Bo Kyung Koo

Lower bone mineral density is associated with higher coronary calcification and coronary plaque burdens by multidetector row coronary computed tomography in pre- and postmenopausal women

Objectives  There is growing evidence for the association between bone mineral density (BMD) and vascular calcification, which is related to cardiovascular disease. Coronary multidetector row computed tomography (MDCT) is a noninvasive tool developed to evaluate coronary status precisely. We used MDCT to evaluate this association.

Gene Expression Pattern in Transmitochondrial Cytoplasmic Hybrid Cells Harboring Type 2 Diabetes-Associated Mitochondrial DNA Haplogroups

Decreased mitochondrial function plays a pivotal role in the pathogenesis of type 2 diabetes mellitus (T2DM). Recently, it was reported that mitochondrial DNA (mtDNA) haplogroups confer genetic susceptibility to T2DM in Koreans and Japanese. Particularly, mtDNA haplogroup N9a is associated with a decreased risk of T2DM, whereas haplogroups D5 and F are associated with an increased risk. To examine functional consequences of these haplogroups without being confounded by the heterogeneous nuclear genomic backgrounds of different subjects, we constructed transmitochondrial cytoplasmic hybrid (cybrid) cells harboring each of the three haplogroups (N9a, D5, and F) in a background of a shared nuclear genome. We compared the functional consequences of the three haplogroups using cell-based assays and gene expression microarrays. Cell-based assays did not detect differences in mitochondrial functions among the haplogroups in terms of ATP generation, reactive oxygen species production, mitochondrial membrane potential, and cellular dehydrogenase activity. However, differential expression and clustering analyses of microarray data revealed that the three haplogroups exhibit a distinctive nuclear gene expression pattern that correlates with their susceptibility to T2DM. Pathway analysis of microarray data identified several differentially regulated metabolic pathways. Notably, compared to the T2DM-resistant haplogroup N9a, the T2DM-susceptible haplogroup F showed down-regulation of oxidative phosphorylation and up-regulation of glycolysis. These results suggest that variations in mtDNA can affect the expression of nuclear genes regulating mitochondrial functions or cellular energetics. Given that impaired mitochondrial function caused by T2DM-associated mtDNA haplogroups is compensated by the nuclear genome, we speculate that defective nuclear compensation, under certain circumstances, might lead to the development of T2DM.

The Incidence and Prevalence of Diabetes Mellitus and Related Atherosclerotic Complications in Korea: A National Health Insurance Database Study

Aims/Introduction The incidence and prevalence of type 2 diabetes mellitus (T2DM) and related macrovascular complications in Korea were estimated using the Health Insurance Review and Assessment (HIRA) database from 2007–2011, which covers the claim data of 97.0% of the Korean population. Materials and Methods T2DM, coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral artery disease (PAD) were defined according to ICD-10 codes. We used the Healthcare Common Procedure Coding System codes provided by HIRA to identify associated procedures or surgeries. When calculating incidence, we excluded cases with preexisting T2DM within two years before the index year. A Poisson distribution was assumed when calculating 95% confidence intervals for prevalence and incidence rates. Results The prevalence of T2DM in Korean adults aged 20–89 years was 6.1–6.9% and the annual incidence rates of T2DM ranged from 9.5–9.8/1,000 person-year (PY) during the study period. The incidence rates of T2DM in men and women aged 20–49 years showed decreasing patterns from 2009 to 2011 (P<0.001); by contrast, the incidence in subjects aged 70–79 years showed increased patterns from 2009 to 2011 (P<0.001). The incidence rates of CAD and CVD in patients newly diagnosed with T2DM were 18.84/1,000 PY and 11.32/1,000 PY, respectively, in the year of diagnosis. Among newly diagnosed individuals with T2DM who were undergoing treatment for PAD, 14.6% underwent angioplasty for CAD during the same period. Conclusions Our study measured the national incidences of T2DM, CAD, CVD, and PAD, which are of great concern for public health. We also confirmed the relatively higher risk of CAD and CVD newly detected T2DM patients compared to the general population in Korea.

Identification of Novel Autoantibodies in Type 1 Diabetic Patients Using a High-Density Protein Microarray

Autoantibodies can facilitate diagnostic and therapeutic means for type 1 diabetes (T1DM). We profiled autoantibodies from serum samples of 16 T1DM patients, 16 type 2 diabetic (T2DM) patients, and 27 healthy control subjects with normal glucose tolerance (NGT) by using protein microarrays containing 9,480 proteins. Two novel autoantibodies, anti-EEF1A1 and anti-UBE2L3, were selected from microarrays followed by immunofluorescence staining of pancreas. We then tested the validity of the candidates by ELISA in two independent test cohorts: 1) 95 adults with T1DM, 49 with T2DM, 11 with latent autoimmune diabetes in adults (LADA), 20 with Graves disease, and 66 with NGT and 2) 33 children with T1DM and 34 healthy children. Concentrations of these autoantibodies were significantly higher in T1DM patients than in NGT and T2DM subjects (P < 0.01), which was also confirmed in the test cohort of children (P < 0.05). Prevalence of anti-EEF1A1 and anti-UBE2L3 antibodies was 29.5% and 35.8% in T1DM, respectively. Of note, 40.9% of T1DM patients who lack anti-GAD antibodies (GADA) had anti-EEF1A1 and/or anti-UBE2L3 antibodies. These were also detected in patients with fulminant T1DM but not LADA. Our approach identified autoantibodies that can provide a new dimension of information indicative of T1DM independent of GADA and new insights into diagnosis and classification of T1DM.

Regulatory Effect of Common Promoter Polymorphisms on the Expression of the 11β-Hydroxysteroid Dehydrogenase Type 1 Gene

Background/Aims: Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts inactive cortisone to active cortisol, has become an emerging therapeutic target for type 2 diabetes mellitus and obesity. In this study, we examined the association between HSD11B1 polymorphisms and type 2 diabetes and metabolic phenotypes in Koreans. Methods: We sequenced all exons including exon-intron boundaries and the promoter region of the HSD11B1 gene. Of 8 polymorphisms identified, we selected 4 common single-nucleotide polymorphisms (g.–19835G>A, g.–19609A>G, g.+27447G>C and g.+27810C>T) based on location, linkage disequilibrium and frequency and which were genotyped in 757 subjects with type 2 diabetes and 644 nondiabetic subjects. Results: There was no association between the 4 common polymorphisms of HSD11B1 and type 2 diabetes. g.–19835G>A and g.–19609A>G showed modest associations with fasting plasma glucose and body mass index but the significance of these associations was lost after adjustment for multiple comparison. With regard to promoter polymorphisms in the HSD11B1 gene, a haplotype construct carrying both g.–19835A and g.–19609G showed significantly decreased promoter activity compared to other common haplotype constructs. Conclusion: The variations in HSD11B1 were not associated with susceptibility to type 2 diabetes or metabolic phenotypes in Koreans. However, the common promoter variants of the gene might exert a polymorphic regulatory effect on HSD11B1 expression.

Effects of Aerobic Exercise Training on C1q Tumor Necrosis Factor α-Related Protein Isoform 5 (Myonectin): Association with Insulin Resistance and Mitochondrial DNA Density in Women

CONTEXT The C1q TNFα-related protein (C1QTNF) families exhibit a C-terminal complement factor C1q globular domain similar to that of TNF. However, their clinical implications are largely unknown. We recently found that the C1q TNFα-related protein isoform 5 (C1QTNF5 or myonectin) level was increased in insulin-resistant rodents and mitochondrial DNA (mtDNA)-depleted myocytes. OBJECTIVE We aimed to determine the effects of aerobic exercise training on C1QTNF5 level and its association with insulin resistance and mtDNA density in young and old healthy women. DESIGN AND SETTING Fourteen healthy young women aged 22.5 ± 2.7 yr and 14 healthy older women aged 60.3 ± 5.2 yr performed aerobic exercise at 60-80% of maximal oxygen consumption (VO(2)max) over three 1-h sessions per week for 10 wk. Insulin resistance was assessed by homeostasis model assessment of insulin resistance and adiponectin concentration. Serum C1QTNF5 level was estimated by immunoblotting. The mtDNA/28S rRNA ratio was used to determine mtDNA density. RESULTS VO(2)max increased significantly after the exercise training from 33.1 ± 6.2 to 35.3 ± 5.3 ml/kg · min in younger women and from 23.2 ± 3.1 to 27.2 ± 4.8 ml/kg · min in older women (P < 0.05). The C1QTNF5 level and homeostasis model assessment of insulin resistance decreased significantly after exercise training and were correlated positively (r = 0.462; P < 0.01). There were negative correlations between the changes in C1QTNF5 level and the changes in VO(2)max, mtDNA density, and adiponectin level (r = -0.495, -0.672, and -0.569, respectively; all P < 0.01). CONCLUSION These findings suggest a physiological function for C1QTNF5 (myonectin) in linking insulin resistance with quantitative changes in mtDNA. Further research exploring the role of C1QTNF5 in the development of insulin resistance is warranted.

Effect of Low Serum Total Bilirubin Levels (£0.32 mg/dl) on Risk of Coronary Artery Disease in Patients With Metabolic Syndrome

The objective of this study was to investigate the effects of low serum bilirubin levels on the risk for future coronary artery disease (CAD) in a prospective cohort. CAD events were examined according to baseline serum bilirubin levels in a prospective large-scale, community-based Korean cohort in 2 subsequent prospective biennial surveys. A total of 8,593 subjects were included, 0.9% of whom reported newly developed CAD events during the 4 years of follow-up. Cox regression analyses showed that the lowest serum total bilirubin level category (bilirubin ≤0.32 mg/dl) was an independent risk factor for future CAD events (adjusted hazard ratio [HR] 1.890, 95% confidence interval [CI] 1.088 to 3.284; p = 0.024). Subjects with metabolic syndrome had a higher risk for future CAD events than those without metabolic syndrome (HR 3.366, 95% CI 2.079 to 5.448, p <0.001). Low bilirubin levels increased the CAD risk in subjects with metabolic syndrome further (HR 2.016, 95% CI 1.069 to 3.800; p = 0.030), with these subjects showing a >6 times higher risk for CAD than subjects with bilirubin levels >0.32 mg/dl and no metabolic syndrome (HR 6.228, 95% CI 3.118 to 12.437; p <0.001). In conclusion, the addition of low serum bilirubin levels to the traditional risk factors for CAD, such as metabolic syndrome, may yield an improvement of risk prediction.

Effects of Aerobic Exercise on Abdominal Fat, Thigh Muscle Mass and Muscle Strength in Type 2 Diabetic Subject

Background Aerobic exercise can effectively reduce visceral fat. However, few studies have examined the effect of daily physical activity on obesity and cardiopulmonary function in the subjects with diabetes. We examined the effect of moderate intensity of walking in obese diabetes patients by monitoring of daily activity and measuring the change in abdominal fat area, muscle are and maximal muscle strength. Methods We randomly assigned 27 obese women with type 2 diabetes to an aerobic exercise group (AG, n = 13) and control group (CG, n = 14). The AG performed moderate intensity walking for 60 minutes per exercise, 5 times per week, and for 12 weeks. The activity energy expenditure was monitored by a multi-record accelerometer. The CG maintained routine daily activities. At the time of the initiation of the study and after 12 weeks of exercise, the aerobic exercise capacity was assessed using oxygen consumption rate at anaerobic threshold (VO2-AT). The abdominal fat area and the quadriceps muscle area were measured by computed tomography, and the maximum muscle strength of the upper and lower limbs was measured by a chest press and a leg press, respectively. Results The mean age of the study subjects was 56.6 ± 8.0 years, the mean duration of diabetes was 6.3 ± 6.0 years, and the body weight index (BMI) was 27.3 ± 2.7 kg/m2. The BMI of the AG was significantly decreased (P = 0.003). In the AG, the visceral fat area and subcutaneous fat area were also significantly decreased (P = 0.018 and P < 0.001, respectively) but not in CG. VO2-AT of the AG was significantly improved, while that of the CG did not change (P = 0.009 and P = 0.115, respectively). The quadriceps muscle mass and the maximal muscle strength of the AG did not change, however, the CG showed a significant decrease. Duration of moderate intensity exercise was correlated with the decrease in total abdominal fat area (r = -0.484; P = 0.011) and that of high intensity exercise was correlated with improvement of cardiopulmonary function (r = 0.414; P = 0.032). Conclusion Daily moderate intensity aerobic exercise is effective at reducing abdominal fat mass, while high intensity exercise improves cardiopulmonary function.

Polymorphisms of ADIPOR1 and ADIPOR2 are associated with phenotypes of type 2 diabetes in Koreans.

Objective  Adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) are considered as candidate genes for type 2 diabetes because they mediate the metabolic effects of adiponectin on target tissues. We investigated whether common polymorphisms of ADIPOR1 and ADIPOR2 are associated with type 2 diabetes or its related phenotypes in Koreans.

The effects of statin use on the development of tuberculosis among patients with diabetes mellitus.

OBJECTIVE To evaluate whether statin use affects the development of tuberculosis (TB) among patients with diabetes mellitus (DM). METHODS This is a retrospective cohort study of patients with newly diagnosed type 2 DM based on the South Korean nationwide claims database. The participants were type 2 DM patients aged 20-99 years who were newly treated with anti-diabetic drugs between 1 January 2007 and 31 December 2010. Patients who had statin prescriptions before a diagnosis of diabetes or were diagnosed with TB before diabetes were excluded. RESULTS Of 840,899 newly diagnosed type 2 DM patients, 281,842 (33.5%) patients were statin users and 559,057 (66.5%) were non-users. During the study period, 4075 [corrected] individuals were diagnosed with TB; the estimated incidence of TB in our cohort was 251/100,000 patient-years (95%CI 243-258). In comparison to non-TB patients, statin users were less frequent among TB patients (19.2% vs. 33.6%). After adjustment for potential baseline confounders, statin use was not associated with the development of TB in DM patients (aHR 0.98; 95%CI 0.89-1.07). CONCLUSIONS TB development among newly diagnosed type 2 DM was considerable, and statin use among these diabetics was not associated with a protective effect on TB incidence.