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This study aimed to determine the effectiveness of analgesics in inhibiting cancer development in patients with diabetes based on a sample cohort supplied by the Korean National Health Insurance Service.Regular users of analgesics included those using prescription analgesics ≥ 15 days per month at least 6 times over 2 years after the diagnosis of diabetes mellitus (baseline). The effectiveness of analgesics in patients with diabetes was evaluated using metformin adherence and three models: model 1 was adjusted for age and sex; model 2 was further adjusted for body mass index (BMI), exercise, cholesterol, hypertension, and Charlson comorbidity index (CCI); and model 3 was further adjusted for analgesics.Based on stringent extraction criteria, the sample had a cancer incidence of 4.6%. The hazard ratios of models 1 and 2 were 0.830 and 0.865, respectively. The adjusted hazard ratio for all variables, including acetaminophen and nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen, was 0.871 (model 3).Regular use of analgesics by patients with diabetes decreased their risk of subsequent cancer development in this large national cohort. Compared with participants who did not develop cancer, those with cancer were older and more likely to be male, did not exercise, have more comorbidities (as assessed by CCI), and did not use analgesics regularly.

Type I diabetes mellitus is an autoimmune disease characterized by the destruction of β-cells, leading to severe insulin deficiency. Environmental factors and genetic predisposition are implicated in β-cell destruction, which is the final step in a cascade of complex events. Possible triggers of β-cell destruction are activation of Fas, activation of perforin, increased generation of reactive oxygen species, increased production of inflammatory cytokines, and endoplasmic reticulum (ER) stress. In this study, we examined whether Gryllus bimaculatus (GB) extract could prevent palmitate-induced β-cell apoptosis. Exposure to GB extract prevented palmitate-induced death of MIN6 cells, a mouse pancreatic β-cell line. Palmitate increased total ceramide levels with the elevation of ceramide synthase (CerS)1, CerS4, and CerS6 expressions. Treatment with GB extract decreased the levels and expressions of ceramides related to insulin resistance. CerS4 and CerS6 overexpression, but not CerS1 overexpression, increased palmitate-induced MIN6 cell death by increasing ceramide synthesis. Oppositely, inhibition of ceramide synthesis by fumonisin B1 treatment partially recovered palmitate-induced MIN6 cell death. Furthermore, GB extract reduced ER stress (phosphorylation of PERK and eIF2α), NF-κB–iNOS signaling, and the phosphorylation of MAP kinase (JNK, p38). GB extract reduced pro-apoptotic Bax protein expression but increased anti-apoptotic Bcl2 expression. In addition, CerS4 and CerS6 overexpression aggravated impairment of insulin secretion by palmitate, but GB extract recovered it. In conclusion, GB could be a functional food that improves palmitate-induced β-cell death and insulin secretion.

Context There are relatively few data on noncardiovascular (non-CV) long-term clinical outcomes of dipeptidyl peptidase 4 inhibitor (DPP4i) treatment. Objective We aimed to evaluate some non-CV effects of DPP4is in patients with diabetes. Methods Based on data from the National Health Insurance Service database in Korea (2007-2018), we conducted 3 pairwise comparisons of metformin-combined antidiabetic therapies in adult patients with diabetes: DPP4is vs (1) all other oral antidiabetic agents, (2) sulfonylureas/glinides, and (3) thiazolidinediones (TZDs). Major outcomes were liver cirrhosis, end-stage renal disease (ESRD), and cancers in the liver, kidney, and pancreas. Adjusted hazard ratios (HRs) and 95% CIs for the outcomes were estimated using an adjusted Cox model. Results Of the 747 124 patients included, 628 217 had received DPP4i therapy for a mean duration of 33.8 ± 25.0 months. Compared with TZD therapy, DPP4i therapy was associated with higher adjusted HRs [95% CIs] for liver cirrhosis (1.267 [1.108-1.449]), ESRD (1.596 [1.139-2.236]), liver cancer (1.117 [1.011-1.235]), and pancreatic cancer (1.158 [1.040-1.290]). Furthermore, apart from liver cirrhosis, a higher risk of each of these outcomes was associated with DPP4i use than with non-DPP4i use. The higher adjusted HRs associated with DPP4i use further increased when patients with long-term exposure to DPP4is were analyzed. Conclusion DPP4i therapy in patients with diabetes was associated with a higher risk of liver cirrhosis and cancer, ESRD, and pancreatic cancer than TZD therapy and, except for liver cirrhosis, the risk of these outcomes was greater with DPP4i treatment than with non-DPP4i treatment.

To explore extracellular vesicle microRNAs (EV miRNAs) and their target mRNAs in relation to diabetic kidney disease (DKD), we performed paired plasma and urinary EV small RNA sequencing (n = 18) in patients with type 2 diabetes and DKD (n = 5) and healthy subjects (n = 4) and metabolic network analyses using our own miRNA and public mRNA datasets. We found 13 common differentially expressed EV miRNAs in both fluids and 17 target mRNAs, including RRM2, NT5E, and UGDH. Because succinate dehydrogenase B was suggested to interact with proteins encoded by these three genes, we measured urinary succinate and adenosine in a validation study (n = 194). These two urinary metabolite concentrations were associated with DKD progression. In addition, renal expressions of NT5E and UGDH proteins were increased in db/db mice with DKD compared to control mice. In conclusion, we profiled DKD-related EV miRNAs in plasma and urine samples and found their relevant target pathways.

Objective The aim of this study was to investigate the effects of omega-3 fatty acids added to statin monotherapy in Korean patients with type 2 diabetes who have persistent hypertriglyceridemia despite statin therapy. Methods This study was a randomized controlled trial conducted in 4 clinical sites between February 2009 and February 2011. The inclusion criteria were patients with type 2 diabetes who had received ≥6 weeks of statin therapy and had fasting triglyceride (TG) levels ≥1.7mmol/L and low-density lipoprotein (LDL) cholesterol levels

Background Sodium-glucose cotransporter 2 inhibitor (SGLT2i) should be considered for patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) having estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) > 30 mg/g. However, SGLT2i is currently underprescribed among eligible, at-risk patients for CKD progression. We analyzed prescription patterns and barriers to initiating SGLT2i in patients with T2D and CKD in real practice. Methods A total of 3,703 consecutive outpatients with T2D from four teaching hospitals during six months (2019 ~ 2020) were reviewed. Five eGFR categories (G1, ≥ 90; G2, 60–89; G3ab, 30–59; G4-5, < 30 mL/min/1.73 m2) and three UACR categories (A1, < 30; A2, 30–300; A3, > 300 mg/g) were used to define CKD status. Results Overall, 25.8 % patients received SGLT2i in the following eGFR and albuminuria categories: G1 (A1, 31 %; A2, 48 %; A3, 45 %); G2 (A1, 18 %; A2, 24 %; A3, 30%); and G3 (A1, 9 %; A2, 7 %; A3, 13 %). Total prevalence estimate of CKD was 33.8 % (n = 1,253), of whom 25.6 % patients received SGLT2i. We defined eGFR ≥ 45 mL/min/1.73 m2 and UACR ≥ 30 mg/g as high-risk CKD group eligible for SGLT2i (n = 905), of whom 32.9 % patients were treated with an SGLT2i. In this high-risk group, SGLT2i initiation showed negative correlations with age ≥ 65 years and recent hospitalization. Conversely, HbA1c level, body mass index (BMI), presence of diabetic retinopathy, and previous heart failure events were positively correlated with SGLT2i initiation. Conclusions Only 32.9 % of T2D with CKD eligible for SGLT2i is currently treated with SGLT2i in real-world clinical practice. The older patient group and clinical inertia are the main barriers to initiate SGLT2i for eligible patients. Clinicians should change the glucocentric approach and focus on reducing renal events in T2D.

Additional file 1: Table S1. Baseline demographic and clinical characteristics of the total study population. Table S2. Trends of SGLT2i initiation in the high-risk CKD group eligible for SGLT2i. Figure S1. Flow diagram of study subjects.

Background: Several noninvasive tools are available for the assessment of nonalcoholic fatty liver disease (NAFLD) including clinical and blood biomarkers, transient elastography (TE), and magnetic resonance imaging (MRI) techniques, such as proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE). In the present study, we aimed to evaluate whether magnetic resonance (MR)-based examinations better discriminate the pathophysiologic features and fibrosis progression in NAFLD than other noninvasive methods.Methods: A total of 133 subjects (31 healthy volunteers and 102 patients with NAFLD) were subjected to clinical and noninvasive NAFLD evaluation, with additional liver biopsy in some patients (n=54).Results: MRI-PDFF correlated far better with hepatic fat measured by MR spectroscopy (r=0.978, P

Aim To investigate the efficacy and safety of evogliptin compared with linagliptin in patients with type 2 diabetes. Materials and Methods In this 12‐week, multicentre, randomized, double‐blind, active‐controlled, and 12‐week open‐label extension study, a total of 207 patients with type 2 diabetes who had HbA1c levels of 7.0%‐10.0% were randomized 1:1 to receive evogliptin 5 mg (n = 102) or linagliptin 5 mg (n = 105) daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint was the change in the mean amplitude of glycaemic excursion (MAGE) assessed by continuous glucose monitoring. In the extension study conducted during the following 12 weeks, evogliptin 5 mg daily was administered to both groups: evogliptin/evogliptin group (n = 95) and linagliptin/evogliptin group (n = 92). Results After 12 weeks of treatment, the mean change in HbA1c in the evogliptin group and in the linagliptin group was −0.85% and −0.75%, respectively. The between‐group difference was −0.10% (95% CI: −0.32 to 0.11), showing non‐inferiority based on a non‐inferiority margin of 0.4%. The change in MAGE was −24.6 mg/dL in the evogliptin group and −16.7 mg/dL in the linagliptin group. These values were significantly lower than the baseline values in both groups. However, they did not differ significantly between the two groups. In the evogliptin/evogliptin group at week 24, HbA1c decreased by −0.94%, with HbA1c values of

The benefit of statin therapy in patients with higher grades of heart failure has yet to be determined. The present study investigated whether statin therapy affects major composite outcomes (MCOs) and all-cause mortality in patients with acute myocardial infarction (AMI) within 1 year after AMI, according to their plasma natriuretic peptide (NP) levels and left ventricular ejection fraction (LVEF).A total of 11,492 patients with AMI from two nationwide registry databases in Korea were analyzed. AMI patients were divided into quartiles by plasma levels of B-type NP (BNP) or N-terminal pro-BNP (NT-proBNP) at admission. Patients with LVEF40% on initial echocardiography were also evaluated. Total mortality and MCOs within 12 months of AMI, including death, nonfatal MI, and revascularization, were assessed.Among AMI patients, statin therapy was included in the discharge medications for 9075 (79.0%) patients, but not for the remaining 2417 patients (21.0%), and statin therapy was associated with a 27.8% lower risk of MCOs. After adjusting for risk factors, statin therapy was associated with lower hazard ratios for MCOs and all-cause mortality in only the third and fourth NP quartile subgroups, being effective only with moderate- to high-intensity statin therapy. However, statins did not modify the outcomes in patients with LVEF40%.Our results show that moderate- to high-intensity statin therapy was associated with a lower risk of major clinical outcomes and all-cause mortality in AMI patients with higher plasma NP, but not in AMI patients with decreased LVEF.

Background/Aims: Diabetic nephropathy (DN), a major diabetic microvascular complication, has a long and growing list of biomarkers, including microRNA biomarkers, which have not been consistent across preclinical and clinical studies. This meta-analysis aims to identify significant blood- and urine-incident microRNAs as diagnostic/prognostic biomarker candidates for DN. Methods: PubMed, Web of Science, and Cochrane Library were searched from their earliest records through 12th Dec 2016. Relevant publications for the meta-analysis included (1) human participants; (2) microRNAs in blood and urine; (3) DN studies; and (4) English language. Four reviewers, including two physicians, independently and blindly extracted published data regarding microRNA profiles in blood and/or urine from subjects with diabetic nephropathy. A random-effect model was used to pool the data. Statistical associations between diabetic nephropathy and urinary or blood microRNA expression levels were assessed. Results: Fourteen out of 327 studies (n=2,747 patients) were selected. Blood or urinary microRNA expression data of diabetic nephropathy were pooled for this analysis. The hsa-miR-126 family was significantly (OR: 0.57; 95% CI: 0.44-0.74; p-value < 0.0001) downregulated in blood from patients with diabetic kidney disease, while its urinary level was upregulated (OR: 2931.12; 95% CI: 9.96-862623.21; p-value = 0.0059). The hsa-miR-770 family microRNA were significantly (OR: 10.24; 95% CI: 2.37-44.25; p-value = 0.0018) upregulated in both blood and urine from patients with diabetic nephropathy. Conclusions: Our meta-analysis suggests that hsa-miR-126 and hsa-miR-770 family microRNA may have important diagnostic and pathogenetic implications for DN, which warrants further systematic clinical studies.

microRNAs (miRNAs) have been established as critical regulators of the pathogenesis of diabetes mellitus (DM), and diabetes microvascular complications (DMCs). However, manually curated databases for miRNAs, and DM (including DMCs) association studies, have yet to be established. Here, we constructed a user-friendly database, &ldquo, miR2Diabetes,&rdquo, equipped with a graphical web interface for simple browsing or searching manually curated annotations. The annotations in our database cover 14 DM and DMC phenotypes, involving 156 miRNAs, by browsing diverse sample origins (e.g., blood, kidney, liver, and other tissues). Additionally, we provide miRNA annotations for disease-model organisms (including rats and mice), of DM and DMCs, for the purpose of improving knowledge of the biological complexity of these pathologies. We assert that our database will be a comprehensive resource for miRNA biomarker studies, as well as for prioritizing miRNAs for functional validation, in DM and DMCs, with likely extension to other diseases.

Kiyoung Lee,1,2 Ie Byung Park,1,2 Seung Hee Yu,2 Soo-Kyung Kim,3 So Hun Kim,4 Da Hea Seo,4 Seongbin Hong,4 Ja Young Jeon,5 Dae Jung Kim,5 Soo Wan Kim,6 Cheol Soo Choi,1,2Dae Ho Lee1,21Department of Internal Medicine, Gachon University College of Medicine, Incheon, Republic of Korea; 2Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; 3Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea; 4Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea; 5Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea; 6Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of KoreaAim: We aimed to evaluate the clinical utility of blood ketone measurement and to test the performance of the diagnostic criteria for diabetic ketoacidosis (DKA) issued by the American Diabetes Association, the Joint British Diabetes Societies, and the American Association of Clinical Endocrinologists and the American College of Endocrinology.Methods: This retrospective analysis included 278 patients with suspected DKA who were hospitalized at 4 university hospitals and aged ≥16years with a blood glucose level of >200mg/dL and a blood ketone level of ≥1.0mmol/L as well as other biochemical data. The patients were categorized into four subgroups (ketosis, typical DKA, atypical DKA, and DKA + lactic acidosis). Atypical DKA in each analysis was defined by our supplementary criteria if the biochemical data did not meet each set of diagnostic criteria from the aforementioned societies.Results: Blood ketone levels in patients with diabetic ketosis and those with DKA varied widely, 1.05–5.13mmol/L and 1.02–15.9mmol/L, respectively. Additionally, there were significant discrepancies between the guidelines in the diagnosis of DKA. Thus, the proportion of patients with atypical DKA ranged from 16.5% to 42.4%. Notably, the in-hospital mortality was comparable between patients with typical and atypical DKA, with a very high mortality in patients with DKA + lactic acidosis (blood lactate >5mmol/L).Conclusions: Our results showed that considering variable presentations of DKA, blood ketone data need to be interpreted cautiously along with other biochemical data and suggested that a new system is required to better characterize DKA.Keywords: Diabetic ketoacidosis, ketone bodies, diagnosis, lactic acidosis, acid base imbalance

Dipeptidyl peptidase 4 inhibitors (DPP4Is) can increase sympathetic activity. We aimed to evaluate the direct association between serum DPP4 activity and sympathetic activity in humans.Fasting serum DPP4 activity and plasma levels of catecholamines and their metabolites were measured in 211 patients with type 2 diabetes mellitus (T2DM) treated with DPP4I (n = 146) or non-DPP4I therapy (n = 65) and in healthy control subjects (n = 30).Although there were no differences in plasma levels of catecholamines and their metabolites between the DPP4I and non-DPP4I groups, the levels in both of these groups were lower than those in the healthy control group. In DPP4I-treated patients, serum DPP4 activity showed an inverse correlation with plasma levels of norepinephrine (NE) (r = -0.339, p 0.01), metanephrine (MET) (r = -0.251, p 0.01) and normetanephrine (r = -0.312, p 0.001). In addition, plasma MET level showed a weak inverse correlation with serum DPP4 activity in the combined T2DM group. In DPP4I-treated patients, the inverse correlation between DPP4 activity and plasma NE remained significant even after multiple adjustments.Our results suggest that although sympathetic activity is lower in patients with T2DM, the greater the suppression of DPP4 activity by DPP4I therapy, the greater the increase in sympathetic activity is, which may have clinical implications in high risk T2DM patients.

Background and Aims: Evogliptin is a new dipeptidyl peptidase-4 (DPP-4) inhibitor. We investigated the efficacy and safety of Evogliptin compared with linagliptin in patients with type 2 diabetes (T2D). Materials and Methods: A total of 207 untreated patients with T2D (mean age, 56.1±10.4 years; body mass index, 26.1±3.4 kg/m2) who had HbA1c 7.0-10.0%, prior to the screening were randomized 1:1 for 5 mg Evogliptin (n=102) or 5 mg linagliptin (n=105) once daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint included the change in mean amplitude of glycemic excursion (MAGE) assessed by 72-hour continuous glucose monitoring. In the extended study for another 12 weeks, open-label treatment with Evogliptin 5 mg qd was conducted in both groups; Evogliptin/Evogliptin group (n=95) and Linagliptin/Evogliptin group (n=92). Results: After 12 weeks of treatment, the mean changes in HbA1c of Evogliptin group and linagliptin group were −0.85% and −0.75%, respectively; the between-group difference was -0.10% (95% confidence interval, −0.32-0.11%), demonstrating non-inferiority, meeting the pre-specified margin of 0.40%. The changes in MAGE were −24.6 mg/dL in the Evogliptin group and −16.7 mg/dL in the linagliptin group, which were significantly lower compared with baseline values in both groups. In the Evogliptin/Evogliptin group at week 24, the mean changes from baseline in HbA1c was −0.94%, achieving HbA1c Conclusion: In this study, once-daily evoglipitin 5 mg treatment significantly decreased HbA1c levels by 0.94% at week 24 and improved glycemic variability without any serious adverse events in Korean patients with T2D (ClinicalTrials.gov Identifier: NCT02974504). Disclosure S. Lim: None. G. Kim: None. H. Kwon: None. I. Park: None. K. Ahn: None. C. Park: None. S. Kwon: None. H. Kim: None. S. Park: None. S. Kim: None. M. Moon: None. E. Kim: None. C.H. Chung: None. K. Won: None. K. Park: None. M. Kim: None. D. Chung: None. C. Lee: None. T. Kim: None. M. Lee: None.

MRI-based examinations of hepatic steatosis and body fat are becoming more familiar and useful for metabolic studies including NAFLD. MRI-estimated proton density fat fraction (MRI-PDFF) can haptic fat exactly without biopsy, enabling us to evaluate the effect of liver fat more sophisticatedly than ever. Although hepatic fat and visceral fats are both important for metabolic and cardiovascular diseases, detailed evaluation of the effect of each fat depot on various metabolic profiles have not been performed, In the present study, we evaluated the differential effect between hepatic and visceral fats on various metabolic profiles including glucose and lipid metabolism, islet cell function, insulin resistance, and inflammation. A total of 82 subjects (25 healthy volunteers and 57 patients with suspected, or proven NAFLD) who underwent MRI examinations for MRI-PDFF and visceral fat measurement. Additionally, anthropometric and laboratory studies and total body fat measurement by DXA were also performed. Other causes of chronic liver diseases, such as alcoholic, autoimmune or viral hepatitis, and other diseases, were excluded from the study. The amounts of hepatic fat and visceral fats measured by MRI showed similar significant correlations with HOMA-IR (r=0.540 vs. r=0.538, p Disclosure I. Park: None. K. Lee: None. D. Lee: None.

Previous preclinical and clinical studies have raised a concern that dipeptidyl peptidase 4 inhibitors (DPP-4i) increased sympathetic activity, which may be related with increased risk of heart failure in DPP-4i-treated type 2 diabetics. In this study, we aimed to evaluate the relationship between DPP-4 activity and catecholamine secretion in patients with type 2 diabetes. Patients with type 2 diabetes (n=119) and normal healthy control subjects (n=25) participated in this cross-sectional study which included the measurement of serum DPP-4 activity and plasma levels of epinephrine (Epi), norepinephrine (NE), metanephrine (MET) and normetanephrine (NMET), other blood and urine biochemical tests, and the collection of demographic and clinical data. The median ages of patients with type 2 diabetes and healthy control subjects were 61 and 56 years, respectively. Compared with the control group, patients with type 2 diabetes were associated with lower plasma levels of catecholamines and their metabolites. In DPP-4i-treated diabetic patients (n=86) had lower plasma NMET level compared with other antidiabetic treatment group (n=36) [0.31 (IQR: 0.21, 0.43)] nmol/L vs. 0.41 (0.29, 0.46) nmol/L, p Disclosure I. Park: None. D. Lee: None. K. Lee: None.

The treatment approach to type 2 diabetes (T2D) should begin with an assessment of atherosclerotic cardiovascular disease (ASCVD). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) should be considered in T2D with established ASCVD or heart failure (HF). In this study, we analyzed the prescription patterns of ant-diabetic treatment in T2D with ASCVD or HF in real-world clinical practice. During 1-year period (2018), we reviewed 1553 consecutive T2D patients with ASCVD or HF visiting an endocrinology outpatient clinic from four teaching hospitals in Seoul Capital Area after excluding patients aged ≥85 years or estimated glomerular filtration rate (eGFR) ≤30 ml/min/1.73m2. Mean age was 65 years, duration of diabetes 11 years, and duration of ASCVD 7 years; HbA1C 7.5%, eGFR 80 ml/min/1.73m2, and body mass index (BMI) 25.6 kg/m2. ASCVD characteristics were stroke 27%, coronary artery disease (CAD) 59%, stroke+CAD 5%, peripheral arterial occlusive disease 1%, and heart failure 8%. Over four years, the initiation of SGLT2i has increased (2015=9% vs. 2018=42%). Compared with SGLT2i non-users (80%, n=1249), SGLT2i users (20%, n=304) tended to be younger (60 vs. 67) and with significantly lower stroke (16% vs. 30%). They also had higher BMI (27 vs. 25), worse HbA1C levels (8.1 vs. 7.4), and higher eGFR (88 vs. 78). Non-users with HbA1C 8 ∼9% (n=245) who might be eligible for switching to SGLT2i showed a longer duration of diabetes (14 vs. 11 years) or ASCVD (7.4 vs. 6.5 years) compared to users. The most common prescription pattern in non-users was triple oral glucose-lowering drugs (OGLD) followed by dual OGLD while in users, dual OGLD followed by triple OGLD. Interestingly, 0.5% were on GLP-1RA in this study. In contrast to clinical guidelines, a small proportion of T2D with ASCVD or HF is currently treated with SGLT2i in real-world clinical practice. The limiting factors for failing to initiate SGLT2i are age, stoke, eGFR, and clinical inertia. Disclosure S. Jeong: None. I. Park: None. S. Lee: None. D. Shin: None. K. Kim: None.

Both exosome and microRNAs (miRNAs) in biological fluids can be good biomarkers for pathologic conditions. Thus, urinary exosome miRNAs would be reasonable non-invasive tools for biomarker development for diabetic kidney disease. To be eligible for exosome miRNA biomarker development, the performance of exosome isolation methods for miRNA profiling need to be tested. In the present study, using urine samples from patients with type 2 diabetes, we compared four different exosome isolation methods for their performance in urine exosome isolation and detectable urinary exosome miRNA profiles. Four methods compared in the present study were ultracentrifugation (UC), size exclusion chromatography using qEV column (qEV), ExoQuick-TC (ExoQuick), and Amicon tube 100K (Amicon). Isolated exosomes were subjected to next generation sequencing (NGS) to profile miRNAs. The counts, RNA concentrations, and protein marker expressions of isolated urine exosome were variable between the extraction methods, with the highest exosome count with the qEV method. The number of miRNAs detected (read count ≥1) in 100 mL urine each were 314, 174, 91, and 130 from UC, qEV, ExoQuicK, and Amiconmethods, respectivley. And, 57 miRNAs were detected with all 4 methods concordantly. There were correlations in the levels of exosomal miRNAs between samples from UC, qEV, and ExoQuick methods, whereas exosome miRNA profiles from Amicon sample showed only a weak correlation with those from other methods. Our results suggest that exosome isolation by using UC or qEV method may be a better option among different isolation methods to profile urinary exosome miRNAs in diabetic kidney disease. However, ultrafiltration method using Amicon tube produced a different profile of miRNAs with other methods. Further studies are needed to characterize both exosome and their genetic materials from different extraction sources. Disclosure K. Lee: None. D. Lee: None. I. Park: None.

In this study, the pattern of depressive mood in patients following radical prostatectomy (RP) for localized prostate cancer (PCa) was determined. A total of 30 patients (aged 68.03±6.1 years) who were diagnosed with localized PCa and underwent RP within 1 month entered the study. Evaluations included body mass index, prostate-specific antigen, testosterone, underlying disease, international prostate symptom score and quality of life (QoL), international index of erectile function as well as Beck depression inventory (BDI), both at the initial stage and 3 months later. Basic demographic data, laboratory results, and questionnaires were analyzed statistically. The BDI score significantly decreased 3 months after the surgery. In correlation analysis, BDI was related with the international prostate symptom score but not with the underlying disease, QoL or international index of erectile function. Body mass index was identified as one of the risk factors to decrease the probability of BDI score (≥3) significantly. Underlying disease increased the probability of BDI score. In the assessment of the correlation between BDI and each subscale, sadness, self-dislike, self-criticalness, and worth-lessness showed high correlation. In the early period, depressive mood was improved at the short-term follow-up in localized PCa patients after RP. Voiding symptoms were only related with the depressive mood, but not with other parameters, including sexual function. The depressive mood had no effect on the QoL in the early stage.

Objective— To determine the effect of probucol on urine albumin excretion in type 2 diabetes mellitus patients with albuminuria using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Approach and Results— This was a 16-week, phase II, randomized, placebo-controlled, parallel-group study in type 2 diabetes mellitus patients with a urinary albumin/creatinine ratio of ≥300 mg/g using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, conducted in 17 tertiary referral hospitals. Eligible patients were randomized to probucol 250 mg/d (n=44), probucol 500 mg/d (n=41), and placebo (n=41) groups in a ratio of 1:1:1 after block randomization procedures, keeping the treatment assignment blinded to the investigators, patients, and study assistants. The primary end point was change in the geometric mean of urinary albumin/creatinine ratio from baseline to week 16 ( ClinicalTrials.gov identifier NCT01726816). The study was started on November 8, 2012, and completed on March 24, 2014. The least squares mean change±SE from baseline in urinary albumin/creatinine ratio at week 16 was −7.2±639.5 mg/g in the probucol 250 mg/d group (n=43; P =0.2077 versus placebo group), 9.3±587.4 mg/g in the probucol 500 mg/d group (n=40; P =0.1975 versus placebo group), and 259.0±969.1 mg/g in the placebo group (n=41). Although the majority of subjects were on statins, probucol treatment significantly lowered total cholesterol and low-density lipoprotein cholesterol levels. QT prolongation occurred in one and two subjects in control and probucol 250 mg/d groups, respectively. Conclusions— Four months of probucol up to 500 mg/d failed to reduce urinary albumin excretion.

Purpose There has been limited research on physicians' perceptions of the specialty characteristics that are needed to sustain a successful career in medical specialties in Korea. Medical Specialty Preference Inventory in the United States or SCI59 (specialty choice inventory) in the United Kingdom are implemented to help medical students plan their careers. The purpose of this study was to explore the characteristics of the major specialties in Korea. Methods Twelve physicians from different specialties participated in an exploratory study consisting of qualitative interviews about the personal ability and emotional characteristics and job attributes of each specialty. The collected data were analysed with content analysis methods. Results Twelve codes were extracted for ability & skill attributes, 23 codes for emotion & attitude attributes, and 12 codes for job attributes. Each specialty shows a different profile in terms of its characteristic attributes. Conclusion The findings have implications for the design of career planning programs for medical students.

Aims MicroRNAs (miRNAs) that circulate in biological fluids are frequently enclosed in extracellular vesicles (EVs). However, urinary EVs and their cargo miRNAs have not been systematically studied according to their EV isolation methods. Methods In type 2 diabetes mellitus persons with diabetic nephropathy (n = 4), we compared miRNA species in urine EVs prepared by ultracentrifugation (UC), qEV original size exclusion column (qEV), ExoQuick-TC Plus (ExoQuick), and ultrafiltration using Amicon Ultra centrifugal filter devices (Amicons) 10 K and 100 K. EV miRNAs were profiled by next-generation sequencing (NGS). Additionally, we evaluated the correlations of EV miRNA expression between the urine and serum samples isolated by UC. Results From each of 100 ml of urine, the UC method yielded the highest number of EV miRNA species (233 ± 37.3), with the ExoQuick yielded the lowest (103 ± 17.4). Urine EV miRNA profiles were highly correlated between UC, qEV, ExoQuick and Amicon 10 K methods. EV miRNA profiles between the urine and serum samples showed variable correlations between the patients (paired sample number = 3, r = 0.39–0.72). Conclusions UC, qEV, ExoQuick, and Amicon 10 K are acceptable for urinary EV isolation to profile miRNAs. Urine- and serum-derived EV miRNA profiles have variable correlations depending on specific patients.

Background: Sedentary behavior (SB) has emerged as a new risk factor for cardiovascular accidents. We investigated whether physical activity levels or SB were related to percent body fat (%BF) in type 2 diabetes mellitus (T2DM). Methods: In this cross sectional study, we measured the duration of SB, light physical activity (LPA), moderate to vigorous physi cal activity (MVPA), total energy expenditure, and step counts using a wireless activity tracker (Fitbit HR; FB) for 7 days in free-living conditions, along with %BF using a bio impedance analyzer (Inbody; Biospace) in 120 smartphone users with T2DM. Sub jects were divided into exercise (Exe, n=68) and non-exercise (nonExe, n=52) groups based on self-reports of whether the rec ommended exercises (30 min/day, 3 days/week for 3 months) were performed. SBt, LPAt, MVPAt were transformed from SB, LPA, MVPA for normally distributed variables. Results: Participants were: female, 59.2%; age, 59.3±8.4 years; body mass index, 25.5±3.4 kg/m2; glycosylated hemoglobin (HbA1c), 7.6%±1.2%; %BF, 30.4%±7.1%. They performed SB for 15.7±3.7 hr/day, LPA for 4.4±1.7 hr/day, and MVPA for 0.9±0.8 hr/day. The %BF was related to SBt and LPAt, but not to MVPA after adjustments for age, gender, and HbA1c. VPA was significantly higher in the Exe group than in the nonExe group, but SB, LPA, and moderate physical activity were not different. Predicted %BF was 89.494 to 0.105 (age), -13.047 (gender), -0.507 (HbA1c), -7.655 (LPAt) (F[4, 64]=62.929, P

Background This study was a multicenter, parallel-group, double-blind, double-dummy, randomized, noninferiority trial to evaluate the efficacy and safety of γ-linolenic acid (GLA) relative to α-lipoic acid (ALA) over a 12-week treatment period in type 2 diabetes mellitus (T2DM) patients with painful diabetic peripheral neuropathy (DPN). Methods This study included 100 T2DM patients between 20 and 75 years of age who had painful DPN and received either GLA (320 mg/day) and placebo or ALA (600 mg/day) and placebo for 12 weeks. The primary outcome measures were mean changes in pain intensities as measured by the visual analogue scale (VAS) and the total symptom scores (TSS). Results Of the 100 subjects who initially participated in the study, 73 completed the 12-week treatment period. Per-protocol analyses revealed significant decreases in the mean VAS and TSS scores compared to baseline in both groups, but there were no significant differences between the groups. The treatment difference for the VAS (95% confidence interval [CI]) between the two groups was -0.65 (-1.526 to 0.213) and the upper bound of the 95% CI did not exceed the predefined noninferiority margin (δ₁=0.51). For the TSS, the treatment difference was -0.05 (-1.211 to 1.101) but the upper bound of the 95% CI crossed the noninferiority margin (δ₂=0.054). There were no serious adverse events associated with the treatments. Conclusion GLA treatment in patients with painful DPN was noninferior to ALA in terms of reducing pain intensity measured by the VAS over 12 weeks.

Background: Although prediabetes increases AMI risk, long-term clinical implication for prevalent prediabetes in AMI patients is not clear. The present study aimed to evaluate whether prediabetes at admission increases long-term cardiovascular (CV) and total mortalities in AMI patients who were discharged alive. Methods: We obtained AMI patient data from The Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) registry. Total and CV mortalities at 12 months after AMI were assessed. Results: A total of 13104 patients with AMI from the registry database were analyzed. 552 patients (4.2%) were destined to in-hospital mortality or hopeless discharge. We classified the remaining patients into control, prediabetes, and diabetes groups according to one of fallowing parameters: prevalent diabetes by past history, diabetes medication during hospitalization, or in the remaining cases with no diabetes history or medication data by hemoglobin A1c level at admission. Patients without any data about above-mentioned parameters were excluded in this study (n= 3583), and a total of 8969 AMI patients were available for analysis (control group, n=2379; prediabetes group, n=2321; and diabetes, n=4269). After adjustment for multiple factors, hazard ratios (HRs) (95% CI) for total mortality in prediabetic group vs. control group and diabetic group vs. control group were 1.536 (0.879-2.685, p=0.132) and 1.94 (1.184-3.190), p Conclusions: Our results show that that prediabetic state at AMI admission do not increase CV mortality and all-cause mortalities at 1-year after survival discharge, whereas diabetes increase 1-year all-cause mortality. Disclosure I. Park: None. D. Lee: None. S. Yu: None. K. Lee: None.

We conducted a 24-week, multicentre, double-blind, randomized study with a 28-week extension to compare the efficacy and safety of anagliptin and sitagliptin as an add-on to metformin in patients with type 2 diabetes. Patients inadequately controlled on metformin were randomized to either anagliptin (100 mg twice daily, n = 92) or sitagliptin (100 mg once daily, n = 88). The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. The mean changes in HbA1c were -0.85 ± 0.70% (p < 0.0001) for anagliptin and -0.83 ± 0.61% (p < 0.0001) for sitagliptin, with a mean difference of -0.02% (95% confidence interval of difference, -0.22 to 0.18%). In both groups, the fasting proinsulin : insulin ratio significantly decreased from baseline, with improved insulin secretion. Safety profiles were similar in each group. In conclusion, the non-inferiority of the efficacy of anagliptin to sitagliptin as an add-on therapy was established with regard to efficacy and safety.

The purpose of this study was to examine the efficacy and safety of adding ω-3 fatty acids to rosuvastatin in patients with residual hypertriglyceridemia despite statin treatment.This study was a multicenter, randomized, double-blind, placebo-controlled study. After a 4-week run-in period of rosuvastatin treatment, the patients who had residual hypertriglyceridemia were randomized to receive rosuvastatin 20 mg/d plus ω-3 fatty acids 4 g/d (ROSUMEGA group) or rosuvastatin 20 mg/d (rosuvastatin group) with a 1:1 ratio and were prescribed each medication for 8 weeks.A total of 201 patients were analyzed (mean [SD] age, 58.1 [10.7] years; 62.7% male). After 8 weeks of treatment, the percentage change from baseline in triglycerides (TGs) and non-HDL-C was significantly greater in the ROSUMEGA group than in the rosuvastatin group (TGs: -26.3% vs -11.4%, P0.001; non-HDL-C: -10.7% vs -2.2%, P = 0.001). In the linear regression analysis, the lipid-lowering effect of ω-3 fatty acids was greater when baseline TG or non-HDL-C levels were high and body mass index was low. The incidence of adverse events was not significantly different between the 2 groups.In patients with residual hypertriglyceridemia despite statin treatment, a combination of ω-3 fatty acids and rosuvastatin produced a greater reduction of TGs and non-HDL-C than rosuvastatin alone. Further study is needed to determine whether the advantages of this lipid profile of ω-3 fatty acids actually leads to the prevention of cardiovascular event. ClinicalTrials.gov identifier: NCT03026933.

SummaryObjective The interrelation between TSH, thyroid hormones and metabolic parameters is complex and has not been confirmed. This study aimed to determine the association of TSH and thyroid hormones in euthyroid subjects and the relationship between thyroid function and metabolic risk factors. Furthermore, this study examined whether thyroid function has predictive power for metabolic syndrome. Design This is a cross-sectional study that included subjects in a medical health check-up programme at a single institution. Patients The study included 132 346 participants (66 991 men and 65 355 women) aged over 18 years who had TSH, free T4 (FT4) and free T3 (FT3) levels within the institutional reference ranges. Measurements Thyrotropin, FT4, FT3 and metabolic parameters including height, weight, waist circumference, blood pressure, serum levels of total cholesterol, triglyceride, high-density lipoprotein cholesterol, insulin and glucose were measured. Results There was a positive association between FT3/FT4 ratio and TSH in both men and women after adjusting for age, body mass index, smoking status and menopausal status (in women). The FT3/FT4 ratio and TSH were positively associated with risk of metabolic syndrome parameters including insulin resistance. The FT3/FT4 ratio had a greater predictive power than TSH for metabolic syndrome in both men and women. Conclusions Thyrotropin levels were positively associated with FT3/FT4 ratio within the euthyroid range. The higher FT3/FT4 ratio is associated with increased risk of metabolic syndrome parameters and insulin resistance. FT3/FT4 ratio has a better predictive power for metabolic syndrome than TSH.

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

Summary Overview Glial cells missing B (GCMB) is a transcription factor that is expressed in the parathyroid hormone (PTH)-secreting cells of the parathyroid glands. Several mutations in GCMB have been reported to cause hypoparathyroidism (HP). We identified a family with two individuals in two generations (mother and son), who are affected by autosomal-dominant hypoparathyroidism (AD-HP). A novel heterozygous mutation in exon 2 of GCMB was identified in both affected individuals that changes cysteine at position 106 of the putative DNA-binding domain of GCMB to arginine (C106R). Methods We performed mutational analysis of the genes encoding GCMB, pre-pro PTH, GATA3 and CaSR using polymerase chain reaction (PCR)-amplified genomic DNA. The identified GCMB mutant was characterized by functional studies including nuclear localization, electrophoretic mobility shift assays (EMSA) and luciferase reporter assays, and homology modelling was performed to generate a three-dimensional structural model for the DNA-binding domain of GCMB to predict the structural consequences of the identified mutation. Results The C106R mutant of GCMB failed to interact with the DNA consensus recognition motif, as determined by EMSA. Furthermore, in comparison with wild-type GCMB, the C106R mutant demonstrated reduced transactivation in luciferase reporter assays; however, the mutant GCMB failed to reduce the activity of the wild-type protein. Consistent with the EMSA findings, homology modelling analysis suggested that replacement of cysteine 106 with arginine would interfere with DNA binding. Conclusions We have identified a novel GCMB mutation that may explain AD-HP in our family. However, the exact mechanism by which this heterozygous mutation leads to the disease in the described family remains to be elucidated.