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1.  Regulation of Glucose Control in People with Type 2 Diabetes: A Review and Consensus 
Korean Diabetes Journal  2010;34(1):16-20.
A conference was convened by the Korean Diabetes Association and the Korean Endocrine Society on September 7, 2009 to discuss and organize the results of research on intensive glucose control for the prevention of cardiovascular disease in patients with type 2 diabetes. Professor Kyung Soo Park led the conference, and Professors Kwang Won Kim and Ho Young Son acted as chairmen. Professors Doo Man Kim, Tae Sun Park, and Bong Soo Cha reported on intensive glucose control and diabetic complications, including the UK Prospective Diabetes Study (UKPDS), Diabetes Control and Complication Trial (DCCT) research results, the recently published Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT) research, as well as meta-analyses. Professor Jeong-Taek Woo reported on the manuscript written by the committee for the Korean Diabetes Association which dealt with the treatment of diabetes mellitus. Professors Kyung Soo Ko, Joong Yeol Park, Hyun Shik Son, Moon-Kyu Lee, Dong-Won Byun, and Yoon-Sok Chung participated in the discussion and collected information for the manuscript from all of the participants. The aim of the debate was to determine how to establish target goals for intensive glucose control and how to individualize those goals. The participants concluded that there was no need to modify the recommendation of maintaining an HbA1c under 6.5%, the current blood glucose treatment goal that is recommended by the Korean Diabetes Association. In addition, individual target goals for glucose control were recommended depending on the situation of each patient. We report on the consensus statement from the meeting.
doi:10.4093/kdj.2010.34.1.16
PMCID: PMC2879906  PMID: 20532015
2.  Metabolic syndrome as a predictor of type 2 diabetes, and its clinical interpretations and usefulness 
Abstract
Metabolic syndrome is defined as a cluster of glucose intolerance, hypertension, dyslipidemia and central obesity with insulin resistance as the source of pathogenesis. Although several different combinations of criteria have been used to define metabolic syndrome, a recently published consensus recommends the use of ethnic‐specific criteria, including waist circumference as an indicator of central obesity, triglyceride and high‐density lipoprotein (HDL) cholesterol as indicators of dyslipidemia, and blood pressure greater than 130/85 mmHg. The definition of dysglycemia, and whether central obesity and insulin resistance are essential components remain controversial. Regardless of the definition, the prevalence of metabolic syndrome is increasing in Western and Asian countries, particularly in developing areas undergoing rapid socioenvironmental changes. Numerous clinical trials have shown that metabolic syndrome is an important risk factor for cardiovascular disease (CVD), type 2 diabetes mellitus and all‐cause mortality. Therefore, metabolic syndrome might be useful as a practical tool to predict these two major metabolic disorders. Comprehensive management of risk factors is very important to the improvement of personal and public health. However, recent studies have focused on the role metabolic syndrome plays as a risk factor for CVD; its importance in the prediction of incident diabetes is frequently overlooked. In the present review, we summarize the known evidence supporting metabolic syndrome as a predictor for type 2 diabetes mellitus and CVD. Additionally, we suggest how metabolic syndrome might be useful in clinical practice, especially for the prediction of diabetes.
doi:10.1111/jdi.12075
PMCID: PMC4020225  PMID: 24843675
Metabolic syndrome; Risk factor; Type 2 diabetes mellitus
3.  Insulin Initiation in Insulin-Naïve Korean Type 2 Diabetic Patients Inadequately Controlled on Oral Antidiabetic Drugs in Real-World Practice: The Modality of Insulin Treatment Evaluation Study 
Diabetes & Metabolism Journal  2015;39(6):481-488.
Background
The Modality of Insulin Treatment Evaluation (MOTIV) study was performed to provide real-world data concerning insulin initiation in Korean type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control with oral hypoglycemic agents (OHAs).
Methods
This multicenter, non-interventional, prospective, observational study enrolled T2DM patients with inadequate glycemic control (glycosylated hemoglobin [HbA1c] ≥7.0%) who had been on OHAs for ≥3 months and were already decided to introduce basal insulin by their physician prior to the start of the study. All treatment decisions were at the physician's discretion to reflect real-world practice.
Results
A total of 9,196 patients were enrolled, and 8,636 patients were included in the analysis (mean duration of diabetes, 8.9 years; mean HbA1c, 9.2%). Basal insulin plus one OHA was the most frequently (51.0%) used regimen. After 6 months of basal insulin treatment, HbA1c decreased to 7.4% and 44.5% of patients reached HbA1c <7%. Body weight increased from 65.2 kg to 65.5 kg, which was not significant. Meanwhile, there was significant increase in the mean daily insulin dose from 16.9 IU at baseline to 24.5 IU at month 6 (P<0.001). Overall, 17.6% of patients experienced at least one hypoglycemic event.
Conclusion
In a real-world setting, the initiation of basal insulin is an effective and well-tolerated treatment option in Korean patients with T2DM who are failing to meet targets with OHA therapy.
doi:10.4093/dmj.2015.39.6.481
PMCID: PMC4696984  PMID: 26616594
Basal insulin; Diabetes mellitus, type 2; Korea; Pragmatic clinical trials as topic
4.  Predictive Clinical Parameters and Glycemic Efficacy of Vildagliptin Treatment in Korean Subjects with Type 2 Diabetes 
Diabetes & Metabolism Journal  2013;37(1):72-80.
Background
The aims of this study are to investigate the glycemic efficacy and predictive parameters of vildagliptin therapy in Korean subjects with type 2 diabetes.
Methods
In this retrospective study, we retrieved data for subjects who were on twice-daily 50 mg vildagliptin for at least 6 months, and classified the subjects into five treatment groups. In three of the groups, we added vildagliptin to their existing medication regimen; in the other two groups, we replaced one of their existing medications with vildagliptin. We then analyzed the changes in glucose parameters and clinical characteristics.
Results
Ultimately, 327 subjects were analyzed in this study. Vildagliptin significantly improved hemoglobin A1c (HbA1c) levels over 6 months. The changes in HbA1c levels (ΔHbA1c) at month 6 were -2.24% (P=0.000), -0.77% (P=0.000), -0.80% (P=0.001), -0.61% (P=0.000), and -0.34% (P=0.025) for groups 1, 2, 3, 4, and 5, respectively, with significance. We also found significant decrements in fasting plasma glucose levels in groups 1, 2, 3, and 4 (P<0.05). Of the variables, initial HbA1c levels (P=0.032) and history of sulfonylurea use (P=0.026) were independently associated with responsiveness to vildagliptin treatment.
Conclusion
Vildagliptin was effective when it was used in subjects with poor glycemic control. It controlled fasting plasma glucose levels as well as sulfonylurea treatment in Korean type 2 diabetic subjects.
doi:10.4093/dmj.2013.37.1.72
PMCID: PMC3579155  PMID: 23439802
Diabetes mellitus; Dipeptidyl peptidase 4; Dipeptidyl peptidase 4 inhibitor; Vildagliptin
5.  Changes in Metabolic Health Status Over Time and Risk of Developing Type 2 Diabetes 
Medicine  2015;94(40):e1705.
Supplemental Digital Content is available in the text
Abstract
Metabolic health and obesity are not stable conditions, and changes in the status of these conditions might lead to different clinical outcomes. We aimed to determine whether changes in metabolic health status or obesity over time have any effect on the risk of future diabetes.
Nondiabetic individuals (n = 2692) from a population-based prospective cohort study with baseline and 2 follow-up examinations at 4-year intervals were included. Being “metabolically obese” (MO) was defined as being in the highest quartile of the TyG index (ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]), whereas falling into the lower 3 quartiles was regarded as being “metabolically healthy” (MH). Individuals were classified as “obese” (O) or “nonobese” (NO) using a body mass index of 25 kg/m2 as a cut-off. The risk of diabetes at year 8 was assessed according to changes of metabolic health status between year 0 and 4.
Multivariate-adjusted relative risks (RRs) (95% confidence interval [CI]) of diabetes were significantly higher in individuals who retained the MONO phenotype (RR 3.72, 95% CI 2.10, 6.60) or who had progressed to MONO from the MHNO phenotype (RR 1.96, 95% CI 1.06, 3.61), whereas it was not significant in individuals who had improved to MHNO from the MONO phenotype (RR 0.67, 95% CI 0.26, 1.74) compared with individuals who retained the MHNO phenotype. In contrast, obese individuals had significantly higher RRs for diabetes, independent of changes in metabolic health status, whereas weight reduction resulted in a decreased risk of diabetes. Sensitivity analysis using the presence or absence of the metabolic syndrome as a definition of metabolic health revealed similar results.
Changes in metabolic health status were an independent risk factor for future diabetes in nonobese individuals, whereas general obesity had a greater contribution to the risk of obese individuals developing diabetes. These observations might imply a different intervention strategy for diabetes prevention according to obesity status.
doi:10.1097/MD.0000000000001705
PMCID: PMC4616763  PMID: 26448024
6.  Family-Based Association Study of Pulmonary Function in a Population in Northeast Asia 
PLoS ONE  2015;10(10):e0139716.
The spirometric measurement of pulmonary function by measuring the forced expiratory volume in one second (FEV1) is a heritable trait that reflects the physiological condition of the lung and airways. Genome-wide linkage and association studies have identified a number of genes and genetic loci associated with pulmonary function. However, limited numbers of studies have been reported for Asian populations. In this study, we aimed to investigate genetic evidence of pulmonary function in a population in northeast Asia. We conducted a family-based association test with 706 GENDISCAN study participants from 72 Mongolian families to determine candidate genetic determinants of pulmonary function. For the replication, we chose seven candidate single nucleotide polymorphisms (SNPs) from the 5 loci, and tested 1062 SNPs for association with FEV1 from 2,729 subjects of the Korea Healthy Twin study. We identified TMEM132C as a potential candidate gene at 12q24.3, which is a previously reported locus of asthma and spirometric indices. We also found two adjacent candidate genes (UNC93A and TTLL2) in the 6q27 region, which has been previously identified as a pulmonary function locus in the Framingham cohort study. Our findings suggest that novel candidate genes (TMEM132C, UNC93A and TTLL2) in two different regions are associated with pulmonary function in a population in northeast Asia.
doi:10.1371/journal.pone.0139716
PMCID: PMC4592257  PMID: 26430897
7.  Diabetic Peripheral Neuropathy Is Associated With Increased Arterial Stiffness Without Changes in Carotid Intima–Media Thickness in Type 2 Diabetes 
Diabetes Care  2011;34(6):1403-1405.
OBJECTIVE
This study was conducted to investigate the association of diabetic peripheral neuropathy (DPN) with both arterial stiffness and intima–media thickness (IMT).
RESEARCH DESIGN AND METHODS
We conducted a cross-sectional analysis of 731 subjects with type 2 diabetes. DPN was diagnosed on the basis of neuropathic symptoms, insensitivity to a 10-g monofilament, abnormal pin-prick sensation, and abnormal current perception threshold. Arterial stiffness was assessed by cardio-ankle vascular index (CAVI), and IMT was assessed by B-mode ultrasonography.
RESULTS
Patients with DPN had higher CAVI than those without DPN in multivariate-adjusted models, whereas no differences in IMT were observed between patients with and without DPN after adjustment for age and sex. In the multivariate analysis, CAVI was a significant determinant of DPN (odds ratio 1.36 [95% CI 1.13–1.65], P = 0.001).
CONCLUSIONS
DPN is significantly associated with arterial stiffness without carotid intimal changes in patients with type 2 diabetes.
doi:10.2337/dc10-2222
PMCID: PMC3114324  PMID: 21515840
8.  Genetic association of APOA5 and APOE with metabolic syndrome and their interaction with health-related behavior in Korean men 
Background
Genome-wide association studies have been used extensively to identify genetic variants linked to metabolic syndrome (MetS), but most of them have been conducted in non-Asian populations. This study aimed to evaluate the association between MetS and previously studied single nucleotide polymorphisms (SNPs), and their interaction with health-related behavior in Korean men.
Methods
Seventeen SNPs were genotyped and their association with MetS and its components was tested in 1193 men who enrolled in the study at Seoul National University Hospital.
Results
We found that rs662799 near APOA5 and rs769450 in APOE had significant association with MetS and its components. The SNP rs662799 was associated with increased risk of MetS, elevated triglyceride (TG) and low levels of high-density lipoprotein, while rs769450 was associated with a decreased risk of TG. The SNPs showed interactions between alcohol drinking and physical activity, and TG levels in Korean men.
Conclusions
We have identified the genetic association and environmental interaction for MetS in Korean men. These results suggest that a strategy of prevention and treatment should be tailored to personal genotype and the population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-015-0111-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12944-015-0111-5
PMCID: PMC4568070  PMID: 26365620
APOA5; APOE; Health behavior; Metabolic syndrome; Triglyceride
9.  A Common Variant of NGEF Is Associated with Abdominal Visceral Fat in Korean Men 
PLoS ONE  2015;10(9):e0137564.
Central adiposity, rather than body mass index (BMI), is a key pathophysiological feature of the development of obesity-related diseases. Although genetic studies by anthropometric measures such as waist circumference have been widely conducted, genetic studies for abdominal fat deposition measured by computed tomography (CT) have been rarely performed. A total of 1,243 participants who were recruited from two health check-up centers were included in this study. We selected four and three single-nucleotide polymorphisms (SNPs) in NGEF and RGS6, respectively, and analyzed the associations between the seven SNPs and central adiposity measured by CT using an additive, dominant, or recessive model. The participants were generally healthy middle-aged men (50.7 ± 5.3 years). In the additive model, the rs11678490 A allele of NGEF was significantly associated with total adipose tissue, visceral adipose tissue (VAT), and subcutaneous adipose tissue (all P < 0.05). The AA genotype of this SNP in the recessive model showed a more significant association with all adiposity traits, and its association with VAT remained significant even after adjustment for BMI (P = 0.005). In the overall or visceral obesity group analysis, the AA genotype of rs11678490 showed no association with overall obesity (P = 0.148), whereas it was significantly associated with visceral obesity both before (P = 0.010) and after (P = 0.029) adjustment for BMI. In particular, an AA genotype effect was conspicuous between lower and upper groups with 5% extreme VAT phenotypes (OR = 9.59, 95% CI = 1.50–61.31). However, we found no significant association between SNPs of RGS6 and central adiposity. We identified a visceral-fat-associated SNP, rs11678490 of NGEF, in Korean men. This study suggests that the genetic background of central adiposity and BMI is different, and that additional efforts should be made to find the unique genetic architecture of intra-abdominal fat accumulation.
doi:10.1371/journal.pone.0137564
PMCID: PMC4560439  PMID: 26340433
10.  Prevalence and Associated Factors of Diabetic Retinopathy in Rural Korea: The Chungju Metabolic Disease Cohort Study 
Journal of Korean Medical Science  2011;26(8):1068-1073.
This study was aimed to investigate the prevalence of diabetic retinopathy and its associated factors in rural Korean patients with type 2 diabetes. A population-based, cross-sectional diabetic retinopathy survey was conducted from 2005 to 2006 in 1,298 eligible participants aged over 40 yr with type 2 diabetes identified in a rural area of Chungju, Korea. Diabetic retinopathy was diagnosed by a practicing ophthalmologist using funduscopy. The overall prevalence of diabetic retinopathy in the population was 18% and proliferative or severe non-proliferative form was found in 5.0% of the study subjects. The prevalence of retinopathy was 6.2% among those with newly diagnosed type 2 diabetes and 2.4% of them had a proliferative or severe non-proliferative diabetic retinopathy. The odds ratio of diabetic retinopathy increased with the duration of diabetes mellitus (5-10 yr: 5.2- fold; > 10 yr: 10-fold), postprandial glucose levels (> 180 mg/dL: 2.5-fold), and HbA1c levels (every 1% elevation: 1.34-fold). The overall prevalence of diabetic retinopathy in rural Korean patients was similar to or less than that of other Asian group studies. However, the number of patients with proliferative or severe non-proliferative diabetic retinopathy was still high and identified more frequently at the time of diagnosis. This emphasizes that regular screening for diabetic retinopathy and more aggressive management of glycemia can reduce the number of people who develop diabetic retinopathy.
doi:10.3346/jkms.2011.26.8.1068
PMCID: PMC3154343  PMID: 21860558
Diabetic Retinopathy; Prevalence; Risk Factors
11.  Comparison of the Efficacy of Glimepiride, Metformin, and Rosiglitazone Monotherapy in Korean Drug-Naïve Type 2 Diabetic Patients: The Practical Evidence of Antidiabetic Monotherapy Study 
Diabetes & Metabolism Journal  2011;35(1):26-33.
Background
Although many anti-diabetic drugs have been used to control hyperglycemia for decades, the efficacy of commonly-used oral glucose-lowering agents in Korean type 2 diabetic patients has yet to be clearly demonstrated.
Methods
We evaluated the efficacy of glimepiride, metformin, and rosiglitazone as initial treatment for drug-naïve type 2 diabetes mellitus patients in a 48-week, double-blind, randomized controlled study that included 349 Korean patients. Our primary goal was to determine the change in HbA1c levels from baseline to end point. Our secondary goal was to evaluate changes in fasting plasma glucose (FPG) levels, body weight, frequency of adverse events, and the proportion of participants achieving target HbA1c levels.
Results
HbA1c levels decreased from 7.8% to 6.9% in the glimepiride group (P<0.001), from 7.9% to 7.0% in the metformin group (P<0.001), and from 7.8% to 7.0% (P<0.001) in the rosiglitazone group. Glimepiride and rosiglitazone significantly increased body weight and metformin reduced body weight during the study period. Symptomatic hypoglycemia was more frequent in the glimepiride group and diarrhea was more frequent in the metformin group.
Conclusion
The efficacy of glimepiride, metformin, and rosiglitazone as antidiabetic monotherapies in drug-naïve Korean type 2 diabetic patients was similar in the three groups, with no statistical difference. This study is the first randomized controlled trial to evaluate the efficacy of commonly-used oral hypoglycemic agents in Korean type 2 diabetic patients. An additional subgroup analysis is recommended to obtain more detailed information.
doi:10.4093/dmj.2011.35.1.26
PMCID: PMC3080564  PMID: 21537410
Diabetes mellitus, type 2; Glimepiride; Metformin; Rosiglitazone
12.  Clinical Significance of Observation without Repeated Radioiodine Therapy in Differentiated Thyroid Carcinoma Patients with Positive Surveillance Whole-Body Scans and Negative Thyroglobulin 
Background/Aims
Currently, there is no consensus on the necessity of repeated radioiodine therapy (RAI) in patients who show iodine uptake in the thyroid bed on a diagnostic whole-body scan (DxWBS) despite undetectable thyroglobulin (Tg) levels after remnant ablation. The present study investigated the clinical outcomes of scan-positive, Tg-negative patients (WBS+Tg-) who did or did not receive additional RAI.
Methods
We retrospectively reviewed 389 differentiated thyroid carcinoma patients who underwent a total thyroidectomy and received high-dose RAI from January 2003 through December 2005. The patients were classified according to surveillance DxWBS findings and TSH-stimulated Tg levels 6 to 12 months after the initial RAI.
Results
Forty-four of the 389 patients (11.3%) showed thyroid bed uptake on a DxWBS despite negative Tg levels (WBS+Tg-). There was no difference in clinical and pathological parameters between WBS+Tg- and WBS-Tg- patients, except for an increased frequency of thyroiditis in the WBS+Tg- group. Among the 44 WBS+Tg- patients, 27 subjects were treated with additional RAI; 25 subjects showed no uptake in subsequent DxWBS. Two patients were evaluated only by ultrasonography (US) and displayed no persistent/recurrent disease. The other 17 patients received no further RAI; Eight patients and two patients showed no uptake and persistent uptake, respectively, on subsequent DxWBS. Six patients presented negative subsequent US findings, and one was lost to follow-up. Over the course of 53.2 ± 10.1 months, recurrence/persistence was suspicious in two patients in the treatment group.
Conclusions
There were no remarkable differences in clinical outcomes between observation and treatment groups of WBS+Tg- patients. Observation without repeated RAI may be an alternative management option for WBS+Tg- patients.
doi:10.3904/kjim.2010.25.4.408
PMCID: PMC2997970  PMID: 21179279
Iodine radioisotopes; Thyroglobulin; Thyroid neoplasms; Whole body scan
13.  The Insulin Resistance but Not the Insulin Secretion Parameters Have Changed in the Korean Population during the Last Decade 
Diabetes & Metabolism Journal  2015;39(2):117-125.
Background
This study aimed to compare the patterns of insulin secretion and resistance between Korean subjects in the 1990s and 2000s.
Methods
Insulin secretion and resistance indices were calculated from subjects who underwent 75-g oral glucose tolerance tests in the year 1997 to 1999 and 2007 to 2011 at the Seoul St. Mary's Hospital, Korea.
Results
A total of 578 subjects from the 1990s (mean age, 48.5 years) and 504 subjects from the 2000s (mean age, 50.2 years) were enrolled. Compared with the subjects from the 1990s, those from the 2000s exhibited increased insulin resistance (increased homeostatic model assessment for insulin resistance), and reduced insulin sensitivity (reduced Matsuda index and quantitative insulin sensitivity check index), regardless of their glucose tolerance status. However, insulinogenic index did not reveal significant differences between the 2 decades in subjects with or without diabetes. A distinct relationship was confirmed between Matsuda index and total area under the curve (insulin/glucose) in each glucose tolerance group. The mean product of the Matsuda index and the total area under the curve (insulin/glucose) as well as the oral disposition index, was lower in subjects with normal glucose tolerance from the 2000s than in those from the 1990s.
Conclusion
After rapid economic growth and changes in lifestyle patterns, insulin resistance has worsened across the glucose tolerance status; however, the insulin secretory function remained unchanged, which resulted in an increase in the susceptibility to the development of type 2 diabetes mellitus among Korean subjects without diabetes. We could not rule out the potential selection bias and therefore, further studies in general Korean population are needed.
doi:10.4093/dmj.2015.39.2.117
PMCID: PMC4411542  PMID: 25922805
Diabetes mellitus; Insulin resistance; Insulin secretion; Korea; Oral glucose tolerance test
14.  Prevalence and Clinical Characteristics of the Metabolic Syndrome in Middle-Aged Korean Adults 
Background
The aim of this study was to analyze the prevalence and clinical characteristic of the metabolic syndrome of adults, over 40 years old, living in Korea.
Methods
This study was carried out for 2 years, 2003-2004, on total 5,330 individuals (2,197 men and 3,133 women) selected by the stratified random cluster sampling among adults over 40 years old. Metabolic syndrome was defined based on both the NCEP-ATP III criteria and Modified ATP III criteria applying the WHO-APR (Asian Pacific Region)'s abdominal obesity criteria (waist circumference > 90 cm in men, 80 cm in women) instead of NCEP-ATP III criteria.
Results
Using NCEP-ATP III criteria, the age-adjusted overall prevalence of metabolic syndrome was 24.8% (17.6% in men, 30.0% in women). Age-adjusted overall prevalence of metabolic syndrome as defined by modified-ATP III criteria was 34.3% (26.3% in men, 40.1% in women). The prevalence of metabolic syndrome for each age group (40-49, 50-59, 60-69, ≥ 70) in men was as follows: 18.8%, 17.4%, 18.3%, 14.5%. In women: 22.3%, 32.7%, 39.9%, 39.3%. The prevalence of hypertriglyceridemia (triglycerides ≥ 1.7 mmol/l) was well correlated with the changing pattern of the prevalence of metabolic syndrome both in men and women.
Conclusions
The peak age of metabolic syndrome in men was age 40 through 49, and the prevalence decreased with aging. Therefore, early intervention for risk factors of metabolic syndrome might be required in men. On the other hand, prevention for cardiovascular disease will be needed for perimenopausal women due to considerably increased prevalence in the age 50 through 59.
doi:10.3904/kjim.2005.20.4.310
PMCID: PMC3891077  PMID: 16491829
Prevalence; Metabolic syndrome
15.  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
16.  Insulin Binding and its Action in Adipocytes of Hyperthyroid and Hypothyroid Rats* 
The studies of the effects of thyroid hormone on insulin secretion and glucose metabolism have been made, but the results have been controversial.
In order to evaluate the effects of thyroid hormone at the cellular level, insulin binding and insulin-induced lipogenesis in isolated rat epididymal fat cells were studied in control, hyperthyroid and hypothyroid rats. Hyperthyroidism was induced by daily intraperitoneal injection of sodium L-thyroxine and hypothyroidism by a single injection of 131I. The adipocytes were isolated by treatment of collagenase as originally described by Gliemann (1967).
The results were as follows: 1) The fasting serum insulin levels of hyperthyroid (21.6 ± 3.7 uU/ml) and hypothyroid groups (20.5 ± 7.0 uU/ml) were not different from the value of control (23.1 ± 11 uU/ml). The fasting blood glucose level of hypothyroid group (164.9 ± 12.0 mg/dl) was higher than the values of the controls (148.2 ± 13.2 mg/dl) or the hyperthyroid group (147.0 ± 12.5 mg/dl), (p<.005).2) The specific 125I-insulin binding of the hyperthyroid group was not different from the value of the controls, but the value of the hypothyroid group was higher than the value of the controls (p<.005).3) The insulin receptor concentration of the hypothyroid group (1.09 ± 0.02 ng/0.5×105 cells) was higher than the value of the controls (0.72 ± 0.01 ng/0.5×105 cells) or the hyperthyroid group (0.79 ± 0.02 ng/0.5×105 cells), (p<.05).4) The average affinities of the receptors in all groups showed an inverse correlation with the insulin concentration. The average affinity of the hypothyroid group was higher than the value of the control or the hyperthyroid group.5) Insulin-induced lipogenesis was reduced proportionately in all insulin concentrations in both the hyperthyroid and hypothyroid groups compared with the dose-response curve of the control group. The maximal amount of lipogenesis of the hyperthyroid and hypothyroid groups were 63.4% (p<.05) and 32.3% (p<.005) of the controls, respectively.
These studies suggest that thyroid hormone may regulate the concentration of insulin receptors, and altered thyroid states reduce insulin-induced lipogenesis in the adipocyte at postreceptor levels.
doi:10.3904/kjim.1987.2.1.18
PMCID: PMC4534924  PMID: 3154813
Insulin binding; Insulin-induced lipogenesis; Insulin receptor concentration; Postreceptor
17.  Predicting the Development of Diabetes Using the Product of Triglycerides and Glucose: The Chungju Metabolic Disease Cohort (CMC) Study 
PLoS ONE  2014;9(2):e90430.
Background
To determine whether the TyG index, a product of the levels of triglycerides and fasting plasma glucose (FPG) might be a valuable marker for predicting future diabetes.
Methods
A total of 5,354 nondiabetic subjects who had completed their follow-up visit for evaluating diabetes status were selected from a large cohort of middle-aged Koreans in the Chungju Metabolic Disease Cohort study. The risk of diabetes was assessed according to the baseline TyG index, calculated as ln[fasting triglycerides (mg/dL) × FPG (mg/dL)/2]. The median follow-up period was 4.6 years.
Results
During the follow-up period, 420 subjects (7.8%) developed diabetes. The baseline values of the TyG index were significantly higher in these subjects compared with nondiabetic subjects (8.9±0.6 vs. 8.6±0.6; P<0.0001) and the incidence of diabetes increased in proportion to TyG index quartiles. After adjusting for age, gender, body mass index, waist circumference, systolic blood pressure, high-density lipoprotein (HDL)-cholesterol level, a family history of diabetes, smoking, alcohol drinking, education level and serum insulin level, the risk of diabetes onset was more than fourfold higher in the highest vs. the lowest quartile of the TyG index (relative risk, 4.095; 95% CI, 2.701–6.207). The predictive power of the TyG index was better than the triglyceride/HDL-cholesterol ratio or the homeostasis model assessment of insulin resistance.
Conclusions
The TyG index, a simple measure reflecting insulin resistance, might be useful in identifying individuals at high risk of developing diabetes.
doi:10.1371/journal.pone.0090430
PMCID: PMC3938726  PMID: 24587359
18.  Olanzapine-Induced Diabetic Ketoacidosis and Neuroleptic Malignant Syndrome with Rhabdomyolysis: A Case Report 
Endocrinology and Metabolism  2013;28(1):70-75.
Atypical antipsychotics have replaced conventional antipsychotics in the treatment of schizophrenia because they have less of a propensity to cause undesirable neurologic adverse events including extrapyramidal symptoms, tardive dyskinesia, and neuroleptic malignant syndrome (NMS). However, atypical antipsychotics have been known to result in various metabolic complications such as impaired glucose tolerance, diabetes and even diabetic ketoacidosis (DKA). In addition, a number of NMS cases have been reported in patients treated with atypical antipsychotics, although the absolute incidence of neurologic side effects is currently significantly low. Here, we report a patient who simultaneously developed DKA, acute renal failure and NMS with rhabdomyolysis after olanzapine treatment. Olanzapine-induced metabolic complications and NMS were dramatically improved with cessation of the olanzapine treatment and initiation of supportive management including fluid therapy, hemodialysis, and intensive glycemic control using insulin. At short-term follow-up, insulin secretion was markedly recovered as evidenced by a restoration of serum C-peptide level, and the patient no longer required any hypoglycemic medications. Despite the dramatic increase in the use of atypical antipsychotics treatment, individualized treatments along with careful monitoring may be prudent for high risk or vulnerable patients in order to avoid the development of metabolic side effects.
doi:10.3803/EnM.2013.28.1.70
PMCID: PMC3811799  PMID: 24396655
Diabetic ketoacidosis; Neuroleptic malignant syndrome; Olanzapine
20.  Effects of a 6-Month Exenatide Therapy on HbA1c and Weight in Korean Patients with Type 2 Diabetes: A Retrospective Cohort Study 
Diabetes & Metabolism Journal  2012;36(5):364-370.
Background
While many studies have shown the good efficacy and safety of exenatide in patients with diabetes, limited information is available about exenatide in clinical practice in Korean populations. Therefore, this retrospective cohort study was designed to analyze the effects of exenatide on blood glucose level and body weight in Korean patients with type 2 diabetes mellitus.
Methods
We reviewed the records of the patients with diabetes who visited Seoul St. Mary's Hospital and for whom exenatide was prescribed from June 2009 to October 2011. After excluding subjects based on their race/ethnicity, medical history, whether or not they changed more than 2 kinds of oral hypoglycemic agents with exenatide treatment, loss to follow-up, or whether they stopped exenatide therapy within 6 months, a total of 52 subjects were included in the final analysis.
Results
The mean glycated hemoglobin (HbA1c) level and weight remarkably decreased from 8.5±1.7% to 6.7±1.0% (P<0.001) and from 82.3±15.8 kg to 78.6±16.3 kg (P<0.001), respectively. The multiple regression analysis indicated that the reduction in HbA1c level was significantly associated with a shorter duration of diabetes, a higher baseline HbA1c level, and greater weight reduction, whereas weight loss had no significant correlation with other factors. No severe adverse events were observed.
Conclusion
These results suggest that a 6-month exenatide injection therapy significantly improved patients' HbA1c levels and body weights without causing serious adverse effects in Korean patients with type 2 diabetes.
doi:10.4093/dmj.2012.36.5.364
PMCID: PMC3486983  PMID: 23130321
Diabetes mellitus, type 2; Exenatide; Glucagon-like peptide 1; Treatment outcome
21.  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
22.  Gene mapping study for constitutive skin color in an isolated Mongolian population 
Experimental & Molecular Medicine  2011;44(3):241-249.
To elucidate the genes responsible for constitutive human skin color, we measured the extent of skin pigmentation in the buttock, representative of lifelong non-sun-exposed skin, and conducted a gene mapping study on skin color in an isolated Mongolian population composed of 344 individuals from 59 families who lived in Dashbalbar, Mongolia. The heritability of constitutive skin color was 0.82, indicating significant genetic association on this trait. Through the linkage analysis using 1,039 short tandem repeat (STR) microsatellite markers, we identified a novel genomic region regulating constitutive skin color on 11q24.2 with an logarithm of odds (LOD) score of 3.39. In addition, we also found other candidate regions on 17q23.2, 6q25.1, and 13q33.2 (LOD ≥ 2). Family-based association tests on these regions with suggestive linkage peaks revealed ten and two significant single nucleotide polymorphisms (SNPs) on the linkage regions of chromosome 11 and 17, respectively. We were able to discover four possible candidate genes that would be implicated to regulate human skin color: ETS1, UBASH3B, ASAM, and CLTC.
doi:10.3858/emm.2012.44.3.020
PMCID: PMC3317488  PMID: 22198297
genetic association studies; genetic linkage; microsatellite repeats; polymorphism, single nucleotide; quantitative trait, heritable; skin pigmentation
23.  Factors Associated with Insulin Resistance in a Middle-Aged Non-Obese Rural Population: The Chungju Metabolic Disease Cohort (CMC) Study 
Epidemiology and Health  2011;33:e2011009.
OBJECTIVES
We aimed to determine the characteristics affecting insulin resistance in non-obese middle-aged adults in a rural community.
METHODS
A total of 1,270 non-diabetic adults aged between 40 and 64 years old with body mass index (BMI) less than 25 kg/m2 were analyzed. Subjects with insulin resistance were defined as those who had the highest quartile value of the homeostasis model assessment of insulin resistance (HOMA-IR) in a non-diabetic population.
RESULTS
A total of 217 subjects (20.6%) had insulin resistance. Prevalence of metabolic syndrome was significantly higher in insulin-resistant subjects in both men (29.3% vs. 10.3%) and women (34.1% vs. 15.6%). Among metabolic syndrome components, elevated waist circumference and elevated triglyceride were higher in insulin-resistant subjects in both genders. After being controlled for socioeconomic status and lifestyle related covariates, the association between insulin resistance and BMI was statistically significant in the category of 23.0-24.9 kg/m2 in men (adjusted OR, 4.63; 95% confidence interval [95% CI], 1.77-12.15) using the category of 18.5-20.9 kg/m2 as a reference. In addition, the association between insulin resistance and abdominal obesity was statistically significant only for men (adjusted OR, 2.57; 95% CI, 1.29-5.11).
CONCLUSION
Insulin resistance appears to be highly associated with high BMI and abdominal obesity, even in non-obese, non-diabetic middle-aged men.
doi:10.4178/epih/e2011009
PMCID: PMC3195816  PMID: 22025967
Abdominal obesity; BMI; Insulin resistance
24.  Exercise Treadmill Test in Detecting Asymptomatic Coronary Artery Disease in Type 2 Diabetes Mellitus 
Diabetes & Metabolism Journal  2011;35(1):34-40.
Background
The present study was designed to develop criteria for screening patients with type 2 diabetes mellitus (T2DM) for asymptomatic coronary artery disease (CAD).
Methods
A total of 213 patients with T2DM without typical angina or chest pain were studied between 2002 and 2007. We also evaluated 53 patients with T2DM who had reported chest discomfort using an exercise treadmill test (ETT).
Results
Thirty-one of the 213 asymptomatic patients had positive ETT results. We performed coronary angiography on 23 of the 31 patients with a positive ETT and found that 11 of them had significant coronary stenosis. The main differences between the patients with significant stenosis and those with a negative ETT were age (63.1±9.4 vs. 53.7±10.1 years, P=0.008) and duration of diabetes (16.0±7.5 vs. 5.5±5.7 years, P<0.001). The positive predictive value (PPV) of the ETT was calculated to be 47.8%. The PPV of the ETT increased to 87.5% in elderly patients (≥60 years) with a long duration of diabetes (≥10 years). The latter value is similar to that of patients with T2DM who presented with chest discomfort or exertional dyspnea. The PPV of the ETT in symptomatic patients was 76.9%.
Conclusion
In the interest of cost-effectiveness, screening for asymptomatic CAD could be limited to elderly patients with a duration of diabetes ≥10 years.
doi:10.4093/dmj.2011.35.1.34
PMCID: PMC3080575  PMID: 21537411
Diabetes mellitus; Duration of diabetes; Exercise treadmill test; Silent myocardial ischemia
25.  Effect of the combination of mitiglinide and metformin on glycemic control in patients with type 2 diabetes mellitus 
Abstract
Aims/Introduction:  Mitiglinide is the newest drug in the meglitinide family. It increases the early‐phase insulin release through rapid association‐dissociation kinetics in the pancreatic β cells. The efficacy and safety of adding meglitinide to metformin monotherapy in patients with type 2 diabetes are unknown.
Materials and Methods:  We carried out a prospective, randomized, multicenter trial to assess the efficacy and safety of combined treatment with mitiglinide and metformin for patients with type 2 diabetes who showed inadequate glycemic control with metformin monotherapy. Subjects with glycated hemoglobin (HbA1c) >7.0% after an 8‐week metformin run‐in phase were randomized to a 16‐week trial phase with metformin plus mitiglinide (Met + Mit) or metformin plus placebo (Met + Pcb).
Results:  Compared with the Met + Pcb group, the Met + Mit group showed a greater reduction in HbA1c (−0.7 ± 0.6%vs−0.4 ± 0.7%, P = 0.002), fasting plasma glucose (−0.77 ± 1.76 mmol/L vs−0.05 ± 1.60 mmol/L, P = 0.015) and 2‐h postprandial glucose (−3.76 ± 3.57 mmol/L vs−0.84 ± 3.07 mmol/L, P < 0.0001). The proportion of the patients who achieved the target HbA1c value of <7% at the end of the study was also higher in the Met + Mit group than the Met + Pcb group (49.3%vs 28.8%, P = 0.016). There were no differences in the adverse event rates between groups.
Conclusions:  Combination therapy with metformin and mitiglinide is effective and safe for the treatment of patients with type 2 diabetes who have inadequate glycemic control with metformin monotherapy. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00023.x, 2010)
doi:10.1111/j.2040-1124.2010.00023.x
PMCID: PMC4008006  PMID: 24843423
Mitiglinide; Metformin; Type 2 diabetes

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