metabolism  2014;29(4):553-560.
Background
Tumor necrosis factor (TNF)-α and AMP-activated protein kinase (AMPK) are known to stimulate and repress lipolysis in adipocytes, respectively; however, the mechanisms regulating these processes have not been completely elucidated.
Methods
The key factors and mechanism of action of TNF-α and AMPK in lipolysis were investigated by evaluating perilipin expression and activity of protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 α (eIF2α) by Western blot and an immunofluorescence assay in 24-hour TNF-α-treated 3T3-L1 adipocytes with artificial manipulation of AMPK activation.
Results
Enhancement of AMPK activity by the addition of activator minoimidazole carboxamide ribonucleotide (AICAR) suppressed TNF-α-induced lipolysis, whereas the addition of compound C, an inhibitor of AMPK phosphorylation, enhanced lipolysis. Perilipin, a lipid droplet-associated protein, was decreased by TNF-α and recovered following treatment with AICAR, showing a correlation with the antilipolytic effect of AICAR. Significant activation of PERK/eIF2α, a component of the unfolded protein response signaling pathway, was observed in TNF-α or vesicle-treated 3T3-L1 adipocytes. The antilipolytic effect and recovery of perilipin expression by AICAR in TNF-α-treated 3T3-L1 adipocytes were significantly diminished by treatment with 2-aminopurine, a specific inhibitor of eIF2α.
Conclusion
These data indicated that AICAR-induced AMPK activation attenuates TNF-α-induced lipolysis via preservation of perilipin in 3T3-L1 adipocytes. In addition, PERK/eIF2α activity is a novel mechanism of the anti-lipolytic effect of AICAR.
doi:10.3803/EnM.2014.29.4.553
PMCID: PMC4285046  PMID: 25325265
AMP-activated protein kinases; Lipolysis; Perilipin; PERK/eIF2α; Adipocytes
5.  Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture 
Journal of medical genetics  2013;50(4):212-219.
Background
Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population.
Methods
Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study.
Results
In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF (rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59×10−8; OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis.
Conclusions
Our findings provide new insights into the genetic architecture underlying OF in East Asians.
doi:10.1136/jmedgenet-2012-101156
PMCID: PMC4169276  PMID: 23349225
6.  Age Is the Strongest Effector for the Relationship between Estimated Glomerular Filtration Rate and Coronary Artery Calcification in Apparently Healthy Korean Adults 
Endocrinology and Metabolism  2014;29(3):312-319.
Background
Chronic kidney disease (CKD) is considered one of the most common risk factors for cardiovascular disease. Coronary artery calcification (CAC) is a potential mechanism that explains the association between renal function and cardiovascular mortality. We aimed to evaluate the association between renal function and CAC in apparently healthy Korean subjects.
Methods
A total of 23,617 participants in a health-screening program at Kangbuk Samsung Hospital were included in the study. Estimated glomerular filtration rate (eGFR) was assessed using the Cockcroft-Gault equation. Coronary artery calcium score (CACS) was measured via multidetector computed tomography. Subjects were divided into three groups according to the CKD Staging system with eGFR grade: stage 1, eGFR ≥90 mL/min/1.73 m2; stage 2, eGFR 60 to 89 mL/min/1.73 m2; and stage 3, eGFR 30 to 59 mL/min/1.73 m2.
Results
The mean age of the participants was 41.4 years and the mean eGFR was 103.6±21.7 mL/min/1.73 m2. Hypertension and diabetes were noted in 43.7% and 5.5% of the participants, respectively. eGFR showed a weakly negative but significant association with CACS in bivariate correlation analysis (r=-0.076, P<0.01). Mean CACS significantly increased from CKD stage 1 to 3. The proportion of subjects who had CAC significantly increased from CKD stage 1 to 3. Although the odds ratio for CAC significantly increased from stage 1 to 3 after adjustment for confounding factors, this significance was reversed when age was included in the model.
Conclusion
In early CKD, renal function negatively correlated with the degree of CAC in Korean subjects. Age was the strongest effector for this association.
doi:10.3803/EnM.2014.29.3.312
PMCID: PMC4192818  PMID: 25309790
Coronary artery calcification; Glomerular filtration rate; Renal insufficiency, chronic
7.  Analysis of Yield of Eleutherosides B and E in Acanthopanax divaricatus and A. koreanum Grown with Varying Cultivation Methods 
The Scientific World Journal  2014;2014:515291.
An analysis of the yield of eleutherosides B and E in Acanthopanax divaricatus and A. koreanum was performed using high performance liquid chromatography to evaluate production by different cultivation methods. In A. divaricatus and A. koreanum, the total content of eleutherosides B and E was 2.466–7.360 mg/g varying by plant section, 3.886–11.506 mg/g by pinching site, 3.655–10.083 mg/g by planting time, and 3.652–10.108 mg/g by fertilizer ratio. Thus the total content of eleutherosides B and E in A. divaricatus and A. koreanum differed depending on cultivation methods. These results present useful information for high eleutheroside content applications in A. divaricatus and A. koreanum. This information can affect selection of plant section and cultivation methods for nutraceutical, pharmaceutical, and cosmeceutical material development.
doi:10.1155/2014/515291
PMCID: PMC4140102  PMID: 25165741
8.  Metabolic Health Is a More Important Determinant for Diabetes Development than Simple Obesity: A 4-Year Retrospective Longitudinal Study 
PLoS ONE  2014;9(5):e98369.
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.
doi:10.1371/journal.pone.0098369
PMCID: PMC4037196  PMID: 24870949
9.  Association of Serum Adipocyte-Specific Fatty Acid Binding Protein with Fatty Liver Index as a Predictive Indicator of Nonalcoholic Fatty Liver Disease 
Endocrinology and Metabolism  2013;28(4):283-287.
Background
Adipocyte-specific fatty acid-binding protein (A-FABP) is a cytoplasmic protein expressed in macrophages and adipocytes and it plays a role in insulin resistance and metabolic syndrome. Recently, the fatty liver index (FLI) was introduced as an indicator of nonalcoholic fatty liver disease (NAFLD). In this study, we aimed to investigate the relationship between baseline serum A-FABP levels and FLI after 4 years in apparently healthy subjects.
Methods
A total of 238 subjects without a past history of alcoholism or hepatitis were recruited from a medical check-up program. The NAFLD state was evaluated 4 years later in the same subjects using FLI. Fatty liver disease was diagnosed as diffusely increased echogenicity of the hepatic parenchyma compared to the kidneys, vascular blurring, and deep-echo attenuation. NAFLD was defined as subjects with fatty liver and no history of alcohol consumption (>20 g/day).
Results
Baseline serum A-FABP levels were significantly associated with FLI after adjustment for age and sex (P<0.001). The subjects with higher A-FABP levels had a higher mean FLI (P for trend=0.006). After adjusting for age and sex, serum A-FABP levels at baseline were shown to be significantly associated with FLI as a marker of development of NAFLD after 4 years (odds ratio, 2.68; 95% confidence interval, 1.24 to 5.80 for highest tertile vs. lowest tertile; P=0.012).
Conclusion
This study demonstrated that higher baseline serum A-FABP levels were associated with FLI as a predictive indicator of NAFLD after 4 years of follow-up in healthy Korean adults.
doi:10.3803/EnM.2013.28.4.283
PMCID: PMC3871043  PMID: 24396693
Fatty acid-binding proteins; Adipocytes; Non-alcoholic fatty liver disease; Ultrasonography
10.  Urinary adiponectin concentration is positively associated with micro- and macro-vascular complications 
Background
A relationship between plasma adiponectin level and a number of metabolic conditions, including insulin resistance, obesity, and type 2 diabetes, has been reported. This study aimed to assess whether urinary adiponectin concentration is correlated with vascular complications.
Methods
The study comprised 708 subjects who enrolled in the Seoul Metro City Diabetes Prevention Program and were carefully monitored from September 2008 to December 2008. Levels of urinary adiponectin were measured using an enzyme linked immunosorbent assay (ELISA) kit (AdipoGen, Korea). Urinary albumin excretion was assessed by the ratio of urinary albumin to creatinine (A/C ratio). Participants were divided into three groups based on tertiles of urinary adiponectin concentration, and we investigated whether urinary adiponectin levels are associated with microalbuminuria and pulse wave velocity.
Results
Urinary adiponectin concentrations were significantly higher in subjects with microalbuminuria than subjects with normoalbuminuria (P < 0.001). Urinary adiponectin concentration was positively correlated with age, fasting plasma glucose level, HbA1C level, triglyceride level, HOMA-IR, systolic/diastolic blood pressure, and urinary A/C ratio (all P < 0.05). Subjects in the highest tertile of urinary adiponectin concentration had an increased likelihood of microalbuminuria than those in the lowest tertile (Odds ratio (OR), 6.437; 95% confidence interval (CI), 4.202 to 9.862; P < 0.001). After adjusting for age, sex, and estimated creatinine clearance rate (eCcr), the OR remained significant (OR, 5.607; 95% CI, 3.562 to 8.828; P < 0.001). Backward multiple linear regression analysis revealed urinary adiponectin concentration to be a significant determinant of mean brachial-ankle pulse wave velocity (baPWV).
Conclusions
An increased urinary adiponectin concentration is significantly associated with microalbuminuria and increased mean baPWV. These results suggest that urinary adiponectin may play an important role as a biomarker for vascular dysfunction.
doi:10.1186/1475-2840-12-137
PMCID: PMC3849544  PMID: 24073643
Adiponectin; Microalbuminuria; Pulse wave velocity
11.  Metabolic Health Is More Closely Associated with Coronary Artery Calcification than Obesity 
PLoS ONE  2013;8(9):e74564.
Background
Recent studies have suggested that metabolic health may contribute more to the atherosclerosis than obesity. The aim of this study is to compare coronary artery calcium scores (CACS) among patients with different metabolic health and obesity status.
Methods
A health-screening program of 24,063 participants (mean age 41 years) was conducted, and CACS was assessed by multi-detector computerized tomography (MDCT). Being metabolically healthy was defined as having fewer than two of the following risk factors: high blood pressure, high fasting blood glucose, high triglyceride, low high-density lipoprotein cholesterol, highest decile of homeostasis model assessment-insulin resistance (HOMA-IR) index, and highest decile of high-sensitivity C-reactive protein (hs-CRP). Obesity status was defined as body mass index (BMI) higher than 25 kg/m2. Analyses were performed in four groups divided according to metabolic health and obesity: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUHNO), and metabolically unhealthy obese (MUHO).
Results
Mean values of CACS in the four groups were significantly different, except those between MHNO and MHO and between MUHNO and MUHO. When multinomial logistic regression analysis was performed with five CACS categories as the dependent variables and after adjusting for age, sex, and smoking status, the MHO, MUHNO, and MUHO groups showed significantly increased odds ratio for increasing CACS categories compared with no calcification status (5.221 for CACS >400 in MUHO group with 95% CI 2.856∼5.032 with MHNO group as the reference). When other variables including the metabolic parameters were included in the same model, the risks were attenuated.
Conclusion
Metabolic health is more closely associated with subclinical atherosclerosis than obesity as assessed by CACS.
doi:10.1371/journal.pone.0074564
PMCID: PMC3770589  PMID: 24040286
12.  The Risk of Metabolic Syndrome According to the White Blood Cell Count in Apparently Healthy Korean Adults 
Yonsei Medical Journal  2013;54(3):615-620.
Purpose
Considerable amount of interest has been focused on the positive relationship between inflammation and the metabolic syndrome (MS). However, few studies have been performed to evaluate the relationship between baseline white blood cell (WBC) count and future risk for developing MS. Therefore, we investigated whether the baseline plasma levels of WBC count could be associated with future risk for MS in apparently healthy Korean.
Materials and Methods
A total of 1135 subjects (781 men and 354 women with a mean age of 49 years), who underwent health examinations at Kangbuk Samsung Hospital in both 2002 and 2005 were enrolled. The presence of MS was defined using the modified criteria of the National Cholesterol Education Program Adult Treatment Panel III using BMI instead of waist circumference.
Results
The baseline levels of WBC count were significantly higher among incident MS cases than among subjects without MS. The relative risks of incident MS were 1.4, 3.2 and 2.7 for WBC quartiles 2, 3, and 4, respectively, when compared with the first quartile (p-value for trend <0.001). These positive associations persisted after adjustment for baseline body mass index, blood pressure, fasting glucose, high density lipoprotein-cholesterol, triglyceride and homeostatic model assessment-insulin resistance; adjusted relative risk of incident MS for the 2nd, 3rd and 4th quartile groups vs. the lowest quartile were 1.2, 2.4 and 1.7, respectively (p-value for trend =0.011).
Conclusion
This retrospective cohort study suggests that an elevated WBC count could be associated with incident MS, suggesting that baseline inflammation mirrored by WBC level can impact future MS development.
doi:10.3349/ymj.2013.54.3.615
PMCID: PMC3635622  PMID: 23549805
White blood cell count; metabolic syndrome; inflammation
13.  The Relationship of Body Composition and Coronary Artery Calcification in Apparently Healthy Korean Adults 
Endocrinology and Metabolism  2013;28(1):33-40.
Background
We investigated the association of coronary artery calcium score (CACS) with body composition and insulin resistance in apparently healthy Korean adults.
Methods
Nine hundred forty-five participants (mean age, 48.9 years; 628 men) in a medical check-up program were selected for analysis. Body composition was assessed by bioelectrical impedance analysis (BIA). Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). The CACS was assessed by multidetector computed tomography.
Results
One hundred forty-six subjects (15.4%) showed coronary artery calcification and 148 subjects (15.7%) had metabolic syndrome. CACS showed a significant positive correlation with age, fasting glucose level, waist circumference (WC), blood pressure, hemoglobin A1c, HOMA-IR, and waist-hip ratio (WHR) assessed by BIA. CACS had a negative correlation with high density lipoprotein cholesterol (HDL-C). Subjects with high CACS showed significantly higher mean WHRs and lower mean values for lean body mass compared with subjects without coronary artery calcification. In logistic regression analyses with coronary artery calcification as the dependent variable, the highest quartile of WHR showed a 3.125-fold increased odds ratio for coronary artery calcification compared with the lowest quartile after adjustment for confounding variables. When receiver operating characteristics analyses were performed with coronary artery calcification as the result variable, WHR showed the largest area under the curve (AUC) value among other variables except for age and WC in women (AUC=0.696 for WHR, 0.790 for age, and 0.719 for WC in women).
Conclusion
In our study population of apparently healthy Korean adults, WHR was the most significant predictor for coronary artery calcification among other confounding factors, suggesting that it may have implication as a marker for early atherosclerosis.
doi:10.3803/EnM.2013.28.1.33
PMCID: PMC3811801  PMID: 24396648
Coronary artery calcium score; Waist-hip ratio; Obesity, abdominal
14.  Tumor Necrosis Factor-α as a Predictor for the Development of Nonalcoholic Fatty Liver Disease: A 4-Year Follow-Up Study 
Endocrinology and Metabolism  2013;28(1):41-45.
Background
Tumor necrosis factor (TNF)-α is associated with insulin resistance and systemic inflammatory responses. The aim of this study was to investigate the relationship between TNF-α and the development of nonalcoholic fatty liver disease (NAFLD) in a longitudinal study.
Methods
Three hundred and sixty-three apparently healthy subjects (mean age, 40.5±6.1 years; male, 57.6%) without NAFLD were enrolled in 2003. Anthropometric and laboratory measurements were performed. The participants were grouped into tertiles according to their serum TNF-α levels from samples taken in 2003. At a 4-year follow-up, we compared the odds ratios (ORs) of the development of NAFLD according to the tertiles of TNF-α levels measured in 2003.
Results
At the 4-year follow-up, the cumulative incidence of NAFLD was 29.2% (106/363). The group that developed NAFLD had higher levels of TNF-α than those in the group without NAFLD (3.65±1.79 pg/mL vs. 3.15±1.78 pg/mL; P=0.016). When the 2003 serum TNF-α levels were categorized into tertiles: incidence of NAFLD observed in 2007 was significantly higher with increasing tertiles (22.6%, 35.8%, and 41.5%, respectively; P<0.05). The risk of developing NAFLD was significantly greater in the highest tertile of TNF-α than in the lowest tertile after adjusting for age, smoking, and BMI (OR, 2.20; 95% confidence interval, 1.12 to 4.01; P<0.05).
Conclusion
Higher serum TNF-α levels in subjects without NAFLD were associated with the development of NAFLD. The results of study might suggest a pathologic role of inflammation in NAFLD.
doi:10.3803/EnM.2013.28.1.41
PMCID: PMC3811803  PMID: 24396649
Inflammation; Non-alcoholic fatty liver disease; Tumor necrosis factor-alpha
15.  Serum 1,5-Anhydroglucitol Concentrations Are a Reliable Index of Glycemic Control in Type 2 Diabetes With Mild or Moderate Renal Dysfunction 
Diabetes Care  2012;35(2):281-286.
OBJECTIVE
To assess the relationship between 1,5-anhydroglucitol (AG) levels, which are a marker of glycemic control, and stages of chronic kidney disease (CKD).
RESEARCH DESIGN AND METHODS
This was a cross-sectional study with 269 subjects with type 2 diabetes who were divided into four groups based on estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease (eGFRMDRD) formula: 57 in control, 111 in CKD stages 1–2, 78 in stage 3, and 23 in stages 4–5.
RESULTS
The study groups differed significantly with respect to 1,5-AG and fasting plasma glucose (FPG), age, duration of diabetes, blood pressure, HDL, and percentage of antihypertension or antidyslipidemia medication use. Stepwise multivariate regression analyses showed that 1,5-AG levels in the control group, the CKD stages 1–2 group, and the CKD stage 3 group could be explained by HbA1c, age, duration of diabetes, FPG, and antihypertension medication. However, eGFRMDRD was the only independent determinant of 1,5-AG levels in CKD stages 4–5. Logarithmic transformed 1,5-AG values (ln[1,5-AG]) had significant inverse correlations with HbA1c and FPG levels for CKD stages 1–2 and CKD stage 3 (all P < 0.001). However, associations between ln(1,5-AG) and HbA1c or FPG were insignificant for CKD stages 4–5 (P = 0.274 and P = 0.080, respectively).
CONCLUSIONS
This study demonstrated that 1,5-AG levels do not appear to be influenced by mild or moderate renal dysfunction, suggesting it is a reliable glycemic marker in type 2 diabetes with CKD stages 1–3.
doi:10.2337/dc11-1462
PMCID: PMC3263896  PMID: 22210564
16.  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 
PLoS ONE  2012;7(10):e46819.
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.
doi:10.1371/journal.pone.0046819
PMCID: PMC3478288  PMID: 23110056
17.  Combined Effect of Nonalcoholic Fatty Liver Disease and Impaired Fasting Glucose on the Development of Type 2 Diabetes 
Diabetes Care  2011;34(3):727-729.
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.
doi:10.2337/dc10-1991
PMCID: PMC3041216  PMID: 21278140
18.  Exendin-4 Improves Steatohepatitis by Increasing Sirt1 Expression in High-Fat Diet-Induced Obese C57BL/6J Mice 
PLoS ONE  2012;7(2):e31394.
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.
doi:10.1371/journal.pone.0031394
PMCID: PMC3281956  PMID: 22363635
19.  Effect on Glycemic, Blood Pressure, and Lipid Control according to Education Types 
Diabetes & Metabolism Journal  2011;35(6):580-586.
Background
Diabetes self-management education and reinforcement are important for effective management of the disease. We investigated the effectiveness of interactive small-group education on glycemic, blood pressure, and lipid levels.
Methods
For this study, 207 type 2 diabetes patients with suboptimal glycemic control (HbA1c levels >6.5%) were enrolled. The conventional education group received an existing education program from April to November in 2006, and the interactive education group received a new small-group education program from December 2006 to July 2007. The two groups were comparatively analyzed for changes in blood sugar, glycated hemoglobin, lipid, and blood pressure at baseline, 3, 6, and 12 months and the proportion of patients achieving target goals at 12 months.
Results
After 12 months of follow-up, HbA1c levels in the interactive education group were significantly lower than in the conventional education group (6.7% vs. 6.4%, P<0.001). Fasting and 2 hour postprandial glucose concentrations, total cholesterol, and low density lipoprotein cholesterol were significantly lower in the interactive education group than in the conventional education group. The proportion of patients that achieved target goals was significantly higher in the interactive education group.
Conclusion
The small-group educational method improved and re-established the existing group educational method. This finding suggests that the importance of education appears to be related to the method by which it is received rather than the education itself. Thus, the use of small-group educational methods to supplement existing educational methods established for diverse age levels should be considered in the future.
doi:10.4093/dmj.2011.35.6.580
PMCID: PMC3253968  PMID: 22247900
Achievement; Diabetes mellitus; Education
20.  Retrospective Analysis on the Efficacy, Safety and Treatment Failure Group of Sitagliptin for Mean 10-Month Duration 
Diabetes & Metabolism Journal  2011;35(3):290-297.
Background
To investigate the clinical results of sitagliptin (SITA) and the characteristics of the treatment failure group or of low responders to SITA.
Methods
A retrospective study of type 2 diabetic patients reviewed 99 cases, including 12 treatment failure cases, who stopped SITA because of worsening patients' condition, and 87 cases, who continued treatment over five visits (total 9.9±10.1 months) after receiving the prescription of SITA from December 2008 to June 2009. Subjects were classified as five groups administered SITA as an initial combination with metformin (MET), add-on to metformin or sulfonylurea, and switching from sulfonylurea or thiazolidinedione. The changes in HbA1c level from the first to last visit (ΔHbA1c) in treatment maintenance group were subanalyzed.
Results
The HbA1c level was significantly reduced in four groups, including initial coadministration of SITA with metformin (ΔHbA1c=-1.1%, P<0.001), add-on to MET (ΔHbA1c=-0.6%, P=0.017), add-on to sulfonylurea (ΔHbA1c=-0.5%, P<0.001), and switching from thiazolidinedione (ΔHbA1c=-0.3%, P=0.013). SITA was noninferior to sulfonlyurea (ΔHbA1c=-0.2%, P=0.63). There was no significant adverse effect. The treatment failure group had a longer diabeties duration (P=0.008), higher HbA1c (P=0.001) and fasting plasma glucose (P=0.003) compared to the maintenance group. Subanalysis on the tertiles of ΔHbA1c showed that low-response to SITA (tertile 1) was associated with a longer diabetes duration (P=0.009) and lower HbA1c (P<0.001).
Conclusion
SITA was effective and safe for use in Korean type 2 diabetic patients. However, its clinical responses and long-term benefit-harm profile is yet to be established.
doi:10.4093/dmj.2011.35.3.290
PMCID: PMC3138093  PMID: 21785750
Diabetes mellitus, type 2; Sitagliptin; Treatment outcome
21.  The Association of Unintentional Changes in Weight, Body Composition, and Homeostasis Model Assessment Index with Glycemic Progression in Non-Diabetic Healthy Subjects 
Diabetes & Metabolism Journal  2011;35(2):138-148.
Background
We performed a retrospective longitudinal study on the effects of changes in weight, body composition, and homeostasis model assessment (HOMA) indices on glycemic progression in subjects without diabetes during a four-year follow-up period in a community cohort without intentional intervention.
Methods
From 28,440 non-diabetic subjects who participated in a medical check-up program in 2004, data on anthropometric and metabolic parameters were obtained after four years in 2008. Body composition analyses were performed with a bioelectrical impedance analyzer. Skeletal muscle index (SMI, %) was calculated with lean mass/weight×100. Subjects were divided into three groups according to weight change status in four years: weight loss (≤-5.0%), stable weight (-5.0 to 5.0%), weight gain (≥5.0%). Progressors were defined as the subjects who progressed to impaired fasting glucose or diabetes.
Results
Progressors showed worse baseline metabolic profiles compared with non-progressors. In logistic regression analyses, the increase in changes of HOMA-insulin resistance (HOMA-IR) in four years presented higher odds ratios for glycemic progression compared with other changes during that period. Among the components of body composition, a change in waist-hip ratio was the strongest predictor, and SMI change in four years was a significant negative predictor for glycemic progression. Changes in HOMA β-cell function in four years was a negative predictor for glycemic progression.
Conclusion
Increased interval changes in HOMA-IR, weight gain and waist-hip ratio was associated with glycemic progression during a four-year period without intentional intervention in non-diabetic Korean subjects.
doi:10.4093/dmj.2011.35.2.138
PMCID: PMC3122898  PMID: 21738896
Glycemic progression; Prediabetes; Skeletal muscle index; Visceral obesity; Weight change
22.  Activation of Peroxisome Proliferator-Activated Receptor Gamma by Rosiglitazone Increases Sirt6 Expression and Ameliorates Hepatic Steatosis in Rats 
PLoS ONE  2011;6(2):e17057.
Background
Sirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ) on hepatic steatosis.
Methods
To investigate the effect of RGZ on hepatic steatosis, rats were treated with RGZ (4 mg·kg−1·day−1) by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes.
Results
RGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α) and Forkhead box O1 (Foxo1) in rat livers. AMP-activated protein kinase (AMPK) phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035), suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects.
Conclusion
Our results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis.
doi:10.1371/journal.pone.0017057
PMCID: PMC3044155  PMID: 21373642
23.  The Association of Brachial-Ankle Pulse Wave Velocity with 30-Minute Post-Challenge Plasma Glucose Levels in Korean Adults with No History of Type 2 Diabetes 
Korean Diabetes Journal  2010;34(5):287-293.
Background
Acute postprandial hyperglycemia is an important affector for atherosclerosis in subjects with glucose intolerance. We analyzed the relationship of brachial-ankle pulse wave velocity (baPWV) with fasting and post-challenge plasma glucose levels according to different time points during oral glucose tolerance test (OGTT).
Methods
In 663 subjects with fasting hyperglycemia, 75 g OGTT were performed to confirm the glucose tolerant status, and fasting, post-challenge 30-minute and 120-minute glucose levels were measured. Anthropometric measurements were done, and fasting lipid profiles were measured. baPWV were measured in all subjects and the relationship between fasting, 30- and 120-minute post-challenge glucose levels and baPWV were analyzed.
Results
Among the participants, 62.9% were prediabetes and 31.7% were diabetes. Mean baPWV value was significantly higher in subjects with diabetes compared with prediabetes group. In bivariate correlation analyses, age, blood pressure, total cholesterol, low density lipoprotein cholesterol, 30-minute and 120-minute post-challenge glucose levels showed significant positive correlation with baPWV value. In multiple regression analysis, 30-minute post-challenge glucose level was a weak but significant determinant for mean baPWV value even after adjustment for other confounding variables.
Conclusions
Postprandial hyperglycemia, especially 30-minute glucose levels showed significant correlation with baPWV in subjects with fasting hyperglycemia. These results can imply the deleterious effect of acute hyperglycemic excursion on arterial stiffness in subjects with glucose intolerance.
doi:10.4093/kdj.2010.34.5.287
PMCID: PMC2972488  PMID: 21076576
Arterial stiffness; Oral glucose tolerance test; Postprandial hyperglycemia; Pulse wave analysis
24.  The Relationship of Adiponectin/Leptin Ratio with Homeostasis Model Assessment Insulin Resistance Index and Metabolic Syndrome in Apparently Healthy Korean Male Adults 
Korean Diabetes Journal  2010;34(4):237-243.
Background
We investigated the relationships of adiponectin/leptin (A/L) ratio with cardiovascular risk factors, insulin resistance index, and metabolic syndrome (MS) in apparently healthy Korean male adults.
Methods
Sixty-eight male subjects were enrolled among the participants of an annual health check-up program (mean age, 55.1 years). Percent body fat (%) was measured using a bioelectric impedance analyzer. Serum leptin level was measured via radioimmunoassay, and adiponectin level was measured using an enzyme-linked immunosorbent assay. Homeostasis model assessment (HOMA)-insulin resistance (IR) index was calculated, and the presence of metabolic syndrome was assessed.
Results
Adiponectin, leptin, and A/L ratio showed significant correlations with percent body fat, lipid profile, and HOMA-IR. Mean leptin and HOMA-IR levels were significantly higher, while A/L ratio was significantly lower in subjects with MS. With increasing number of MS components, the mean values of leptin and HOMA-IR increased and the A/L ratio decreased. In multiple regression analysis, HOMA-IR was significantly correlated with triglyceride, fasting glucose, and A/L ratio, while A/L ratio was significantly correlated with body mass index and HOMA-IR. HOMA-IR and A/L ratio were significant predictors for each other after adjustment for other factors.
Conclusion
A/L ratio correlated well with lipid profile, HOMA-IR, and the presence and number of MS components in Korean male subjects.
doi:10.4093/kdj.2010.34.4.237
PMCID: PMC2932893  PMID: 20835341
Adiponectin/leptin ratio; Insulin resistance; Metabolic syndrome
25.  The Effect of Simvastatin on the Proliferation and Differentiation of Human Bone Marrow Stromal Cells 
Journal of Korean Medical Science  2005;20(3):438-444.
Statins have been postulated to affect the bone metabolism. Recent experimental and epidemiologic studies have suggested that statins may also have bone protective effects. This study assessed the effects of simvastatin on the proliferation and differentiation of human bone marrow stromal cells (BMSCs) in an ex vivo culture. The bone marrow was obtained from healthy donors. Mononuclear cells were isolated and cultured to osteoblastic lineage. In the primary culture, 10-6 M simvastatin diminished the mean size of the colony forming units-fibroblastic (CFU-Fs) and enhanced matrix calcification. At near confluence, the cells were sub-cultured. Thereafter, the alkaline phosphatase (ALP) activities of each group were measured by the time course of the secondary culture. Simvastatin increased the ALP activity in a dose dependent manner, and this stimulatory effect was more evident during the early period of culture. A 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay was performed during the secondary culture in order to estimate the effect of simvastatin on the proliferation of human BMSCs. When compared to the control group, simvastatin significantly decreased the proliferation of cells of each culture well. 10-6 M of simvastatin also significantly enhanced the osteocalcin mRNA expression level. This study shows that simvastatin has a stimulatory effect on bone formation through osteoblastic differentiation, and has an inhibitory effect on the proliferative potential of human BMSCs
doi:10.3346/jkms.2005.20.3.438
PMCID: PMC2782200  PMID: 15953866
Simvastatin; Osteoblasts; Cell Proliferation; Cell Differentiation; Bone Marrow Cells; Stromal Cells

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