Ki-Hyun Baek

Relationship of serum osteoprotegerin levels with coronary artery disease severity, left ventricular hypertrophy and C-reactive protein.

OPG (osteoprotegerin) is an inhibitor of osteoclastogenesis and recent work suggests it has a role in atherosclerosis. Therefore we measured serum OPG levels in patients with coronary artery disease, compared the serum OPG levels among the different groups according to the number of stenotic vessels and determined whether there was any correlation with aortic calcification, LV (left ventricular) mass index and serum CRP (C-reactive protein) levels. Subjects (n=100; mean age, 57 years) who underwent coronary angiograms were enrolled. Blood pressure, body mass index, fasting blood glucose, lipid profiles and CRP levels were measured and the LV mass indices were calculated using ECGs. Serum OPG levels were measured by ELISA. The presence of calcification in the aortic notch was checked by a chest X-ray. The subjects were divided into four groups according to the number of stenotic vessels. The mean serum OPG levels increased significantly as the number of stenotic vessels increased, and the mean serum OPG levels were higher in the group with three-vessel disease compared with the groups with no- or one-vessel disease. The mean serum CRP level was significantly higher in the group with three-vessel disease compared with the groups with no-, one- and two-vessel disease. Age and LV mass index showed significant positive correlations with serum OPG levels, although significance was lost after an adjustment for age. Serum CRP levels were positively correlated with serum OPG levels even after an adjustment for age. There were no differences in serum OPG levels according to the presence of fasting hyperglycaemia or aortic calcification. In conclusion, serum OPG level was related to the severity of stenotic coronary arteries and serum CRP levels. LV mass indices showed no significant correlation with OPG levels. The precise mechanism for the role of OPG in atherosclerosis needs to be investigated further.

Transitional CpG methylation between promoters and retroelements of tissue‐specific genes during human mesenchymal cell differentiation

In general, methylation of the promoter regions is inversely correlated with gene expression. The transitional CpG area between the promoter‐associated CpG islands and the nearby retroelements is often methylated in a tissue‐specific manner. This study analyzed the relationship between gene expression and the methylation of the transitional CpGs in two human stromal cells derived from the bone marrow (BMSC) and adipose tissue (ATSC), both of which have a multilineage differentiation potential. The transitional CpGs of the osteoblast‐specific (RUNX2 and BGLAP), adipocyte‐specific (PPARγ2), housekeeping (CDKN2A and MLH1), and mesenchyme‐unrelated (RUNX3) genes were examined by methylation‐specific PCR. The expression of each gene was measured using reverse‐transcription PCR analysis. The RUNX2, BGLAP, and CDKN2A genes in the BMSC, and the PPARγ2 gene in the ATSC exhibited hypomethylation of the transitional CpGs along with the strong expression. The CpG island of RUNX3 gene not expressed in both BMSC and ATSC was hypermethylated. Transitional hypomethylation of the MLH1 gene was accompanied by the higher expression in the BMSC than in the ATSC. The weakly methylated CpGs of the PPARγ2 gene in the BMSC became hypomethylated along with the strong expression during the osteoblastic differentiation. There were no notable changes in the transitional methylation and expression of the genes other than PPARγ2 after the differentiation. Therefore, the transitional methylation and gene expression established in mesenchymal cells tend to be consistently preserved under the induction of differentiation. Weak transitional methylation of the PPARγ2 gene in the BMSC suggests a methylation‐dependent mechanism underlying the adiopogenesis of bone marrow. J. Cell. Biochem. 102: 224–239, 2007.

Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation

Summary:Cytokines including IL-6 and TNF-α play an important role in the pathogenesis of postmenopausal osteoporosis. However, the relationship between changes in the cytokine levels and subsequent bone loss in patients undergoing a bone marrow transplantation (BMT) is unclear. A total of 46 patients undergoing an allogeneic BMT were prospectively investigated. The bone turnover markers and the serum cytokines were measured before BMT and serially after BMT. Bone mineral density (BMD) was measured before and 1 year after BMT. At 1 year after BMT, the lumbar spine BMD had decreased by 4.8%, and the total proximal femoral BMD had decreased by 12.3%. The serum IL-6 and TNF-α levels increased until 2 and 3 weeks after BMT, respectively. The lumbar BMD was significantly decreased as the serum IL-6 and TNF-α levels increased by post-BMT 3 weeks. The lumbar BMD decreased significantly as the cumulative prednisolone and cyclosporine dose increased. Patients with GVHD ⩾grade II had higher lumbar bone loss than patients with GVHD <grade I. In conclusion, immunosuppressants, GVHD occurrence and increase in bone-resorbing cytokines in the early post-BMT period were associated with later bone loss after BMT. Further studies are needed to elucidate the precise mechanism.

Age, body mass index, current smoking history, and serum insulin-like growth factor-I levels associated with bone mineral density in middle-aged Korean men

Osteoporosis is a growing health problem in women and in men. This cross-sectional study examined the association of anthropometric, lifestyle, and hormonal factors with bone mineral density (BMD) in 152 healthy Korean middle-aged men. Smoking habits and alcohol consumption were assessed by interview. Serum testosterone and insulin-like growth factor-I (IGF-I) levels were measured by radioimmunoassay, and serum growth hormone (GH) levels were measured by immunoradiometric assay. GH stimulation tests were performed after the ingestion of 500 mg of L-dopa. BMD was measured at the lumbar spine and at the femoral neck by dual-energy X-ray absorptiometry. Of the middle-aged men, 3.9% were osteoporotic and 28.3% were osteopenic at the lumbar spine site, and 5.9% were osteoporotic and 45.4% were osteopenic at the femoral neck site. Lumbar spine BMD correlated significantly with body mass index (BMI), and femoral neck BMD correlated significantly with age, BMI, and serum IGF-I levels. The lowest quartile group for serum IGF-I levels showed the lowest femoral neck BMD. Osteoporotic men by lumbar spine BMD showed significant differences from the normal BMD group in terms of BMI and smoking habits. Also, osteoporotic men by femoral neck BMD were significantly different for mean age, BMI, and serum IGF-I levels compared with the normal BMD group. On multiple regression analysis, BMI was found to be the only independent predictor of lumbar spine BMD, whereas both BMI and serum IGF-I levels were found to be the independent predictors of femoral neck BMD. Overall, 28.3%–45.4% of middle-aged Korean men were osteopenic. We suggest that higher age, a lower BMI, current smoking history, and lower serum IGF-I levels are risk factors for lower BMD in middle-aged Korean men; however, serum testosterone levels and GH secretory capacity were not found to be correlated with BMD.

Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women

Background: Recently, klotho has been proposed as a link between cardiovascular diseases and premature aging, but the relationship between KLOTHO genes and cardiovascular risk factors, especially glucose metabolism, in humans is unclear. Objectives: We investigate the relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. Material and methods: In 251 women (mean age 51.3±6.9 yr), body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose, insulin and lipid profiles were measured. The genotyping of polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene was performed by allelic discrimination using a 5′ nuclease polymerase chain reaction assay. Results: Allele frequencies of G395A polymorphism was 0.829 for the G allele and 0.171 for the A allele and allele frequencies of C1818T polymorphism were 0.804 for the C allele and 0.196 for the T allele, both of which were in compliance with Hardy-Weinberg equilibrium and the two polymorphisms were in linkage disequilibrium (D′=0.43, p<0.01). Mean systolic blood pressure was significantly higher in A allele carriers of G395A polymorphism compared with non-carriers, and the significance was persistent even after adjustment for age and BMI. Mean fasting plasma glucose was significantly higher in T allele carriers of C1818T polymorphism compared with non-carriers, and the significance was persistent even after adjustment for age and BMI. Subjects without any minor allele from either single nucleotide polymorphisms (SNP) had significantly lower mean values for systolic, diastolic blood pressure and fasting plasma glucose levels compared with subjects with both minor allele from either SNP. Conclusions: We observed that KLOTHO G395A polymorphism was associated with blood pressure and KLOTHO C1818T polymorphism was associated with glucose metabolism in Korean women. Further studies are needed to clarify this relationship.

Visceral Obesity Is a Negative Predictor of Remission of Diabetes 1 Year After Bariatric Surgery

Our aim was to identify preoperative anthropometric and clinical parameters that predict the remission of diabetes after Roux‐en‐Y gastric bypass (RYGB). Fifty severely obese Korean patients with type 2 diabetes underwent RYGB. Visceral and abdominal subcutaneous fat area (SFA) was assessed using computed tomography before and 6 and 12 months after RYGB. Remission was defined as a glycated hemoglobin (A1C) level <6.5% and a fasting glucose concentration <126 mg/dl for 1 year or more without the use of medication. The visceral‐to‐SFA ratio decreased from 0.60 ± 0.30 to 0.53 ± 0.29 (P = 0.001) after 6 months and decreased further to 0.42 ± 0.24 (P < 0.001) after 12 months. Thirty‐four of the 50 patients (68%) had remission of diabetes (remission group). Compared with patients in the nonremission group, patients in the remission group had a shorter duration of diabetes and lower preoperative A1C level, and were less likely to use insulin preoperatively. Preoperative BMI did not differ in two groups. However, the preoperative visceral‐to‐SFA ratio was greater in the nonremission group compared with the remission group (0.79 ± 0.29 vs. 0.53 ± 0.26, P = 0.003). Finally, the preoperative visceral‐to‐SFA ratio was an independent predictor of the remission of diabetes after RYGB in multiple stepwise logistic regression analysis. In conclusion, our data suggest that visceral adiposity negatively influence the likelihood of the patient experiencing the remission of diabetes after RYGB.

Effects of Thyroid Hormone on A1C and Glycated Albumin Levels in Nondiabetic Subjects With Overt Hypothyroidism

OBJECTIVE We aimed to determine the effects of thyroid hormone on A1C and glycated albumin (GA) in nondiabetic patients with overt hypothyroidism. RESEARCH DESIGN AND METHODS A1C levels were measured in 45 nondiabetic patients with overt hypothyroidism and 180 euthyroid control subjects. A1C, GA, fasting blood glucose (FBG), 1,5-anhydroglucitol, and erythrocyte indexes were determined in 30 nondiabetic patients with overt hypothyroidism before and after thyroid hormone replacement. RESULTS A1C levels were higher in patients with hypothyroidism compared with control subjects. A1C levels were decreased by thyroid hormone replacement. Thyroid hormone replacement increased serum erythropoietin, reticulocyte count, and mean corpuscular hemoglobin (MCH). The change in A1C level was significantly correlated with the change in reticulocyte count or MCH. Thyroid hormone replacement decreased serum levels of albumin and GA. However, FBG and 1,5-anhydroglucitol levels were not altered. CONCLUSIONS Levels of A1C and GA are spuriously high in nondiabetic patients with overt hypothyroidism.

The association of Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma gene with serum osteoprotegerin levels in healthy Korean women.

Recent evidences suggest that the activation of peroxisome proliferator-activated receptor (PPAR)-γ, which is an important transcriptional factor in adipocyte differentiation, also plays an important role in the bone microenvironment. The objective of the study was to clarify whether Pro12Ala polymorphism was related to the serum OPG levels and bone mineral metabolism in healthy Korean women. In 239 Korean women (mean age 51 years), who participated in medical check-up program in a health promotion center, anthropometric measurements, lumbar spine and femoral neck bone mineral density (BMD), bone turnover markers, such as serum total alkaline phosphatase (ALP) levels, urine deoxypyridinoline levels, and 24-h urine calcium excretion were measured. Serum levels of OPG were measured with ELISA method. DNAs were extracted from the samples and the genotyping of the Pro12Ala polymorphism (rs1801282) in the PPAR-γ gene was performed via an allelic discrimination assay using a TaqMan probe. In addition, we examined the haplotype analysis between two polymorphisms of PPAR-γ gene, Pro12Ala in exon B and C161T in exon 6 (rs3856806). Allelic frequencies were 0.950 for Pro allele and 0.050 for Ala allele, which was in compliance with Hardy- Weinberg equilibrium, and there was no Ala12Ala genotype among the genotyped subjects. Mean serum OPG level was significantly lower (P=0.035), and serum total ALP was significantly higher (P=0.014) in the Pro12Ala genotype group compared with the Pro12Pro genotype group, which were consistently significant even after adjustment for weight, height, and serum follicle stimulating hormone (FSH). In multiple regression analysis with serum OPG as the dependent variable and age, weight, ALP, femoral neck BMD and Pro12Ala genotype included in the model, only Pro12Ala genotype was significant determinant of serum OPG level (β=-0.136, P=0.035). The haplotype analysis with C161T polymorphism revealed that subjects with Ala and T alleles showed significantly lower serum OPG levels compared with those with Pro12Pro/CC genotype, which were consistently significant even after adjustment for age, weight, height and FSH (P=0.010). This result suggests statistically significant association of Pro12Ala polymorphisms with serum OPG levels in Korean females.

Effects of bariatric surgery on metabolic and nutritional parameters in severely obese Korean patients with type 2 diabetes: A prospective 2‐year follow up

Little is known about the long‐term effects of Roux‐en‐Y gastric bypass (RYGB) in severely obese Asian individuals.

The association between ectopic fat in the pancreas and subclinical atherosclerosis in type 2 diabetes

AIMS Evidence that pancreatic fat accumulation has a role in obesity, metabolic syndrome and type 2 diabetes mellitus (DM) is emerging. However, data on the influence of pancreatic steatosis on subclinical atherosclerosis are lacking. METHODS We examined 198 patients with type 2 DM. Pancreatic computed tomography (CT) attenuations were assessed using CT imaging. Obesity was defined as BMI ≥ 25 kg/m(2) according to the Asian-specific BMI cut-offs. We defined pancreatic steatosis as pancreatic attenuations below median levels. RESULTS The pancreatic attenuations was significantly correlated with age (r=-0.302, p<0.001), visceral fat area (r=-0.194, p=0.006) and vascular stiffness (r=-0.242, p=0.001). In the non-obese group (BMI<25 kg/m(2)), pancreatic steatosis was associated with a higher prevalence of carotid artery plaque and vascular stiffness. In the non-obese group, patients with pancreatic steatosis, compared with those without, had an odds ratio (OR) of 3.1 (95% CI 1.2-8.1) for carotid atherosclerosis, after adjusting for age, gender and BMI. However, significant associations between pancreatic steatosis and atherosclerosis were not found in the obese group. CONCLUSION Ectopic fat in the pancreas is strongly associated with carotid atherosclerosis in non-obese subjects with type 2 DM. This finding highlights the importance of pancreatic fat deposits related to a higher risk of cardiovascular disease, especially in non-obese subjects.