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Background: The severity of coronavirus disease 2019 (COVID-19) among patients with long-term glucocorticoid treatment (LTGT) has not been established. We aimed to evaluate the association between LTGT and COVID-19 prognosis.Methods: A Korean nationwide cohort database of COVID-19 patients between January 2019 and September 2021 was used. LTGT was defined as exposure to at least 150 mg of prednisolone (≥5 mg/day and ≥30 days) or equivalent glucocorticoids 180 days before COVID-19 infection. The outcome measurements were mortality, hospitalization, intensive care unit (ICU) admission, length of stay, and mechanical ventilation.Results: Among confirmed patients with COVID-19, the LTGT group (n=12,794) was older and had a higher proportion of comorbidities than the control (n=359,013). The LTGT group showed higher in-hospital, 30-day, and 90-day mortality rates than the control (14.0% vs. 2.3%, 5.9% vs. 1.1%, and 9.9% vs. 1.8%, respectively; all P

Background: Conventional diagnostic approaches for adrenal tumors require multi-step processes, including imaging studies and dynamic hormone tests. Therefore, this study aimed to discriminate adrenal tumors from a single blood sample based on the combination of liquid chromatography-mass spectrometry (LC-MS) and machine learning algorithms in serum profiling of adrenal steroids.Methods: The LC-MS-based steroid profiling was applied to serum samples obtained from patients with nonfunctioning adenoma (NFA, n=73), Cushing’s syndrome (CS, n=30), and primary aldosteronism (PA, n=40) in a prospective multicenter study of adrenal disease. The decision tree (DT), random forest (RF), and extreme gradient boost (XGBoost) were performed to categorize the subtypes of adrenal tumors.Results: The CS group showed higher serum levels of 11-deoxycortisol than the NFA group, and increased levels of tetrahydrocortisone (THE), 20α-dihydrocortisol, and 6β-hydroxycortisol were found in the PA group. However, the CS group showed lower levels of dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S) than both the NFA and PA groups. Patients with PA expressed higher serum 18-hydroxycortisol and DHEA but lower THE than NFA patients. The balanced accuracies of DT, RF, and XGBoost for classifying each type were 78%, 96%, and 97%, respectively. In receiver operating characteristics (ROC) analysis for CS, XGBoost, and RF showed a significantly greater diagnostic power than the DT. However, in ROC analysis for PA, only RF exhibited better diagnostic performance than DT.Conclusion: The combination of LC-MS-based steroid profiling with machine learning algorithms could be a promising one-step diagnostic approach for the classification of adrenal tumor subtypes.

Introduction A psychometric analysis on type 2 diabetic (T2D) patients was performed to assess whether glycated hemoglobin (HbA1c) levels were dependent upon either the psychologic or economic attitude toward the use of insulin as a treatment for their diabetic condition. Methods A cross-sectional study was designed using 271 patients with T2D who regularly visited a tertiary referral hospital in South Korea from June 2019 to December 2019. Each patient enrolled in this protocol was treated with insulin for at least 6 months, had recordings of their plasma HbA1c measurement, and completed validated questionnaires consisting of items focusing on patient attitudes toward insulin use [Insulin Treatment Appraisal Scale (ITAS)] and cost-related issues related to diabetic supply purchase. Multiple regression analyses were performed to determine the association between their HbA1c and each item on the questionnaires. Results In both males and females, there was a significant association (P

AIMS To investigate the long-term effectiveness and safety of two distinct sodium-glucose co-transporter 2 (SGLT2) inhibitors, empagliflozin and dapagliflozin, in inadequately controlled type 2 diabetes (T2D) despite a combined administration of metformin, glimepiride and dipeptidyl peptidase-4 inhibitor. METHODS A total of 362 patients with T2D were enrolled for this 3-year open-label, prospective observational study. Empagliflozin (25 mg/day, n = 185) or dapagliflozin (10 mg/day, n = 177) was added to the existing triple drug regimen. HbA1c, fasting plasma glucose (FPG), body weight, and other cardiometabolic variables and adverse events were evaluated. RESULTS At 3 years, changes in HbA1c and FPG were -1.7% (standard error [SE] 0.10) and -60.0 mg/dL(2.2), and -1.1%(0.12) and -48.1 mg/dL(3.6), for empagliflozin and dapagliflozin group, respectively (P = 0.001 and P = 0.055). Empagliflozin group showed significantly greater body weight reduction (-4.5 kg [SE 0.35] vs. -1.0 kg [SE 0.40], P = 0.024) and had beneficial effects on HDL cholesterol and LDL cholesterol (both P

Context Thyroid dysfunction is associated with an increased risk of cardiovascular disease (CVD) in the general population; however, it remains controversial whether differentiated thyroid cancer (DTC) treatment, including thyroidectomy and thyroid-stimulating hormone suppression, further increases the risk of CVD. Objective This study aimed to evaluate the risk of CVD in patients with DTC. Methods We performed a review of observational studies on associations between DTC and cardiovascular outcomes, indexed in MEDLINE, Embase, and Web of Science. We excluded studies that evaluated CVD as comorbidity before DTC diagnosis and those that used active surveillance without thyroidectomy as an intervention. Risk estimates were pooled using random- and fixed-effects models when 3 or more studies reported on the outcome of interest. Echocardiographic and hemodynamic parameters were examined. Results Eighteen studies were included in the quantitative analysis (193 320 cases with DTC and 225 575 healthy controls). DTC was associated with an increased risk of atrial fibrillation (pooled risk ratio [RR] = 1.55 [95% CI: 1.30-1.84]), coronary artery disease (RR = 1.10 [1.00-1.21]), cerebrovascular accidents (RR = 1.15 [1.09-1.20]), and all-cause mortality (RR = 1.95 [1.03-3.69]). DTC was associated with higher diastolic blood pressure (standardized mean difference [SMD], 0.22 [0.01-0.42]), heart rate (0.37 [0.17-0.57]), left ventricular mass index (0.66 [0.45-0.88]), and interventricular septal thickness (0.91 [0.33-1.49]) and lower early to late ventricular filling velocities (−0.42 [−0.79 to −0.05]), but not with ejection fraction. Conclusion Patients with DTC are at an increased risk of atrial fibrillation, CVD, increased heart rate, and left ventricular mass development.

Context Because subclinical hyperthyroidism increases the risk of osteoporosis and fractures, concerns are growing about the long-term skeletal safety of TSH suppression therapy after total thyroidectomy in patients with differentiated thyroid cancer (DTC). Objective We aimed to determine the effect of TSH suppression therapy on bone mineral density (BMD) in DTC patients. Methods We searched PubMed, Embase, the Cochrane library, and other sources. Eligible observational studies included DTC patients who underwent TSH suppression therapy and BMD measurement. Two independent reviewers extracted data on the studies’ characteristics and outcomes and determined their risk of bias. Data were extracted from each study for postmenopausal/premenopausal women’s and men’s lumbar spine (LS), femoral neck (FN), and total hip (TH) BMD and summed using a random-effects meta-analysis model. The weighted mean differences with 95% CIs are expressed for the differences in outcome measurements between groups. Results Seventeen studies (739 patients and 1085 controls) were included for quantitative analysis. In postmenopausal women, TSH suppression therapy showed a significant decrease in LS BMD (-0.03; -0.05, -0.02), and a similar trend was seen in TH. In premenopausal women, TSH suppression therapy significantly increased LS BMD (0.04; 0.02, 0.06) and FN BMD (0.02; 0.01, 0.04). In men, there was no significant association between TSH suppression therapy and BMD at any site compared with the controls. Conclusion Evidence from observational studies suggests that postmenopausal women treated with TSH suppression therapy are at risk for lower BMD. Attention should be paid to long-term skeletal safety in DTC survivors.

IntroductionMonogenic diabetes is attributed to genetic variations in a single gene. Maturity-onset diabetes of the young (MODY) is the most common phenotype associated with monogenic diabetes, but is frequently misdiagnosed as either type 1 or type 2 diabetes. Increasing our basic understanding of genetic variations in MODY may help to improve the accuracy of providing the correct diagnosis and personalize subsequent treatment regimens in different racial populations. For this reason, this study was designed to identify nucleotide variants in early onset diabetes patients with clinically suspected MODY in a Korean population.Research design and methodsAmong 2908 Korean patients diagnosed with diabetes, we selected 40 patients who were diagnosed before 30 years old and were clinically suspected of MODY. Genetic testing was performed using a targeted gene sequencing panel that included 30 known monogenic diabetes genes. The pathogenicity of the identified variants was assessed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG-AMP) guidelines.ResultsA total of six rare missense variants (p.Ala544Thr in HNF1A, p.Val601Ile and p.His103Tyr in ABCC8, p.Pro33Ala in PDX1, p.Gly18Glu in INS, and p.Arg164Gln in PAX4) in five distinct MODY genes were identified in five patients. In addition, a variant was identified in mitochondrial DNA at 3243A>G in one patient. The identified variants were either absent or detected at a rare frequency in the 1000 Genomes Project. These variants were classified as uncertain significance using the ACMG-AMP guidelines.ConclusionUsing a targeted gene sequencing panel, we identified seven variants in either MODY genes or mitochondrial DNA using a Korean patient population with early onset diabetes who were clinically suspected of MODY. This genetic approach provides the ability to compare distinct populations of racial and ethnic groups to determine whether specific gene is involved in their diagnosis of MODY.

Background Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. Methods This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. Conclusion The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

ObjectiveTo compare the efficacy and safety of an initial triple therapy using metformin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and thiazolidinedione with a stepwise approach using sulfonylurea and metformin in new-onset, drug-naïve patients with type 2 diabetes.Research design and methodsAmong drug-naïve patients with 9.0%–12.0% glycated hemoglobin (HbA1c) but no hyperglycemic symptoms, 100 subjects who started triple medications (metformin 1000 mg/day, sitagliptin 100 mg/day, and lobeglitazone 0.5 mg/day) were selected as an initial triple therapy group. Age and body mass index-matched subjects (n=100) who started glimepiride (≥2 mg/day with uptitration) and metformin (≥1000 mg/day with uptitration) were selected as a conventional therapy group. We investigated changes in HbA1c level, dynamic indexes for insulin sensitivity and β-cell function, and hypoglycemia.ResultsAfter 12 months of treatment, HbA1c levels decreased significantly in both groups: from 10.7%±1.0% to 6.7%±1.3% in the triple group, and from 10.5%±1.0% to 7.3%±1.2% in the conventional therapy group. At 12 months, achievement of the HbA1c target (ConclusionsInitial triple combination therapy with the DPP4 inhibitor, metformin, and thiazolidinedione showed a higher achievement of the target HbA1c goal with a lower risk of hypoglycemia, better restoration of β-cell function, and multiple metabolic benefits, implying durable glycemic control. This strategy may be useful for patients presenting with type 2 diabetes and high HbA1c levels.

IntroductionCardiovascular disease (CVD) in patients with diabetes is the leading cause of death. Finding early biomarkers for detecting asymptomatic patients with CVD can improve survival. Recently, plasma proteomics—targeted selected reaction monitoring/multiple reaction monitoring analyses (MRM)—has emerged as highly specific and sensitive tools compared with classic ELISA methods. The objective was to identify differentially regulated proteins according to the severity of the coronary artery atherosclerosis.Research design and methodsA discovery cohort, a verification cohort and a validation cohort consisted of 18, 53, and 228 subjects, respectively. The grade of coronary artery stenosis was defined as a percentage of luminal stenosis of the major coronary arteries. Participants were divided into six groups, depending on the presence of diabetes and the grade of coronary artery stenosis. Two mass spectrometric approaches were employed: (1) conventional shotgun liquid chromatography tandem mass spectrometry for a discovery and (2) quantitative MRM for verification and validation. An analysis of the covariance was used to examine the biomarkers’ predictivity beyond conventional cardiovascular risks.ResultsA total of 1349 different proteins were identified from a discovery cohort. We selected 52 proteins based on the tandem mass tag quantitative analysis then summarized as follows: chemokine (C-X-C motif) ligand 7 (CXCL7), apolipoprotein C-II (APOC2), human lipopolysaccharide-binding protein (LBP) and dedicator of cytokinesis 2 (DOCK2) in diabetes; CXCL7, APOC2, LBP, complement 4A (C4A), vitamin D-binding protein (VTDB) and laminin β1 subunit in non-diabetes. Analysis of covariance showed that APOC2, DOCK2, CXCL7 and VTDB were upregulated and C4A was downregulated in patients with diabetes showing severe coronary artery stenosis. LBP and VTDB were downregulated in patients without diabetes, showing severe coronary artery stenosis.ConclusionWe identified significant associations between circulating APOC2, C4A, CXCL7, DOCK2, LBP and VTDB levels and the degree of coronary artery stenosis using the MRM technique.

Context The long-term association between multiple cytokines and progression to diabetes is still uncertain. Objective To identify which cytokines could predict progression to prediabetes and type 2 diabetes over 10 years. Methods The study included 912 participants aged 40 to 69 years at baseline from the Ansung cohort, part of the Korea Genome Epidemiology Study. At baseline, a 75-g oral glucose tolerance test and 8 cytokines were measured: plasminogen activator inhibitor 1 (PAI-1), resistin, interleukin 6, leptin, monocyte chemoattractant protein 1, tumor necrosis factor alpha, retinol binding protein 4 (RBP4), and adiponectin. People with normal glucose tolerance (NGT, n = 241) and prediabetes (n = 330) were followed-up biennially for 10 years. Multinomial logistic regression analysis was used to evaluate the predictability of cytokines on the new-onset prediabetes and type 2 diabetes. Results At 10 years, 38 (15.8%) and 82 (34.0%) of those with NGT had converted to prediabetes and type 2 diabetes, respectively. Of those with prediabetes, 228 (69.1%) had converted to type 2 diabetes. In people with NGT or prediabetes at baseline, the highest tertile of RBP4 was associated with a 5.48-fold and 2.43-fold higher risk of progression to type 2 diabetes, respectively. The odds for converting from NGT to prediabetes in the highest tertile of PAI-1 and the lowest tertile of adiponectin were 3.23 and 3.37, respectively. In people with prediabetes at baseline, those in the highest tertile of resistin were 2.94 time more likely to develop type 2 diabetes (all P < 0.05). Conclusions In this 10-year prospective study, NGT with higher serum RBP4 and PAI-1, and with lower adiponectin were associated with new-onset prediabetes and type 2 diabetes.

The aim of this study was to evaluate whether a combination drug therapy that consists of dapagliflozin with three other oral hypoglycemic agents (OHAs) would have a beneficial safety and efficacy profile in T2DM patients who have uncontrolled glucose levels compared to a treatment regimen that contains of basal insulin with two different OHAs.A total of 162 type 2 diabetic patients who are unable to control glucose on their current therapy consisting of 3 OHAs were enrolled in dapagliflozin group and 148 patients in insulin glargine group for the 24-week study period.The mean changes in HbA1c level were comparable as -0.97 ± 1.29% in dapagliflozin group and -0.95 ± 1.41% in insulin glargine group (p = 0.911). Also, the fasting plasma glucose or post-prandial 2 h glucose were comparably decreased in dapagliflozin or insulin glargine. In terms of the body-weight, there was a significant decrease of -2.36 ± 0.51 kg following treatment of dapagliflozin, whereas the increment of 1.93 ± 0.49 kg was in insulin glargine (p 0.001). In terms of adverse events, hypoglycemic events were higher in insulin glargine rather than dapagliflozin (15.1% vs. 1.6%, p 0.05).Our findings demonstrated that the addition of dapagliflozin to an existing drug regimen consisting of three different OHAs in patients exhibiting inadequate blood glucose control could be alternate treatment modality in T2D who hesitate to initiate insulin therapy.

BackgroundFibroblast growth factor 21 (FGF21) is a novel metabolic regulator that has beneficial effects on glucose and lipid metabolism. However, plasma FGF21 levels are paradoxically increased in type 2 diabetes mellitus (T2DM) and obesity, suggesting resistance to this ligand. FGF21 acts mainly on adipose tissue and ectopic fat accumulation is a typical feature in metabolic deterioration such as diabetes, metabolic syndrome, and cardiovascular disease.ObjectiveTo investigate the relationship between FGF21 resistance and ectopic fat accumulation.Research design and methodsSubjects who underwent 64-slice multidetector CT (MDCT) were enrolled (n=190). Plasma FGF21 levels and MDCT data of ectopic fats at various sites were analyzed. Human visceral and subcutaneous fat tissues from abdominal and coronary artery bypass surgery were obtained. FGF21 receptor expression and postreceptor signaling in different fat deposits of both control and T2DM subjects were analyzed.ResultsPlasma FGF21 levels were significantly associated with body mass index, triglyceride, homeostatic model assessment of insulin resistance, and Matsuda index. Plasma FGF21 levels were significantly higher in patients with T2DM than in the pre-diabetes and normal glucose tolerance groups. The ectopic fat phenotypes (visceral, epicardial, intrahepatic, and intramuscular fat) of T2DM were significantly higher than controls. Plasma FGF21 levels were elevated and exhibited a strong positive correlation with ectopic fat accumulation in T2DM. The expression of genes comprising the FGF21 signaling pathway was also lower in visceral fat than in subcutaneous fat in this disease.ConclusionsHuman FGF21 resistance in T2DM could result from increases in FGF21-resistant ectopic fat accumulation. Our study provides novel clinical evidence linking FGF21 resistance and T2DM pathogenesis.

Introduction: SLC2A1 polymorphism may play a role in the smooth muscle cell proliferation and extracellular matrix synthesis in vessels. However, the role of SLC2A1 polymorphism on diabetic cardiovascular disease (CVD) have not yet been identified. In this study, we aimed to investigate the association between SLC2A1 HaeIII polymorphism and CVD in Korean patients with type 2 diabetes mellitus (T2DM) according to disease duration. Methods: A total of 846 patients with T2DM who visited the Chungbuk National University Hospital were investigated. The HaeIII polymorphism of SLC2A1 gene was determined by real time polymerase chain reaction method. Genotyping results were presented GG, AG, or AA. Subgroup analysis was performed according to duration of T2DM (⩽10, 11–20, >20 years). Results: The AA genotype was significantly associated with higher prevalence of CVD in patients with DM duration less than 10 years (26.3% vs 9.2%, p = 0.014). There was no significant association between SLC2A1 HaeIII polymorphism and other diabetic complications including, retinopathy, nephropathy, neuropathy, cerebrovascular disease, and peripheral artery disease. Conclusions: The SLC2A1 HaeIII polymorphism was associated with CVD in Korean patients with T2DM with short disease duration.

The relative contribution of genetic and clinical factors for bone loss is not well known. This study aimed to investigate the annualized percentage change in total hip bone mineral density (BMD) and the genetic and clinical risk factors for bone loss in a Korean prospective cohort study over a 6-year period.We included 645 men aged ≥50 years and 683 postmenopausal women who had repeated BMD testing between 2007 and 2014. The association between covariates and annualized percentage change in hip BMD was analyzed through the multivariate linear regression analysis. A total of 2614 single-nucleotide polymorphisms (SNPs) from 23 known BMD-related candidate genes and genome-wise association study were investigated.Hip bone loss increased more rapidly in women than in men with advancing age. Hip bone loss in men increased with lean mass (LM) loss (%/year) (P 0.001) and current smoking (P = 0.024) and decreased with increasing waist circumference (WC) (P 0.001), alcohol consumption (P = 0.049), and increase in red blood cell counts (P = 0.031). Decreasing WC (P = 0.009), LM loss (%/year) (P 0.001), and years since menopause ≤ 3 years (P = 0.003) significantly correlated with hip bone loss in women aged 45-59 years. Hip bone loss in women aged ≥60 years increased with advancing age (P = 0.012), alcohol consumption (P = 0.028), LM loss (%/year) (P = 0.031), and fat mass loss (%/year) (P 0.001) and decreased with increasing WC (P = 0.025). LRP5 rs498830 (β = 0.127, P = 0.007) and TNFSF11 rs7325635 (β = 0.146, P = 0.001) were the top SNPs related to hip bone loss in men and postmenopausal women, respectively. However, none of the SNPs were associated with hip bone loss after Benjamini-Hochberg adjustment.In this study, decreasing WC and LM were significant risk factors for hip bone loss in both men and women. Those factors were also identified that had sex-specific or age-specific effects on hip bone loss. None of the SNPs were associated with hip bone loss after multiple testing adjustments. The understanding of the modifiable factors contributing to bone loss has been broadened, and this may have implications such as in developing individualized preventive strategy. Further studies are needed to better predict the risk for bone loss in men and women.

Objectives: To directly compare the effectiveness of HbA1c reduction between two distinct SGLT2 inhibitors, Empagliflozin (EMPA, 25 mg/day) and Dapagliflozin (DAPA, 10 mg/day), as part of a quadruple OAD drug regimen. Research Design and Methods: This study was an open-labeled, prospective, observational, 52-week study conducted in a clinical practice. T2D patients (HbA1c, 7.5-12.0%) with three different OADs (metformin, glimepiride, and dipeptidyl peptidase-4 inhibitors) were enrolled to either EMPA or DAPA. The outcome measures included changes in HbA1c, fasting plasma glucose (FPG), and cardiometabolic variables at week 52 and the safety outcomes of treatment-emergent adverse events. Results: In total, 350 patients were enrolled with EMPA (N=176) and DAPA (N=174), respectively. After 52 weeks, both groups showed significant reductions (P Conclusions: Our present study demonstrated that SGLT2 inhibitors can be safely and effectively used as a fourth OAD in T2D patients who are already being treated with three other OADs to control their hyperglycemia. More specifically, Empagliflozin was more effective in reducing HbA1c and improving other cardiometabolic parameters affecting patient health in T2D. Our findings show that 4 different OADs can be used as a viable therapeutic regimen to treat T2D, especially in patients who are unwilling to use injectable therapies as their alternate method to control blood glucose. Disclosure E. Ku: None. D. Lee: None. H. Jeon: None. T. Oh: None.

Aims To directly compare the effectiveness and safety between two distinct sodium-glucose co-transporter 2 (SGLT2) inhibitors, empagliflozin and dapagliflozin, as part of a quadruple oral antidiabetic agents (OADs) in patients with inadequately controlled type 2 diabetes (T2D). Methods This study was an open-labeled, prospective, 52-week study conducted in T2D patients with glycated hemoglobin (HbA1c) ranging 7.5–12.0% with metformin, glimepiride and dipeptidyl peptidase-4 inhibitors. Patients were divided into either empagliflozin (25 mg/day) or dapagliflozin (10 mg/day). The outcome measures included changes in HbA1c, fasting plasma glucose (FPG), and cardiometabolic variables and the safety profiles. Results In total, 350 patients were enrolled with empagliflozin (n = 176) and dapagliflozin (n = 174), respectively. After 52 weeks, both groups showed significant reductions in HbA1c and FPG, but the reduction was greater in the empagliflozin group (P Conclusions Our study demonstrated that SGLT2 inhibitors can be effectively used as a fourth OAD in T2D patients who are treated with three other OADs. More specifically, empagliflozin was more effective in reducing HbA1c and improving other cardiometabolic parameters than dapagliflozin. Clinical Trial Number NCT03748810 ( ClinicalTrials.gov ).

Hypopituitary patients have a reduced life expectancy owing to cardiovascular events. We investigated the prevalence of metabolic syndrome in hypopituitary patients for a follow-up period of at least 1 year in comparison with an age- and sex-matched nationwide control group. A total of 515 patients with hypopituitarism who visited Seoul National University Hospital between January 2000 and December 2010 were included. Data for an age- and sex-matched control group were obtained from the Korean National Health and Nutrition Examination Surveys (KNHANES) (n = 1545). Metabolic syndrome was defined according to the modified National Cholesterol Education Program (NCEP-ATPIII). The prevalence of metabolic syndrome did not differ significantly between the hypopituitary and control groups for men (34.9 versus 30.3 %), but the risk of metabolic syndrome was higher in hypopituitary women than in controls (39.8 versus 28.5 %). In both sexes, the risks of central obesity and dyslipidemia were higher in the hypopituitary group than in the control group. Men had lower risks of hypertension and hyperglycemia in the hypopituitary group, which attenuated the risk of metabolic syndrome. Age greater than 40 years and obesity (BMI ≥25 kg/m2) contributed to a higher risk of metabolic syndrome. The metabolic syndrome prevalence was higher in the hypopituitry group than in the control group in Korean women, and this was attributed to an increased risk of central obesity and dyslipidemia. Accordingly, early intervention to reduce metabolic syndrome needed in hypopituitary patients, i.e. women.

Background Dipeptidyl peptidase-4 (DPP-4) inhibitor add-on therapy is a new option for patients with inadequately controlled type 2 diabetes who are taking combined metformin and sulfonylurea (SU). We evaluated the efficacy and safety of this triple therapy and the characteristics of rapid responders and hypoglycemia-prone patients. Methods We included 807 patients with type 2 diabetes who were prescribed a newly added DPP-4 inhibitor to ongoing metformin and SU in 2009 to 2011. Glycemia and other metabolic parameters at baseline, 12, 24, and 52 weeks, as well as episodes of hypoglycemia were analyzed. Rapid responders were defined as patients with ≥25% reduction in glycosylated hemoglobin (HbA1c) within 12 weeks. Results At baseline, while on the submaximal metformin and SU combination, the mean HbA1c level was 8.4%. Twelve weeks after initiation of DPP-4 inhibitor add-on, 269 patients (34.4%) achieved an HbA1c level ≤7%. Sixty-six patients (8.2%, 47 men) were rapid responders. The duration of diabetes was shorter in rapid responders, and their baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and homeostasis model assessment of insulin resistance were significantly higher. Patients who experienced hypoglycemia after taking DPP-4 inhibitor add-on were more likely to be female, to have a lower body weight and lower triglyceride and FPG levels, and to have higher homeostasis model assessment of β-cells. Conclusion An oral hypoglycemic triple agent combination including a DPP-4 inhibitor was effective in patients with uncontrolled diabetes. Proactive dose reduction of SU should be considered when a DPP-4 inhibitor is added for rapid responders and hypoglycemia-prone patients.

Aim: The aim of this study was to investigate the association between the transcription factor 7-like 2 gene ( TCF7L2) rs7903146 polymorphism and peripheral arterial disease in type 2 diabetes. Methods: In total, 1818 Korean type 2 diabetes patients were enrolled from January 2013 to December 2017. Subjects were categorized into two groups according to their duration of type 2 diabetes: long (⩾10 years, n = 771) and short (Results: The frequency of the minor T-allele was 7.6% ( n = 139), and this allele was significantly associated with a 2.6-fold higher risk of peripheral arterial disease (odds ratio = 2.595, 95% confidence interval = 1.177–5.722, p = 0.018) in patients exhibiting a long duration of type 2 diabetes (⩾10 years). This result was significant after adjusting for age, sex, body mass index, familial history of diabetes, smoking, duration of diabetes and laboratory measurements, which included glycated haemoglobin, fasting plasma glucose and lipid profiles. In patients with diabetes Conclusion: Our results provide evidence that genetic variation in TCF7L2 rs7903146 could increase risk for peripheral arterial disease in patients exhibiting long-standing type 2 diabetes.

This open-label, prospective study evaluated the effectiveness and safety of empagliflozin as add-on therapy in inadequately controlled type 2 diabetes (T2D) patients (glycated haemoglobin [HbA1c], 7.5-12%) who were already using three other types of orally active antidiabetic agents. A total of 268 T2D patients were enrolled and divided into two groups, empagliflozin (EMPA 25 mg/d, n = 142) or insulin glargine (INS, n = 126), respectively. After the treatment period of 24 weeks, HbA1c and fasting plasma glucose (FPG) were significantly reduced (HbA1c, P = 0.004; FPG, P = 0.008, respectively) in the EMPA group compared to the INS group. Also, EMPA treatment evoked a significant reduction in body weight (P < 0.001) and systolic blood pressure (P = 0.017) compared to the INS group. Hypoglycaemic adverse events were significantly higher in the INS group compared to the EMPA group (P = 0.001). In conclusion, this study demonstrated that a regimen comprising four different orally active antidiabetic agents, including EMPA, was effective and safe as a therapeutic strategy for treating T2D patients for glycaemic control and improvement of other cardiovascular and metabolic indices.

In a prospective community-based cohort study, we investigated the relationship between trabecular bone score (TBS) and regional fat depots in 1474 Korean postmenopausal women. TBS was positively related with subcutaneous fat and negatively related with visceral fat. The effect of fat distribution (visceral/subcutaneous) on bone quality or microarchitecture has rarely been investigated due to measurement difficulty. We aimed to investigate the relationship between TBS reflecting bone microarchitecture and regional fat depots in Korean women. Cross-sectional data evaluation was made from subjects participating in an ongoing prospective community-based cohort study since 2001. A total of 1474 postmenopausal women in the Ansung cohort were analyzed. Regional body fat mass, bone mineral density (BMD) at the lumbar spine, and total hip and lumbar spine TBS were measured by dual energy X-ray absorptiometry (DXA). In an age-adjusted partial correlation analysis, TBS was not associated with total fat mass, but negatively associated with trunk fat mass. However, TBS was positively related with leg (r = 0.102, P

The aim of present study is to compare the efficacy and safety of adding vildagliptin with sulfonylurea dose-increasing as an active comparator in patients who had inadequately controlled type 2 diabetes mellitus (T2DM) using metformin plus sulfonylurea in real clinical practice. Patients using metformin plus sulfonylurea were assigned to either vildagliptin add-on (50 mg twice a day, n=172) or sulfonylurea dose-increasing by 50% (n=172) treatment groups. The primary endpoint was a change in HbA(1c) after 24 weeks. The secondary endpoints were patients achieving HbA(1c)≤7.0% (53 mmol/mol) and changes in the fasting plasma glucose (FPG), 2-h postprandial glucose (2pp), lipid profiles, and urine albumin-to-creatinine ratio. Body weight and hypoglycemia were also investigated. The mean HbA(1c) at baseline was 8.6% (70 mmol/mol) in both groups. At week 24, the adjusted mean HbA(1c) levels decreased by -1.19% (-13.09 mmol/mol) with vildagliptin add-on and -0.46% (-5.06 mmol/mol) with sulfonylurea (P0.001). Significantly more vildagliptin add-on patients achieved HbA(1c)≤7.0% (53 mmol/mol) than did sulfonylurea patients (40.1% vs. 7.9%; P0.001). Greater reductions in FPG and 2pp were observed with vildagliptin add-on than with sulfonylurea (P0.001). The vildagliptin add-on group exhibited no clinically relevant weight gain and had a lower incidence of hypoglycemia compared with the sulfonylurea group. Vildagliptin add-on therapy might be a suitable option for patients with T2DM that is controlled inadequately by metformin and sulfonylurea, based on its greater glucose control and better safety profile (ClinicalTrial.gov: NCT01099137).

ObjectiveUnilateral adrenalectomy is the first-line treatment for aldosterone-producing adenomas (APA). Hyperkalemia after adrenalectomy because of contralateral zona glomerulosa insufficiency has been reported. We investigated clinical risk factors to predict postoperative hyperkalemia in patients with APA undergoing adrenalectomy.Design and methodsThis study was conducted by retrospectively reviewing medical records from 2000 to 2012 at Seoul National University Hospital and two other tertiary centers. Data from 124 patients who underwent adrenalectomy were included. Hyperkalemia was defined as serum potassium >5.5 mmol/l. Clinical preoperative risk factors included age, blood pressure, plasma renin activity (PRA), plasma aldosterone concentration (PAC), serum potassium, serum creatinine, glomerular filtration rate (GFR), the mass size on pathology, and mineralocorticoid receptor (MR) antagonist use.ResultsOut of 124 patients, 13 (10.5%) developed postoperative hyperkalemia. The incidences of transient and persistent hyperkalemia were 3.2 and 7.3% respectively. Preoperative PRA and PAC were not significantly different in postoperative hyperkalemic patients compared with normokalemic patients. Patients with persistent hyperkalemia were older, had a longer duration of hypertension, larger mass size on pathology, and lower GFR (all PConclusionOlder age (≥53 years), longer duration of hypertension (≥9.5 years), larger mass size on pathology (≥1.95 cm), and impaired preoperative renal function (GFR

Trabecular bone score (TBS) is a novel texture index that evaluates the pixel gray-level variations in lumbar spine dual-energy X-ray absorptiometry images and is related to bone microarchitecture independent of bone mineral density (BMD).We investigated lumbar spine TBS as an indicator for skeletal deterioration in diabetes.Cross-sectional data were collected from subjects participating in an ongoing prospective, community-based, cohort study from 2009 to 2010.We included 1229 men and 1529 postmenopausal women older than 50 years in the Ansung cohort.Biochemical parameters, lumbar spine TBS, and BMD from dual-energy X-ray absorptiometry images were measured.Lumbar spine TBS was lower in men with diabetes than in nondiabetic men (1.287 ± 0.005 vs 1.316 ± 0.003, P.001), whereas lumbar spine BMD was higher in men with diabetes (1.135 ± 0.010 vs 1.088 ± 0.006 g/cm(2)). Lumbar spine TBS was lower in women with diabetes than in nondiabetic women only in an unadjusted model (1.333 ± 0.004 vs 1.353 ± 0.003). However, women younger than 65 years (n = 707) with diabetes had a lower TBS than those without diabetes, even after adjusted for covariates (P.001). Diabetes was not associated with BMD at femur sites in both genders. TBS was negatively correlated with glycated hemoglobin, fasting plasma glucose, fasting insulin, and homeostasis model assessment for insulin resistance but not with homeostasis model assessment for β-cell function in both genders.The inverse association between lumbar spine TBS and insulin resistance may make it an indicator for determining skeletal deterioration in diabetic patients who have high BMD.

The clinical implications of prediabetes for development of type 2 diabetes may differ for Asian ethnicity. We investigated various indices derived from a 2-h oral glucose tolerance test (OGTT) in people with prediabetes to predict their future risk of diabetes.We recruited 406 consecutive subjects with prediabetes from 2005 to 2006 and followed them up every 3-6 months for up to 9 years. Prediabetes was defined as isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), combined glucose intolerance (CGI), or isolated elevated HbA1c (5.7-6.4%, 39-46 mmol/mol) without IFG or IGT. The rate of diabetes conversion was compared between prediabetes categories. The association of glycemic indices with development of diabetes was also investigated.Eighty-one patients were diagnosed with diabetes during the 9-year follow-up (median 46.0 months). The rate of diabetes conversion was higher in subjects with CGI (31.9%), or isolated IGT (18.5%) than in those with isolated IFG (15.2%) or isolated elevated HbA1c (10.9%). Surrogate markers reflecting β-cell dysfunction were more closely associated with diabetes conversion than insulin resistance indices. Subjects with a 30-min postload glucose ≥ 165 mg/dL and a 30-min C-peptide5 ng/mL had 8.83 times greater risk (95% confidence interval 2.98-26.16) of developing diabetes than other prediabetic subjects.In Asians, at least Koreans, β-cell dysfunction seems to be the major determinant for diabetes conversion. A combination of high glucose and low C-peptide levels at 30 min after OGTT may be a good predictor for diabetes conversion in this population.

Objective Abdominal obesity is considered to be a risk factor for mortality. However, recent studies indicate that overweight may be negatively associated with mortality (“obesity paradox”). The relationships between mortality and various obesity markers in an elderly Asian cohort were evaluated. Methods Subjects of the Korean Longitudinal Study on Health and Aging (KLoSHA) (n = 1000, age ≥65 years) were included. The visceral fat area (VFA) and subcutaneous fat area (SFA) were measured using computed tomography. Results A total of 222 deaths occurred during the 6-year follow-up (median = 5.2 [range 0.1–6.3] years). Body mass index (BMI), VFA, SFA, and total fat mass were negatively associated with all-cause mortality in the univariable analyses (hazard ratio [HR] 0.67 per 1 SD [95% CI 0.57-0.77], 0.66 [0.55-0.79], 0.73 [0.61-0.86], and 0.74 [0.63-0.87], respectively). BMI and VFA were significantly associated with all-cause mortality in the multivariable analyses (HR 0.85 per 1 SD [95% CI 0.73-0.99] and 0.64 [0.47-0.87], respectively). When stratified by quartiles, the HR associated with VFA was the lowest in the third quartile. Conclusions In this observational study with a short follow-up of elderly Asian people, higher amounts of visceral fat, a marker for central obesity, were associated with decreased all-cause mortality.

We report here the cases of two females with Graves' disease who developed insulin autoimmune syndrome after treatment with methimazole. The patients exhibited a sudden altered mental state after treatment with methimazole for approximately 4 weeks. Patients had hypoglycemia with serum glucose below 70 mg/dL, and laboratory findings showed both high levels of serum insulin and high titers of insulin autoantibodies. The two women had never been exposed to insulin or oral antidiabetic agents, and there was no evidence of insulinoma in imaging studies. After glucose loading, serum glucose, and total insulin levels increased abnormally. One of the patient was found to have HLA-DRB1*0406, which is known to be strongly associated with methimazole-induced insulin autoimmune syndrome. After discontinuation of methimazole, hypoglycemic events disappeared within 1 month. Insulin autoantibody titer and insulin levels decreased within 5 months and there was no further development of hypoglycemic events. We present these cases with a review of the relevant literature.

Our study showed that serum osteocalcin levels are closely related to glucose metabolism in men of all ages and younger women. This association disappeared in postmenopausal women in which increases bone turnover rates. The association between serum osteocalcin levels and glucose homeostasis should be interpreted according to age and sex. Osteocalcin, a marker of bone formation, appears to be associated with glucose homeostasis. We investigated the age- and sex-specific association of serum osteocalcin level with variables related to glucose metabolism. This study was based on cross-sectional analysis from 719 participants aged 20–85 years after excluding patients taking antidiabetic or antiosteoporotic drugs. The subjects were divided into four groups according to age and sex as follows: men

Background The complement component C1q triggers activation of the classical immune pathway and can bind to adiponectin (APN). Recently, some studies have been reported that serum C1q-APN/total APN ratio correlates with atherosclerosis and coronary artery disease (CAD). We assessed the relationships between C1q related variables and the severity of CAD, and investigated the localization of the C1q–APN complex. Methods The sample included 153 subjects comprising healthy controls and patients with subclinical or overt CAD. We measured the serum concentrations of C1q, total APN, and high-molecular weight (HMW)-APN, and the amount of C1q–APN complex. We identified the sites of C1q–APN complex deposition in various adipose tissues and blood vessels. Results Serum concentrations of C1q and HMW-APN and the C1q/HMW-APN ratio were independently associated with the severity of coronary stenosis. The amount of C1q–APN complex was significantly higher in patients with CAD compared with controls. C1q and APN co-localized in perivascular areas of subcutaneous, visceral, and pericardial fat tissues, and the internal mammary artery of patients with severe CAD. Conclusions Serum C1q concentration and the C1q/HMW-APN ratio were independent markers of coronary artery stenosis. The amount of C1q–APN complex was significantly greater in serum from CAD patients. C1q and APN co-localized to perivascular areas in adipose tissue and blood vessels. The association between the increased amount of the C1q–APN complex and CAD should be investigated further.

A 48-year-old woman was incidentally found to have bilateral adrenal masses, 2.8 cm in diameter on the right, and 2.3 cm and 1.7 cm in diameter on the left, by abdominal computed tomography. The patient had a medical history of hypertension, which was not being controlled by carvedilol, at a dose of 25 mg daily. She presented with signs and symptoms that suggested Cushing Syndrome. We diagnosed adrenocorticotropic hormone (ACTH)-independent Cushing Syndrome based on the results of basal and dynamic hormone tests. Adrenal vein sampling (AVS) was performed to localize a functioning adrenal cortical mass. AVS results were consistent with hypersecretion of cortisol from both adrenal glands, with a cortisol lateralization ratio of 1.1. Upon bilateral laparoscopic adrenalectomy, bilateral ACTH-independent adrenal adenomas were found. The patient's signs and symptoms of Cushing Syndrome improved after surgery just as the blood pressure was normalized. After surgery, the patient was started on glucocorticoid and mineralocorticoid replacement therapy.

Background: In approach to an adrenal incidentaloma, early exclusion of pheochromocytoma is clinically important, due to the risk of catecholamine crisis. The aims of this study are to investigate the characteristics of incidentally detected pheochromocytomas, compared with that of the other adrenal incidentalomas, and to compare these characteristics with those of symptomatic pheochromocytomas. Methods: In this retrospective study, we reviewed the medical records of 198 patients with adrenal incidentaloma from 2001 to 2010. We analyzed the clinical, laboratory and radiological data of pheochromocytomas, in comparison with those of the other adrenal incidentalomas. We also compared the characteristics of these incidentally detected pheochromocytomas with the medical records of 28 pathologically proven pheochromocytomas, diagnosed based on typical symptoms. Results: Among the 198 patients with adrenal incidentaloma, nineteen patients were diagnosed with pheochromocytoma. Pheochromocytomas showed larger size and higher Hounsfield unit at precontrast computed tomography (CT) than did non-pheochromocytomas. All pheochromocytomas were larger than 2.0 cm, and the Hounsfield units were 19 or higher in precontrast CT. When both criteria of size > 2.0 cm and Hounsfield unit > 19 were met, the sensitivity and specificity for the diagnosis of pheochromocytoma were 100% and 79.3%, respectively. Compared with patients with pheochromocytoma, diagnosed based on typical symptoms, patients with incidentally detected pheochromocytoma were older, presented less often with hypertension, and showed lower levels of 24-hour urine metanephrine. Conclusion: Adrenal incidentaloma with < 2.0 cm in size or ≤ 19 Hounsfield units in precontrast CT imaging was less likely to be a pheochromocytoma. Patients with incidentally discovered pheochromocytoma showed lower catecholamine metabolites, compared with those patients with symptomatic pheochromocytoma. (Endocrinol Metab 27:132-137, 2012)