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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

Purpose: Obesity is associated with an increased risk of papillary thyroid carcinoma (PTC). Evidence of the impact of obesity on PTC aggressiveness is scarce. We aimed to evaluate the association between the body mass index (BMI) and the presence of aggressive features of low- to intermediate-risk PTC in a prospective cohort. Methods: A total of 1,088 patients with low- to intermediate-risk PTC who underwent lobectomy at 22 hospitals in Korea were prospectively enrolled and divided into three groups according to BMI, as follows: normal/underweight (2), overweight (23–24.9 kg/m2), and obese (≥25 kg/m2). Clinicopathological features of PTC at diagnosis were evaluated. Results: Obese patients had a larger primary tumor size, higher rate of macro-PTC (>1 cm), and greater incidence of extra-thyroidal extension (ETE) and vascular invasion than those who were not classified as obese. Increased BMI was positively associated with the incidence of macro-PTC (p for trend = 0.019), ETE (p for trend = 0.013), and vascular invasion (p for trend = 0.021). After adjusting for age, sex, pathological features, metabolic syndrome, and thyroid function test, obesity was a risk factor for ETE (odds ratio = 1.6, 95% confidence interval: 1.1–2.3, p = 0.007) in women. This association was significant regardless of whether or not the women had metabolic syndrome. There was no significant association between obesity and aggressive PTC features in men. Conclusion: These results suggest that BMI at the time of thyroid cancer diagnosis may affect the aggressiveness of low- to intermediate-risk PTC, especially in women.

Background: The purpose of this study was to investigate the association between responses to intravitreal bevacizumab injection and renal function in diabetic macular edema (DME) patients. Methods: A retrospective study of the medical records of 104 treatment-naïve DME patients who received intravitreal bevacizumab injection (IVBI) was conducted. Based on the estimated glomerular filtration rate (eGFR, mL/min/1.73 m2), the participants were classified into three groups. Intergroup comparisons of the best-corrected visual acuity (BCVA) and central subfield retinal thickness (CST) changes were performed after three-monthly consecutive IVBIs. In the groups with decreased renal function, the response to further treatment with a different drug was investigated. Results: A total of 104 participants were included in the study: 60 participants in the preserved renal function group (eGFR ≥ 60), 25 participants in the moderate chronic kidney disease (CKD) group (30 ≤ eGFR < 60), and 19 participants in the severe CKD group (eGFR < 30). After three-monthly consecutive IVBIs, BCVA (p < 0.001) and CST (p < 0.001) were significantly improved only in the preserved renal function group. Following further treatment of patients with decreased renal function, the treatment results were significantly better in those who were switched to aflibercept or dexamethasone implant than in those who were maintained on IVBI. Conclusions: From this preliminary study, we observed that renal function might affect the response to IVBI treatment in patients with DME. In the case of a poor response to initial IVBI treatment for DME in patients with moderate to severe CKD, our study supports switching to the aflibercept or dexamethasone implant.

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.

BACKGROUND Smartphones have become novel healthcare tools for patients with diabetes. However, it is uncertain whether the smartphone application support system helps in glycaemic control in patients with type 2 diabetes. AIMS To evaluate the efficacy and plausibility of smartphone-based integrated online real-time diabetes care. METHODS Forty patients with type 2 diabetes were randomly assigned to the smartphone-based care (SC) (n = 20) and conventional care (CC) (n = 20) groups for 12 weeks. The SC group was instructed to use smartphone application (Noom Coach) and a glucose meter, and was provided medical supervision based on blood glucose level and food intake information sent to the central database server. The efficacy was evaluated by glycated haemoglobin (A1C ≤ 6.5%). The Summary of Diabetes Self-Care Activities (SDSCA) questionnaire was collected at baseline and at week 12. RESULTS Seventeen and 18 patients of the SC and CC groups completed the study respectively. In the SC group, more patients achieved target A1C compared with the CC group (47.1% vs 11.1%, P = 0.019). In both group, SDSCA scores excluding the exercise item showed overall improvement (general diet, 1.4 ± 2.0 → 2.6 ± 2.3 vs 0.4 ± 1.1 → 1.8 ± 2.2; specific diet, 4.2 ± 1.7 → 5.4 ± 1.2 vs 3.8 ± 1.6 → 5.1 ± 1.1; blood glucose test, 3.3 ± 2.8 → 4.9 ± 2.3 vs 1.0 ± 2.2 → 4.7 ± 2.3; foot care, 1.5 ± 1.6 → 3.6 ± 2.8 vs 1.4 ± 1.9 → 6.1 ± 1.4; all P

Curiosity concerning the process of human creation has been around for a long time. Relevant questions seemed to be resolved with the knowledge of how cells divide after fertilization obtained through in vitro fertilization experiments. However, we still do not know how human life is created at the cellular level. Recently, the value of cadavers as a resource from which to obtain “normal” cells and tissues has been established, and human research using postmortem bodies has attracted growing scientific attention. As the human genome can be analyzed at the level of nucleotides through whole-genome sequencing, individual cells in a postmortem body can be traced back to determine what developmental processes have transpired from fertilization. These retrospective lineage tracing studies have answered several unsolved questions on how humans are created. This review covers the methodologies utilized in lineage tracing research in a historical context and the conceptual basis for reconstructing the division history of cells in a retrospective manner using postzygotic somatic variants in postmortem tissue. We further highlight answers that postmortem research could potentially address and discuss issues that wait to be solved in the future.

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.

The bone mineral densities (BMDs) of the femoral neck and total hip, and the lumbar spine trabecular bone score (TBS), tended to decrease with age in both men and women, whereas the lumbar spine BMD tended to increase. Lumbar spine BMD is thus inappropriate for evaluating longitudinal changes in bone loss; the lumbar spine TBS is an alternative measure. Aging is associated with a decrease in bone mass and quality. This community-based prospective cohort study investigated longitudinal changes in bone phenotype in Korean adults. We analyzed data from a prospective community-based cohort study, the Korean Genome and Epidemiology Study. Postmenopausal women and men who underwent dual-energy X-ray absorptiometry at least twice from 2007 to 2014 were included. Longitudinal changes in bone mineral density (BMD) and trabecular bone score (TBS) over 6 years were analyzed by sex, age, and body mass index. A total of 1895 subjects were enrolled (men 965; postmenopausal women 929). The femoral neck (FN) BMD, total hip (TH) BMD, and lumbar spine (LS) TBS decreased significantly over time, but the LS BMD increased significantly. In men, the average annual changes were 0.3% in LS BMD (p

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.

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 (

Patients with type 2 diabetes (T2DM) have a higher risk of bone fracture even when bone mineral density (BMD) values are normal. The trabecular bone score (TBS) was recently developed and used for evaluating bone strength in various diseases. We investigated the effect of DPP-4 inhibitors on bone health using TBS in patients with T2DM. This was a single-center, retrospective case-control study of 200 patients with T2DM. Patients were divided into two groups according to whether they were administered a DPP-4 inhibitor (DPP-4 inhibitor group vs. control group). Parameters related to bone health, including BMD, TBS, and serum markers of calcium homeostasis, were assessed at baseline and after one year of treatment. We found TBS values increased in the DPP-4 group and decreased in the control, indicating a significant difference in delta change between them. The BMD increased in both groups, with no significant differences in delta change between the two groups observed. Serum calcium and 25-hydroxy vitamin D3 increased only in the DPP-4 inhibitor group, while other glycemic parameters did not show significant differences between the two groups. Treatment with DPP-4 inhibitors was associated with favorable effects on bone health evaluated by TBS in patients with T2DM.

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.

Background Diabetic nephropathy (DN) is the most serious microvascular complication of diabetes mellitus and is one of the leading causes of end stage renal failure. In previous studies, the contribution of genetic susceptibility to DN showed inconsistent results. In this study, we investigated the association between the solute carrier family 2 facilitated glucose transporter member 1 (SLC2A1) HaeIII polymorphism and DN in Korean patients with type 2 diabetes mellitus (T2DM) according to disease duration. Methods A total of 846 patients with T2DM (mean age, 61.3 ± 12.3 years; mean duration of T2DM, 10.3 ± 7.9 years; 55.3% men) who visited the Chungbuk National University Hospital were investigated. The HaeIII polymorphism of the SLC2A1 gene was determined by the real time polymerase chain reaction method. Genotyping results were presented as GG, AG, or AA. A subgroup analysis was performed according to duration of T2DM (≤ 10 years, > 10 years). Results The AG + AA genotype showed a significantly higher risk of DN compared with the GG genotype in patients with a type 2 DM duration less than 10 years (12.4% vs. 4.2%; P < 0.001). No significant differences were observed in terms of other diabetic complications, including retinopathy, peripheral neuropathy, cardiovascular disease, cerebrovascular disease or peripheral artery disease, according to the genotypes of the SLC2A1 HaeIII polymorphism. Conclusion The SLC2A1 HaeIII polymorphism was associated with DN in Korean patients with T2DM, particularly in the group with a relatively short disease duration., Graphical Abstract

BACKGROUND Diabetic nephropathy (DN) is the most serious microvascular complication of diabetes mellitus and is one of the leading causes of end stage renal failure. In previous studies, the contribution of genetic susceptibility to DN showed inconsistent results. In this study, we investigated the association between the solute carrier family 2 facilitated glucose transporter member 1 (SLC2A1) HaeIII polymorphism and DN in Korean patients with type 2 diabetes mellitus (T2DM) according to disease duration. METHODS A total of 846 patients with T2DM (mean age, 61.3 ± 12.3 years; mean duration of T2DM, 10.3 ± 7.9 years; 55.3% men) who visited the Chungbuk National University Hospital were investigated. The HaeIII polymorphism of the SLC2A1 gene was determined by the real time polymerase chain reaction method. Genotyping results were presented as GG, AG, or AA. A subgroup analysis was performed according to duration of T2DM (≤ 10 years, > 10 years). RESULTS The AG + AA genotype showed a significantly higher risk of DN compared with the GG genotype in patients with a type 2 DM duration less than 10 years (12.4% vs. 4.2%; P < 0.001). No significant differences were observed in terms of other diabetic complications, including retinopathy, peripheral neuropathy, cardiovascular disease, cerebrovascular disease or peripheral artery disease, according to the genotypes of the SLC2A1 HaeIII polymorphism. CONCLUSION The SLC2A1 HaeIII polymorphism was associated with DN in Korean patients with T2DM, particularly in the group with a relatively short disease duration.

Supplemental material, Supplementary_data for Genetic variation in TCF7L2 rs7903146 correlating with peripheral arterial disease in long-standing type 2 diabetes by Eu Jeong Ku, Gun Woo Won, Yong Hee Lee, Dong-Hwa Lee, Hyun Jeong Jeon and Tae Keun Oh in Diabetes & Vascular Disease Research

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 ).

Objective To assess the impact of intraoperative intravenous dexamethasone on the reduction of postoperative morbidity in children undergoing adenotonsillectomy. Methods A double blind randomized controlled trial conducted among children undergoing adenotonsillectomy at a tertiary hospital in Korea from November 2018 to June 2019. Children were randomly assigned to receive dexamethasone (0.5 mg/kg, maximum dose 24 mg) or placebo intravenously after induction of anesthesia. The primary endpoint was the reduction of postoperative pain and postoperative nausea and vomiting (PONV); secondary endpoints were adverse effects like postoperative hemorrhage. Results The study included 105 children, and 67 were male. Their mean age was 6.2 ± 2.1 years. There was no significant difference between the groups in terms of demographic data or the operation time. The pain scores of the dexamethasone group were lower than those of the control group, but no significant difference was found (all P > .05). The average pain visual analog scale (VAS) during the study period (day 0-7) was 3.67 ± 1.59 and 4.40 ± 2.01 in the dexamethasone group and control group, respectively (P-value = .107). When we compared early pain VAS (day 0-2) and late pain VAS (day 5-7), the dexamethasone group showed significantly lower early mean VAS compared to the control group (4.55 ± 1.78 vs 5.40 ± 2.05, P-value = .046). The mean VAS for PONV was significantly lower in the dexamethasone group than in the control group (1.89 ± 2.22 vs 3.00 ± 2.37, P value = .044). Conclusion In children undergoing adenotonsillectomy, dexamethasone decreased the early postoperative pain and PONV without increasing postoperative hemorrhage.

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.

Among several sarcopenic indices, height-adjusted appendicular lean mass (ALM) in men and BMI-adjusted ALM in women are associated with fragility fracture. Handgrip strength is the risk factor for fragility fracture. Various sarcopenia definitions and cutoff points result in mixed skeletal health results. Here, we aimed to determine a suitable definition and elucidate the cutoff values of sarcopenic indices for identifying fracture risk in a community-dwelling Korean cohort. In an Ansung cohort study (2009–2010), we included 1201 men aged > 50 years and 1627 postmenopausal women with a median age of 64 years. Body composition and bone mineral density were derived on dual-energy X-ray absorptiometry. Grip strength was measured using a hand dynamometer. Fragility fractures included the history of osteoporotic fractures using self-reported questionnaires. Among appendicular lean mass (ALM)/body mass index (BMI), ALM/height2, and ALM/weight, ALM/height2 for men and ALM/BMI for women significantly predicted fragility fractures. On receiver operating characteristic curve analysis, the cutoff values of ALM/height2 in men and ALM/BMI in women were 7.69 kg/m2, and 0.57, respectively. The optimal grip strength values were 31 kg in men and 19 kg in women. The odds ratios of low ALM/height2 (95% confidence interval) and weak grip strength for fragility fracture were 1.95 (1.03–3.68) and 2.05 (1.01–4.18), respectively, in men after covariate adjustment. The combination of low ALM/height2 and weak grip strength increased fragility fractures 2.16-fold in men. Only the combination of low ALM/BMI and grip strength increased the fracture risk by 1.76-fold in women. In men, low ALM/height2 or grip strength played a role in fragility fractures. In women, only the combination of low ALM/BMI and grip strength had discriminatory power for fragility fractures.

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.

The aim of our study was to assess the frequency of germline mutations and develop the genetic testing strategy in patients with apparently sporadic pheochromocytoma/paraganglioma (PPGL) in Korea. We included 53 patients diagnosed with non-syndromic PPGL without a family history of PPGLs in three referral centers from 2004 to 2011. Succinate dehydrogenase complex B (SDHB), SDHD, Von Hippel-Lindau (VHL), and rearranged during transfection (RET) genes were examined by direct sequencing and multiple ligation-dependent probe amplification. The study patients were composed of 26 men and 27 women, and mean age was 50.1 ± 13.5 years. The frequency of germline mutations was 13.2% (7/53): RET (n = 2), VHL (n = 1), SDHB (n = 2), and SDHD (n = 2). Six of seven mutation carriers were diagnosed before the age of 50. One of two patients harboring an SDHB mutation had malignant PPGLs. One patient with multifocal head and neck paraganglioma (PGL) and pheochromocytoma (PHEO) carried a SDHD mutation. The carriers of germline mutations in patients with apparently sporadic PPGL were 13.2% in our study. We recommend genetic testing in patients below 50 years and SDHD genetic testing in patients with multifocal PPGLs. In malignant PPGLs, SDHB genetic testing may be performed.

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.

Background The relationship between adiponectin concentration and mortality is unclear. We examined whether serum adiponectin concentration is associated with all-cause and cardiovascular mortality in elderly Asians. Methods We analyzed the data for community-dwelling adults ≥65years of age (439 men and 561 women) who were enrolled in the Korean Longitudinal Study on Health and Aging (KLoSHA) cohort in prospective manner. The baseline serum total and high molecular weight adiponectin were measured using an enzyme-linked immunosorbent assay. Using Cox regression, we determined the associations between serum adiponectin concentration and all-cause and cardiovascular mortality after adjusting for well-known cardiovascular risk factors. Results Over a mean follow-up time of 6.2years, 222 individuals died, and 52 deaths (23.4%) were by cardiovascular disease. After adjusting confounding factors, elevated baseline serum adiponectin concentration was independently associated with all-cause mortality (adjusted hazard ratio [HR] 1.38; 95% confidence interval [CI] 1.17–1.64) and cardiovascular mortality (HR 1.50; 1.06–2.14). We evaluated the effect modification by baseline body mass index (BMI). High serum adiponectin and low BMI were synergistically associated with increased all-cause mortality (HR 6.25; 3.08–12.71) and cardiovascular mortality (HR 13.94; 1.82–106.58). Conclusions Higher serum adiponectin concentration was associated with increased all-cause and cardiovascular mortality in community-dwelling elderly Asian population. Our data supported the recent theory so called "adiponectin paradox". This relationship was strengthened when combined with low BMI. We suggest that measurement of adiponectin concentration and BMI together could be an additional predictive marker of survival among elderly adults.

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.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.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.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.

ObjectivesWe investigated the efficacy of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes for 4 years in clinical practice.MethodsBetween 2009 and 2010, we reviewed 1,178 patients with type 2 diabetes (HbA1c ≥7.5% or 58 mmol/mol) prescribed initial combination therapy with sitagliptin and metformin. After excluding 288 patients without a second follow-up, 890 individuals (age, 58.0 ± 12.5 years; BMI, 25.4 ± 3.5 kg/m2; HbA1c, 8.6 ± 1.1%) were followed up with every 3-6 months for 4 years. Homeostasis model assessments for insulin resistance and β-cell function (HOMA-β) were recorded at baseline. The response criterion was HbA1c reduction by ≥0.8% from baseline or attainment of the target HbA1c (≤7.0% or 53 mmol/mol). At the end of every year of treatment, changes in HbA1c from the baseline were assessed.ResultsAfter 1 year, 72.2% of patients with initial combination therapy had responded, defined as HbA1c reduction ≥0.8% or attainment of the target HbA1c ≤7.0%. After 4 years, 35.4% of the patients still showed a response, with an HbA1c level of 7.0 ± 0.9%. A high HbA1c level at baseline was the most significant independent predictor of the long-term response (PConclusionsThis real-world follow-up study shows a persistent glucose-reducing effect of initial combination therapy with sitagliptin and metformin for up to 4 years.

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.

To the Editor, Metabolic bone disease has been reported in patients with chronic liver disease, especially those with cholestatic type and those awaiting liver transplantation. Osteoporotic fractures occur in 3% to 6.7% of patients with cirrhosis [1]. Within the general population, common fracture sites induced by osteoporosis are the spine, distal radius, and proximal femur. Among these, vertebral fractures are almost always observed in cirrhotic patients because other fractures commonly occur about a decade later than vertebral fractures, and the life expectancy of patients with cirrhosis is shorter than a decade [2]. We herein present a case of multiple nonvertebral fractures mimicking bone metastases in a patient with hepatitis B virus (HBV)-related liver cirrhosis and hepatocellular carcinoma (HCC). A 65-year-old Korean woman visited the emergency department complaining of sudden-onset right hip pain without trauma. She was previously diagnosed with HBV-related liver cirrhosis and had begun taking entecavir 7 months previously. The patient was neither a heavy drinker nor a smoker. She had been postmenopausal for the last 15 years. Her height, weight, and body mass index at the time of presentation were 149.0 cm, 37.9 kg, and 17.07 kg/m2, respectively. Four months previously, she underwent transarterial chemoembolization chemoembolization for treatment of a 15 mm single nodular HCC in segment six of the liver. Three months prior to presentation, a compression fracture at the third lumbar vertebra was found on simple X-ray films during an evaluation of lower back pain. She was diagnosed with osteoporosis and was started on calcium, vitamin D, and ibandronate at another hospital. Physical examination showed tenderness of the right hip area and limitation of motion due to pain. Initial laboratory findings were as follows: white blood cell count, 7,700/µL; hemoglobin, 8.5 g/dL; platelet count, 63,000/µL; total protein, 6.3 g/dL; albumin, 3.3 g/dL; total bilirubin, 2.0 mg/dL; alkaline phosphatase, 230 IU/L; aspartate aminotransferase, 32 IU/L; alanine aminotransferase, 10 IU/L; prothrombin time, 16.8 seconds (INR, 1.42); and alpha-fetoprotein, 6.1 IU/mL. She had Child-Pugh class B liver disease. The latest hepatitis B e antigen and serum HBV-DNA level detected by polymerase chain reaction were negative. Simple pelvic X-ray (Fig. 1) and hip computed tomography (CT) (Fig. 2A) showed a sclerotic lesion with a focal bulging contour at the left ischial tuberosity and multiple fractures of the pelvic bone. The patient underwent several treatments of immobilization with pain control for these minor pelvic fractures after consultation with an orthopedic surgeon. Figure 1 Anteroposterior radiograph of the pelvis demonstrated a focal sclerotic bulging contour lesion at the left inferior pubic ramus (arrow). Figure 2 (A) Hip computed tomography with 3D reconstruction revealed a sclerotic lesion with a fracture line at the left pubic ramus (arrow). (B) Pelvic bone magnetic resonance imaging showed a bone marrow signal change and fracture line at the left pubic ramus ... To evaluate the possibility of bone metastases, pelvic magnetic resonance imaging (MRI) (Fig. 2B), bone scintigraphy (Fig. 3A and 3B), and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/CT (Fig. 3C and 3D) were performed. They demonstrated multiple fractures in both sets of ribs, sternum, T-L spine, and both pelvic bones. However, there were no abnormal findings or hypermetabolic lesions suggesting malignancy. Moreover, there was no definite mass or osteolytic bony lesion on pelvic MRI. Dual energy X-ray absorptiometry showed a femur neck and total hip joint T score of -4.3, which is within the osteoporosis category. Blood tests revealed secondary hyperparathyroidism and low vitamin D levels as follows: corrected calcium, 8.5 mg/dL; serum parathyroid hormone (PTH), 150 pg/mL (normal range, 8 to 76); and total vitamin D level, 4.2 ng/mL (recommended range, > 20). After obtaining these values, treatment with a calcium/vitamin D combination and bisphosphonate therapy was continued. Two months after the initial emergency department visit, analgesic therapy was stopped. Figure 3 (A, B) Bone scintigraphy demonstrated multiple fractures in both sets of ribs, sternum, T-L spine, and both pelvic bones. (C, D) 18F-fluorodeoxyglucose positron emission tomography/computed tomography revealed a fracture with hypermetabolism at the left ... Hepatic osteodystrophy, which was first reported in 1956, is a generic definition of a metabolic bone process that has a multifactorial origin and is associated with chronic liver disease. The biological mechanism of hepatic osteodystrophy is not clear. However, both decreased 25-hydroxylation of vitamin D in the liver and a defect of Kupffer cell-mediated cleavage of PTH from hepatic dysfunction can contribute to the higher prevalence of metabolic bone diseases in patients with chronic liver disease compared with those without liver disease [3]. Despite its high incidence, however, the clinical importance of hepatic osteodystrophy is undervalued in practical fields. Almost all fractures originating from hepatic osteodystrophy are limited to the vertebra [1]. Our report might be the first case report of multiple pelvic bone fractures induced by hepatic osteodystrophy and mimicking bone metastases from HCC. Bone was once considered to be a rare site of metastasis from HCC. However, improving long-term survival rates combined with technical advances in diagnostic modalities have led to an increased incidence of bone metastases. Although 18F-FDG-PET/CT is very a sensitive modality with which to detect metastatic HCC, Ho et al. [4] reported that 38% of bone metastasis reveals no uptake on FDG-PET scans. Thus, we used various imaging modalities (simple X-ray, hip CT, and pelvic MRI) to evaluate the possibility of bone metastasis in the present case, and the results revealed no osteolytic lesions suggesting typical bone metastasis from HCC. Because osteoblastic bone metastasis from HCC has never been reported, these imaging findings suggest that the pelvic fractures in this case were induced by hepatic osteodystrophy rather than bone metastasis. In this case, the patient was elderly, underweight, and postmenopausal and had a previous history of compression fractures. Moreover, she had been closely monitored because of liver cirrhosis of Child-Pugh class B. Because of these risk factors, fractures of multiple sites occurred despite treatment with bisphophonates. Only a few small, randomized controlled studies of interventions for preventing osteoporosis and fractures in patients with chronic liver disease have been performed. Most were conducted on patients with primary biliary cirrhosis, and none showed significant differences in intervention and reduction in the risk of osteoporotic fractures [5]. Collier et al. [5] suggested that diagnostic workup and treatment of osteoporosis are necessary in patients with T scores of less than -2.5 or previous fragility fractures. According to their guidelines, hypogonadal female patients are recommended to undergo treatment with hormonal replacement therapy (HRT). However, multiple fractures arose during treatment with bisphosphonates in the present case; therefore, we continued the calcium/vitamin D combination therapy and bisphosphonates instead of HRT. In conclusion, although multiple pelvic bone fractures associated with hepatic osteodystrophy is a very rare complication, we should consider this possibility in patients with severe chronic liver disease, even HCC. After fragility fractures have occurred, a diagnostic workup and active intervention for metabolic bone disease are mandatory.

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)