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Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a randomized controlled trial.Setting & Participants: Participants in the CREDENCE trial.Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.

Relationships among autonomic nervous system, diabetes and metabolic syndrome.

Background Cardiovascular autonomic neuropathy (CAN) is a common microvascular complication of diabetes and related to albuminuria in diabetic nephropathy (DN). Urinary N-acetyl-β-D-glucosaminidase (uNAG) is a renal tubular injury marker which has been reported as an early marker of DN even in patients with normoalbuminuria. This study evaluated whether uNAG is associated with the presence and severity of CAN in patients with type 1 diabetes mellitus (T1DM) without nephropathy. Methods This cross-sectional study comprised 247 subjects with T1DM without chronic kidney disease and albuminuria who had results for both uNAG and autonomic function tests within 3 months. The presence of CAN was assessed by age-dependent reference values for four autonomic function tests. Total CAN score was assessed as the sum of the partial points of five cardiovascular reflex tests and was used to estimatethe severity of CAN. The correlations between uNAG and heart rate variability (HRV) parameters were analyzed. Results The association between log-uNAG and presence of CAN was significant in a multivariate logistic regression model (adjusted odds ratio, 2.39; 95% confidence interval [CI], 1.08 to 5.28; P=0.031). Total CAN score was positively associated with loguNAG (β=0.261, P=0.026) in the multivariate linear regression model. Log-uNAG was inversely correlated with frequency-domain and time-domain indices of HRV. Conclusion This study verified the association of uNAG with presence and severity of CAN and changes in HRV in T1DM patients without nephropathy. The potential role of uNAG should be further assessed for high-risk patients for CAN in T1DM patients without nephropathy.

Aims/Introduction Using an investigational diet plan based on the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet comprised of substitute ingredients that mimic the average East Asian diet, this study assessed the glycemic benefits in comparison with a food exchange system‐based diet in established type 2 diabetes patients. Materials and Methods This was a 12‐week, open‐label randomized clinical trial carried out among 60 Korean adults with type 2 diabetes having a median body mass index of 23.5 kg/m2. Glycemic benefits in the investigational diet (group A) were compared with those obtained with a food exchange system‐based diet, either in the form of ready meals provided to participants (group B) or not (group C). The primary end‐point was changes in glycated hemoglobin from baseline to week 12. Results Changes in glycated hemoglobin (%) from baseline to week 12 were −0.97 ± 0.97 in group A (vs group B, P = 0.085 in the full analysis set, and P = 0.028 in the per‐protocol set; vs group C, P = 0.030 in the full analysis set and P = 0.020 in the per‐protocol set), −0.51 ± 0.65 in group B (vs group C, P > 0.05 in the full analysis set and the per‐protocol set), and −0.36 ± 0.74 in group C. Decreases from baseline in body mass index, waist circumference and blood pressure were greater in group A than in group C. Conclusion With the provision of ready meals, the glycemic benefits of the investigational diet plan were demonstrable over a self‐prepared food exchange system‐based diet in Korean adults with established type 2 diabetes., This article describes 12‐week, open‐label, randomized controlled trial (RCT) to compare the efficacy of the three strategies of diabetes medical nutrition therapy. The results of the current study showed that the semi‐cooked prepackaged diet plan, which was comprised of substitute ingredients that mimic the average Asian diet but still maintain the common characteristics of global healthful eating patterns, had a greater efficacy in lowering HbA1c than usual care in study participants with type 2 diabetes (median BMI, 23.3 to 23.7 kg/m2).

Optimal blood glucose control warrants both early intensive therapy and individualization strategies in patients with diabetes mellitus.

Background Type 2 diabetes and cardiovascular disease (CVD) are the most important sequelae of obesity and the leading cause of death. We evaluated the association between body mass index (BMI) and the risk of incident type 2 diabetes, CVD, and all-cause mortality in a prospective study of a Korean population. Methods The shapes of the associations were modeled by restricted cubic splines regression analysis. After categorizing all subjects (n=8,900) into octiles based on their BMI levels, we estimated the hazard ratio (HR) for the association of categorized BMI levels with the risk of incident CVD and type 2 diabetes using a Cox's proportional hazard analysis. Results The mean age of participants was 52 years and 48% were men. Of the subjects at baseline, 39.0% of men and 45.6% of women were classified as obese (BMI ≥25 kg/m2). Over a mean follow-up of 8.1 years, CVD events occurred in 509 participants; 436 died; and 1,258 subjects developed type 2 diabetes. The increased risk of incident diabetes began to be significant at BMI 23 to 24 kg/m2 in both sexes (HR, 1.8). For CVD events, the risk began to increase significantly at BMI 26 to 28 kg/m2 (HR, 1.6). We found a reverse J-shaped relationship between BMI and all-cause mortality, with an increased risk among individuals with BMI values in lower range (BMI l21 kg/m2). Conclusion These results suggest that the BMI cut-off points for observed risk were varied depending on the diseases and that the BMI classification of obesity need to be revised to reflect differential risk of obesity-related diseases.

In patients with type 2 diabetes mellitus (T2DM) who require additional glucose-lowering on top of first-line metformin monotherapy, sulfonylureas are the most common choice for second-line therapy followed by dipeptidyl peptidase inhibitors (DPP-4i). This article summarises presentations at a symposium entitled "Real-World Evidence and New Perspectives with Gliclazide MR" held at the International Diabetes Federation Congress in Busan, South Korea on 4 December 2019. Although guideline recommendations vary between countries, the guidelines with the highest quality ratings include sulfonylureas as one of the preferred choices as second-line therapy for T2DM. Data from randomised controlled trials (RCTs) have consistently demonstrated that sulfonylureas are effective glucose-lowering agents and that the risk of severe hypoglycaemia with these agents is low. In addition, both RCTs and real-world observational studies have shown no increased risk of mortality or cardiovascular disease with the use of newer-generation sulfonylureas compared with other classes of glucose-lowering treatments. However, differences between sulfonylureas do exist, with gliclazide being associated with a significantly lower risk of mortality or cardiovascular mortality compared with glibenclamide, as well as the lowest incidence of severe hypoglycaemia compared with other agents in this class. Recent real-world studies into the effectiveness and safety of gliclazide appear to confirm these findings, and publication of new data from these studies in patients with T2DM in the UK, and in Muslim patients who are fasting during Ramadan, are awaited with interest. Another study being undertaken with gliclazide is a pan-India study in patients with maturity-onset diabetes of the young (MODY) subtypes 1, 3 and 12. Patients with these MODY subtypes respond particularly well to sulfonylurea treatment, and sulfonylureas are the first-line agents of choice in these patients. These new and ongoing studies will add to the cumulative data on the efficacy and safety of certain sulfonylureas in patients with diabetes.

We aimed to identify the association between low skeletal muscle, sarcopenic obesity, and the incidence of albuminuria in the general population using a longitudinal study. Data from 29,942 subjects who underwent two or more routine health examinations from 2006 to 2013 were retrospectively reviewed. Relative skeletal muscle mass was presented using the skeletal muscle mass index (SMI), a measure of body weight-adjusted appendicular skeletal muscle mass estimated by bioelectrical impedance analysis. The cumulative incidence of albuminuria was 981 (3.3%) during the 7-year follow-up period. The hazard ratio of incident albuminuria was 1.44 (95% CI: 1.22–1.71, p for trend p for trend = 0.001) and 1.30 (95% CI: 1.08–1.56, p for trend = 0.003), respectively. Furthermore, the risk of developing albuminuria was much higher in the sarcopenic obesity group (HR: 1.49, 95% CI: 1.21–1.81, p for trend

Vegetation segmentation in a field color image is a process of distinguishing vegetation objects of interests like crops and weeds from a background of soil and/or other residues. The performance of the process is crucial in automatic precision agriculture which includes weed control and crop status monitoring. To facilitate the segmentation, color indices have predominantly been used to transform the color image into its gray-scale image. A thresholding technique like the Otsu method is then applied to distinguish vegetation parts from the background. An obvious demerit of the thresholding based segmentation will be that classification of each pixel into vegetation or background is carried out solely by using the color feature of the pixel itself without taking into account color features of its neighboring pixels. This paper presents a new pixel-based segmentation method which employs a multi-layer perceptron neural network to classify the gray-scale image into vegetation and nonvegetation pixels. The input data of the neural network for each pixel are 2-dimensional gray-level values surrounding the pixel. To generate a gray-scale image from a raw RGB color image, a well-known color index called Excess Green minus Excess Red Index was used. Experimental results using 80 field images of 4 vegetation species demonstrate the superiority of the neural network to existing threshold-based segmentation methods in terms of accuracy, precision, recall, and harmonic mean.

Background: We aimed to describe the outcome of a computerized intravenous insulin infusion (CII) protocol integrated to the electronic health record (EHR) system and to improve the CII protocol in silico using the EHR-based predictors of the outcome. Methods: Clinical outcomes of the patients who underwent the CII protocol between July 2016 and February 2017 and their matched controls were evaluated. In the CII protocol group (n=91), multivariable binary logistic regression analysis models were used to determine the independent associates with a delayed response (taking ≥6.0 hours for entering a glucose range of 70 to 180 mg/dL). The CII protocol was adjusted in silico according to the EHR-based parameters obtained in the first 3 hours of CII. Results: Use of the CII protocol was associated with fewer subjects with hypoglycemia alert values (P=0.003), earlier (P=0.002), and more stable (P=0.017) achievement of a glucose range of 70 to 180 mg/dL. Initial glucose level (P=0.001), change in glucose during the first 2 hours (P=0.026), and change in insulin infusion rate during the first 3 hours (P=0.029) were independently as sociated with delayed responses. Increasing the insulin infusion rate temporarily according to these parameters in silico signifi cantly reduced delayed responses (P

The endocrine pancreatic β-cells play a pivotal role in maintaining whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate β-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homeostasis.Mice lacking ROCK1 in pancreatic β-cells (RIP-Cre; ROCK1Mice with a deficiency of ROCK1 in pancreatic β-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, β-ROCK1Our findings demonstrate that β-cell ROCK1 is essential for glucose-stimulated insulin secretion and for glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling.

Aims/Introduction Several cross‐sectional studies have shown that delayed heart rate recovery (HRR) after exercise is associated with the development of metabolic syndrome (MetS). However, there has been a lack of comprehensively designed longitudinal studies. Therefore, our aim was to evaluate the longitudinal association of delayed HRR following a graded exercise treadmill test (GTX) with incident MetS. Materials and Methods This was a retrospective longitudinal cohort study of participants without MetS, diabetes, or cardiovascular diseases. The HRR was calculated as the peak heart rate minus the resting heart rate after a 1 min rest (HRR1), a 2 min rest (HRR2), and a 3 min rest (HRR3). Multivariate Cox proportional hazards analysis was performed to investigate the association between HRR and development of MetS. Results There were 676 (31.2%) incident cases of MetS identified during the follow‐up period (9,683 person‐years). The only statistically significant relationship was between HRR3 and the development of MetS. The hazard ratios (HRs) (95% confidence interval [CI]) of incident MetS comparing the first and second tertiles to the third tertile of HRR3 were 1.492 (1.146–1.943) and 1.277 (1.004–1.624) with P = 0.003 after adjustment for multiple risk factors. As a continuous variable, the HR (95% CI) of incident MetS associated with each one‐beat decrease in HRR3 was 1.015 (1.005–1.026) with P = 0.004 after full adjustments. An HRR3 value ≤45 beats per minute (bpm) was associated with a higher risk of incident MetS compared with values >45 bpm, with an HR (95% CI) of 1.304 (1.061–1.602) and P = 0.001. Conclusions The slow phase of HRR, particularly HRR3, might be more sensitive at predicting the risk of MetS., Delayed HRR3 after exercise could predict incident MetS in a general population, even after adjusting for fasting plasma glucose, HOMA‐IR, and HbA1c. And a HRR3 value of 45 beats per minute (bpm) or below was associated with a significantly higher risk of incident MetS compared with values over 45 bpm.

Background: Metformin, sulfonylurea, and dietary fiber are known to affect gut microbiota in patients with type 2 diabetes melli tus (T2DM). This open and single-arm pilot trial investigated the effects of the additional use of fiber on glycemic parameters, in sulin, incretins, and microbiota in patients with T2DM who had been treated with metformin and sulfonylurea. Methods: Participants took fiber for 4 weeks and stopped for the next 4 weeks. Glycemic parameters, insulin, incretins during mixed-meal tolerance test (MMTT), lipopolysaccharide (LPS) level, and fecal microbiota were analyzed at weeks 0, 4, and 8. The first tertile of difference in glucose area under the curve during MMTT between weeks 0 and 4 was defined as ‘responders’ and the third as ‘nonresponders,’ respectively. Results: In all 10 participants, the peak incretin levels during MMTT were higher and LPS were lower at week 4 as compared with at baseline. While the insulin sensitivity of the ‘responders’ increased at week 4, that of the ‘nonresponders’ showed opposite re sults. However, the results were not statistically significant. In all participants, metabolically unfavorable microbiota decreased at week 4 and were restored at week 8. At baseline, metabolically hostile bacteria were more abundant in the ‘nonresponders.’ In ‘re sponders,’ Roseburia intestinalis increased at week 4. Conclusion: While dietary fiber did not induce additional changes in glycemic parameters, it showed a trend of improvement in insulin sensitivity in ‘responders.’ Even if patients are already receiving diabetes treatment, the additional administration of fiber can lead to additional benefits in the treatment of diabetes.

Background: Cardiovascular risk remains increased despite optimal low density lipoprotein cholesterol (LDL-C) level induced by intensive statin therapy. Therefore, recent guidelines recommend non-high density lipoprotein cholesterol (non-HDL-C) as a secondary target for preventing cardiovascular events. The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (OM3-FAs) in combination with atorvastatin compared to atorvastatin alone in patients with mixed dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group, and phase III multicenter study included adults with fasting triglyceride (TG) levels ≥200 and

The American College of Cardiology/American Heart Association (ACC/AHA) recently published a Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. However, the data in other ethnic groups are not well known. We evaluated the prevalence and associated cardiovascular prognosis of Korean subjects with newly reclassified hypertension based on the 2017ACC/AHA guideline. We analyzed data from the Korean Health and Genome Study (n = 10,038). Supine blood pressure (BP) was measured thrice following a standardized protocol and averaged. There was a significant linear relation between BP profiles and cardiovascular disease (CVD)/mortality. Hazard ratio for CVD increased above a systolic BP of 120mm Hg. Systolic BP ≥130mm Hg was significantly associated with increased risk of CVD, coronary heart disease, stroke, CVD death, and total deaths. There was a similar significant linear relation with diastolic BP categories between CVD risk and death. BP is associated with an increased risk of CVD or all-cause mortalities. Moreover, the new BP categories of the 2017ACC/AHA guideline could be applicable for predicting CVD and death in Korean population.

Background: Combination of metformin to reduce the fasting plasma glucose level and an α-glucosidase inhibitor to decrease the postprandial glucose level is expected to generate a complementary effect. We compared the efficacy and safety of a fixed-dose combination of voglibose plus metformin (vogmet) with metformin monotherapy in drug-naive newly-diagnosed type 2 diabetes mellitus. Methods: A total of 187 eligible patients aged 20 to 70 years, with a glycosylated hemoglobin (HbA1c) level of 7.0% to 11.0%, were randomized into either vogmet or metformin treatments for 24 weeks. A change in the HbA1c level from baseline was mea sured at week 24. Results: The reduction in the levels of HbA1c was -1.62%±0.07% in the vogmet group and -1.31%±0.07% in the metformin group (P=0.003), and significantly more vogmet-treated patients achieved the target HbA1c levels of

Thiazolidinediones are synthetic PPARγ ligands that enhance insulin sensitivity, and that could increase insulin secretion from β-cells. However, the functional role and mechanism(s) of action in pancreatic β-cells have not been investigated in detail.

Highlights • Diabetes is one of the major risk factors for fatal outcomes from COVID-19. • Patients with diabetes are vulnerable to COVID-19 because of hyperglycemia; impaired immune function; vascular complications, and comorbidities such as hypertension, obesity, and cardiovascular disease. • Even though angiotensin-converting enzyme (ACE) 2 molecule is a receptor for SARS-CoV-2 viral entry, there is no evidence for the deleterious influence of ACE inhibitor or angiotensin receptor blocker (ARB) medication on the COVID-19 outcomes. It is strongly recommended that ACE inhibitor or ARBs should not be withdrawn without consultation of physician or healthcare provider. • Optimal glucose control is necessary for critically ill patients with diabetes. Also, anti-diabetic medications should be individualized according to the degree of hyperglycemia, contraindications, adverse reactions, and severity of COVID-19. • Various online services of glucose management such as remote consultation, wearable monitoring system, and educational tools will be helpful for comprehensive management for patients with diabetes during pandemic period. • South Korea's strategies for favorable outcomes are early recognition, transparent and prompt sharing of information, rapid establishment of extensive diagnostic testing facilities, implementing innovative and aggressive measures for control and preventing community transmission, redesigning the triage and treatment system, mobilizing the necessary resources for clinical care., The coronavirus disease-2019 (COVID-19) has been designated as a highly contagious infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) since December 2019, when an outbreak of pneumonia cases emerged in Wuhan, China. The COVID-19 pandemic has led to a global health crisis, devastating the social, economic and political aspects of life. Many clinicians, health professionals, scientists, organizations, and governments have actively defeated COVID-19 and shared their experiences of the SARS-CoV2. Diabetes is one of the major risk factors for fatal outcomes from COVID-19. Patients with diabetes are vulnerable to infection because of hyperglycemia; impaired immune function; vascular complications; and comorbidities such as hypertension, dyslipidemia, and cardiovascular disease. In addition, angiotensin-converting enzyme 2 (ACE2) is a receptor for SARS-CoV-2 in the human body. Hence, the use of angiotensin-directed medications in patients with diabetes requires attention. The severity and mortality from COVID-19 was significantly higher in patients with diabetes than in those without. Thus, the patients with diabetes should take precautions during the COVID-19 pandemic. Therefore, we review the current knowledge of COVID-19 including the global and regional epidemiology, virology, impact of diabetes on COVID-19, treatment of COVID-19, and standard of care in the management of diabetes during this critical period.

Nonalcoholic fatty liver disease (NAFLD) has been associated with relative skeletal muscle mass in several cross-sectional studies. We explored the effects of relative skeletal muscle mass and changes in relative muscle mass over time on the development of incident NAFLD or the resolution of baseline NAFLD in a large, longitudinal, population-based 7-year cohort study. We included 12,624 subjects without baseline NAFLD and 2943 subjects with baseline NAFLD who underwent health check-up examinations. A total of 10,534 subjects without baseline NAFLD and 2631 subjects with baseline NAFLD were included in analysis of changes in relative skeletal muscle mass over a year. Subjects were defined as having NAFLD by the hepatic steatosis index, a previously validated NAFLD prediction model. Relative skeletal muscle mass was presented using the skeletal muscle mass index (SMI), a measure of body weight-adjusted appendicular skeletal muscle mass, which was estimated by bioelectrical impedance analysis. Of the 12,624 subjects without baseline NAFLD, 1864 (14.8%) developed NAFLD during the 7-year follow-up period. Using Cox proportional hazard analysis, compared with the lowest sex-specific SMI tertile at baseline, the highest tertile was inversely associated with incident NAFLD (adjusted hazard ratio [AHR] = 0.44, 95% confidence interval [CI] = 0.38-0.51) and positively associated with the resolution of baseline NAFLD (AHR = 2.09, 95% CI = 1.02-4.28). Furthermore, compared with the lowest tertile of change in SMI over a year, the highest tertile exhibited a significant beneficial association with incident NAFLD (AHR = 0.69, 95% CI = 0.59-0.82) and resolution of baseline NAFLD (AHR = 4.17, 95% CI = 1.90-6.17) even after adjustment for baseline SMI. Conclusion: Increases in relative skeletal muscle mass over time may lead to benefits either in the development of NAFLD or the resolution of existing NAFLD.

이 논문에서는 허웅 선생의 국어 음운학의 학사적 위상을, 음운론의 내용 체계를 수립하고 그 속에 담길 음운 체계 및 변동, 변천에 대한 설명을 완성했다는 점을 중심으로 살피는 한편, 이러한 성과를 가능하게 한 그의 학문관과 연구 태도를 조명하였다. 허웅 선생은 말소리와 관계되는 모든 언어 요소와 현상을 음운 연구의 대상으로 삼고 언어 체계를 총체적으로 기술하려는 학문관을 가지고 있었다. 그는 서로 관련되면서도 차원이 다른 개념들을 엄격히 구별하는 태도를 견지하면서, 국어 음운 연구의 대상 항목을 모두 찾아내어 그들을 체계화하고 설명하였다. 그리고 말소리에 대한 정밀한 관찰을 바탕으로, 음소 분석의 절차와 방법을 엄격하게 적용하였으며, 그 과정에서 발견되는 미세한 문제까지 꼼꼼히 검토하였다. 국어의 음운 변동 현상을 최대한 많이 찾아내어 분류하고 설명하였고, 공시태와 통시태의 관계에 대한 인식 속에서 국어 음운의 변천사를 기술하였다. 아울러, 국어 음운학의 체계화와 정밀화를 위해 끊임없이 자신의 관점을 수정하고 보완하는 연구 태도를 보여 주었다.

BACKGROUND Heart failure with preserved ejection fraction is an emerging global health issue attributed to an ageing population. However, the association between low skeletal muscle mass, sarcopenic obesity, and left ventricular diastolic dysfunction remains unclear. In the current study, we aimed to investigate the relationship between low skeletal muscle mass, sarcopenic obesity, and diastolic dysfunction in a large cohort of Korean adults. METHODS We conducted a cross-sectional study of 31 258 subjects who underwent health examinations at Samsung Medical Centre's Health Promotion Centre in Seoul, Republic of Korea. Relative skeletal muscle mass was calculated using the skeletal muscle mass index [SMI (%) = appendicular skeletal muscle mass (kg)/body weight (kg) × 100], which was estimated by bioelectrical impedance analysis. Cardiac structure and function were evaluated by echocardiography. RESULTS Amongst the 31 258 subjects, 3058 (9.78%) were determined to have diastolic dysfunction. The odds ratio (OR) of diastolic dysfunction was 1.56 [95% confidence interval (CI): 1.31-1.85; p for trend

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

AIM To evaluate the efficacy and safety of ipragliflozin vs placebo as add-on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM). METHODS This double-blind, placebo-controlled, multi-centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT). RESULTS In total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add-on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were -0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference -0.83% [95% CI -1.07 to -0.59]; P < .0001). More ipragliflozin-treated patients than placebo-treated patients achieved HbA1c target levels of

Purpose Religiosity can be important in the everyday life of persons with epilepsy (PWE). How PWE live with religiosity can be influenced by their cultural background. We determined whether religiosity is associated with anxiety, depressive symptoms, and well-being in Korean adults with epilepsy. Methods This multicenter cross-sectional study was conducted in the outpatient clinics of five university hospitals in Korea. Religiosity was assessed using the five-item Duke University Religion Index (DUREL). The WHO-Five Well-Being Index (WHO-5) and Hospital Anxiety Depression Scale were used. The participants were categorized into three subgroups bounded by the 33rd and 66th percentiles of their DUREL scores. Results Of a total of 226 participants, 61.1% declared that they had religious affiliation. The median DUREL score was 11 (interquartile ranges 6, 18). All three subscales of the DUREL were significantly related to WHO-5 (p Conclusions Religiosity is significantly associated with anxiety, depressive symptoms, and well-being in Korean adults with epilepsy.

Background We investigated whether glycated albumin (GA) and its variability are associated with cardiovascular autonomic neuropathy (CAN) and further compared their associations with glycated hemoglobin (HbA1c). Methods This retrospective longitudinal study included 498 type 2 diabetic patients without CAN. CAN was defined as at least two abnormal results in parasympathetic tests or presence of orthostatic hypotension. The mean, standard deviation (SD), and coefficient of variance (CV) were calculated from consecutively measured GA (median 7 times) and HbA1c levels (median 8 times) over 2 years. Logistic regression analysis was used to compare the associations between CAN and GA- or HbA1c-related parameters. Receiver operating characteristic (ROC) curve analysis was used to compare the predictive power for CAN between GA- and HbA1c-related parameters. Results A total of 53 subjects (10.6%) developed CAN over 2 years. The mean, SD, and CV of GA or HbA1c were significantly higher in subjects with CAN. Higher mean GA and GA variability were associated with the risk of developing CAN, independent of conventional risk factors and HbA1c. In ROC curve analysis, the SD and CV of GA showed higher predictive value for CAN compared to the SD and CV of HbA1c, whereas the predictive value of mean GA did not differ from that of mean HbA1c. The mean, SD, and CV of GA showed additive predictive power to detect CAN development along with mean HbA1c. Conclusions Higher serum GA and its variability are significantly associated with the risk of developing CAN. Serum GA might be a useful indicator for diabetic complications and can enhance HbA1c’s modest clinical prediction for CAN. Electronic supplementary material The online version of this article (doi:10.1186/s12933-017-0619-2) contains supplementary material, which is available to authorized users.

OBJECTIVEThe small diameter of cervical pedicles and a large transverse cervical pedicle angle are challenges that have led spinal surgeons to investigate how they could achieve a wider safety trajectory and reduce the insertion angle during cervical pedicle screw (CPS) placement. In this paper, the authors detail the advantages of using a curved pedicle probe and a laterally located entry point for overcoming these challenges.METHODSFrom March 2012 to May 2016, the authors performed posterior cervical fusions using CPSs on 119 consecutive patients. The lateral mass screw conversion and the CPS breach rate were analyzed. Using preoperative CT, it was determined that θlat is similar to the anatomical pedicle angle, and θmed is the minimally acceptable medial angle. The actual insertion medial angle (θins) was determined by postoperative CT. To identify how much of the medial angle on θins could be reduced from the anatomical pedicle angle (θlat), and how much closer to θmed, (θins−θmed) / (θlat−θmed) was calculated. To verify shifting of the entry point and widening of the trajectory, the mean df/Df (i.e., shifted facet point/planned facet point) values were analyzed.RESULTSThe total number of planed CPSs was 759, the conversion rate was 4.61% (35/759), and the accuracy rate was 95.9% (694/724). The authors could calculate that θins could be expected near the 90%, 80%, 80%, 80%, and 110% value of θlat on C-3, C-4, C-5, C-6, and C-7 levels, respectively, with the (θins−θmed) / (θlat−θmed) equation. The mean df/Df values were 0.64, 0.62, 0.63, 0.63, and 1.24 on the C3–7 levels, respectively.CONCLUSIONSThrough the use of a curved pedicle probe and a laterally located starting point, the planned and laterally located entry point medial shift was made during CPS placement. The entry point shift yielded a wider, safe trajectory and reduced the burden of making a large medial angle, similar to an anatomical cervical pedicle lateral angle, for safe CPS placement without creating a funnel-shaped hole.

Background Despite the established benefits of diabetes camps for the continuing education of children with type 1 diabetes mellitus, little is known about the long-term metabolic benefits of diabetes camps for middle-aged and elderly people with type 2 diabetes mellitus (T2DM), especially in terms of glycosylated hemoglobin (HbA1c) variability. Methods The 1-year mean and variability of HbA1c before and after the diabetes camp was compared between the participants of the diabetes camp (n=57; median age 65 years [range, 50 to 86 years]; median diabetes duration 14 years [range, 1 to 48 years]). Additional case-control analysis compared the metabolic outcomes of the participants of the diabetes camp and their propensity score-matched controls who underwent conventional diabetes education (n=93). Results The levels of HbA1c during the first year after the diabetes camp were comparable to those of the matched controls (P=0.341). In an analysis of all participants of the diabetes camp, the 1-year mean±standard deviation (SD) of HbA1c decreased (P=0.010 and P=0.041) after the diabetes camp, whereas the adjusted SD and coefficient of variance (CV) of HbA1c did not decrease. The adjusted SD and CV significantly decreased after the diabetes camp in participants whose 1-year mean HbA1c was ≥6.5% before the diabetes camp (n=40) and those with a duration of diabetes less than 15 years (n=32). Conclusion The 1-year mean and SD of HbA1c decreased after the diabetes camp, with significant reduction in the adjusted SD and CV in those with higher baseline HbA1c and a shorter duration of diabetes.

BACKGROUND This is a subgroup analysis of Korean patients from a phase 3 clinical trial investigating the efficacy and safety of ipragliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin. METHODS This multicenter, placebo-controlled, double-blind, parallel-group study was carried out between November 2011 and January 2013. Patients entered a 2-week placebo pretreatment period, followed by a 24-week treatment period with either ipragliflozin (50 mg/day) or placebo, while continuing metformin. Efficacy outcomes (glycosylated hemoglobin [HbA1c], fasting plasma glucose [FPG], and body weight) and safety outcomes (treatment-emergent adverse events [TEAEs]) were measured and compared between the two treatment groups for patients enrolled in all 18 study sites in Korea. RESULTS Eighty-two Korean patients received ipragliflozin (n=43) or placebo (n=39) during the study period. Mean changes in HbA1c levels from baseline to the end of treatment were -0.97% in the ipragliflozin group and -0.31% in the placebo group, with an adjusted between-group difference of -0.60% (P

Background An association between serum calcium level and risk of metabolic syndrome (MetS) has been suggested in cross-sectional studies. This study aimed to evaluate the association between baseline serum calcium level and risk of incident MetS in a longitudinal study. Methods We conducted a retrospective longitudinal study of 12,706 participants without MetS who participated in a health screening program, had normal range serum calcium level at baseline (mean age, 51 years), and were followed up for 4.3 years (18,925 person-years). The risk of developing MetS was analyzed according to the baseline serum calcium levels. Results A total of 3,448 incident cases (27.1%) of MetS developed during the follow-up period. The hazard ratio (HR) for incident MetS did not increase with increasing tertile of serum calcium level in an age- and sex-matched model (P for trend=0.915). The HRs (95% confidence interval [CI]) for incident MetS comparing the second and the third tertiles to the first tertile of baseline serum calcium level were 0.91 (95% CI, 0.84 to 0.99) and 0.85 (95% CI, 0.78 to 0.92) in a fully adjusted model, respectively (P for trend=0.001). A decreased risk of incident MetS in higher tertiles of serum calcium level was observed in subjects with central obesity and/or a metabolically unhealthy state at baseline. Conclusion There was no positive correlation between baseline serum calcium levels and incident risk of MetS in this longitudinal study. There was an association between higher serum calcium levels and decreased incident MetS in individuals with central obesity or two components of MetS at baseline.

Aim MLR-1023, called Tolimidone when evaluated unsuccessfully by Pfizer for gastric ulcer disease, has been repurposed as a novel oral insulin sensitizer with its effects mediated by selective activation of Lyn kinase. We aimed to evaluate the optimal dose, efficacy and safety of MLR-1023 in patients with type 2 diabetes. Methods Type 2 diabetes patients (18–75 years) on diet/exercise therapy were randomized and double-blinded to receive MLR-1023 (100-mg or 200-mg, once-daily [qd] or twice-daily [bid]) or matching placebo for 28 days. The primary endpoint was postprandial glucose (PPG) area under the curve (AUC0–3h) in a mixed meal tolerance test (MMTT) at day 29. Secondary endpoints included changes in fasting plasma glucose (FPG), insulin, HbA1c, lipids and body weight and adverse events. ANCOVA model was used for efficacy analysis. Results The placebo-corrected least-squares mean differences (ΔLSM) in MMTT PPG AUC0-3 h (mmol/L) were −5.96 and −5.6 (both p = 0.03) in the MLR-1023 100-mg qd and 100-mg bid groups, respectively. The placebo-corrected ΔLSM in FPG (mmol/L) was −2.34 (p = 0.003) in the MLR-1023 100-mg qd group. Triglycerides improved with MLR-1023 (ΔLSM, −0.56 mmol/L, p = 0.07 and −0.59 mmol/L, p = 0.05) in the 200mgqd and 200 mg bid groups, respectively. Reductions in fasting insulin, HbA1c and body weight were not statistically significant. Most common adverse events with MLR-1023 treatment were headache (4.2%) and somnolence (2.5%). Conclusions MLR-1023 100-mg once-daily for 4 weeks was the most effective dose with significant reduction in PPG AUC following a MMTT. MLR-1023 was safe and well-tolerated in patients with type 2 diabetes. Clinical Trials Registration Number: NCT02317796

Objectives: The fact that metabolic syndrome is accompanied by a low-grade inflammation suggests inflammation may play an important role in the etiology. The aim of our study was to assess the association between heterogeneity of inflammation status and the incidence of metabolic syndrome (MetS) in the metabolically healthy persons who are either obese or nonobese. Methods: This longitudinal study included all metabolically healthy persons who underwent four or more follow-up comprehensive health examinations either annually or biennially from August 2006 through August 2013 at the Health Promotion Center at Samsung Medical Center, Seoul, Republic of Korea. Metabolic health was defined as absence of any component of the MetS except obesity. We defined obesity using the BMI, which is classified into categories of normal (18.0-22.9 kg/m2), overweight (23-24.9 kg/m2), and obesity (25 kg/m2). Hematological indices such as WBC count or its subtypes (neutrophils, lymphocytes, monocytes) and hsCRP were measured. The outcome was the 7-year cumulative incidence of MetS. Results: The person-years follow-up were 17,786 in normal weight, 10,376 in overweight, and 7,391 in obesity group. Baseline age, sex, physical activity, smoking, exercise, fasting plasma glucose, HbA1c, blood pressure, lipid profile, hematologic parameters, hsCRP were adjusted. Cox regression multivariate analysis resulted in neutrophil count (> 2,750/mm3) was associated with increased incidence of MetS in normal weight (HR 1.7; CI 1.29-2.35; p Conclusion: This longitudinal analysis showed the neutrophil count is associated with the incidence of MetS in the metabolically heathy persons who are either obese or nonobese. Therefore, inflammatory status could be an independent risk factor for the development of metabolic syndrome irrespective of obesity. Disclosure K. Hur: None. M. Choi: None. S. Park: None. S. Lee: None. J. Ahn: None. J. Park: None. H. Park: None. G. Kim: None. S. Jin: None. J. Kim: None. M. Lee: None.

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.

Background: There have been several cross-sectional studies reporting that delayed heart rate recovery (HRR) after exercise is associated with the development of the metabolic syndrome (MetS). However, there have been few longitudinal studies. We evaluated the longitudinal association of delayed HRR following a graded exercise treadmill test (GTX) with the incident MetS including metabolic parameters as adjusting factors. Methods: A retrospective longitudinal cohort study of participants without MetS, diabetes or cardiovascular diseases has been designed. HRR was calculated as peak heart rate minus heart rate after a 1-minute rest (HRR 1), heart rate after a 2-minute rest (HRR 2), and heart rate after a 3-minute rest (HRR 3). To investigate the association between HRR and incident MetS, multivariate Cox proportional hazards analysis was performed. Results: During 9,683 person-years of follow-up between 2006 and 2012, there were 676 (31.2%) incident cases of the MetS. After adjustment for age, sex, smoking status, baseline heart rate, peak heart rate, peak oxygen uptake, hs-CRP, waist circumference, systolic blood pressure, TG, LDL-C, HDL-C, fasting plasma glucose, HOMA-IR, and HbA1c, the hazard ratios (HR) [95% confidence interval (CI)] of incident MetS comparing the first and second tertiles to the third tertile of HRR 3 were 1.492 (1.146-1.943) and 1.277 (1.004-1.624) (P for trend = 0.003). As a continuous variable, after full adjustments, the HR (95% CI) of incident MetS associated with each 1-second decrease in HRR3 was 1.015 (1.005 -1.026) (P = 0.004). Conclusion: Delayed HRR 3 after exercise could predict incident MetS, even after adjusting for metabolic parameters. However, HRR 1 and HRR 2 have not shown the statistic significance. Disclosure T. Yu: None. S. Jin: None. K. Hur: None. J. Bae: None. J. Jee: None. J. Kim: None. M. Lee: None.

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Background Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy. Methods A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90. Results Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; P = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 μol/L to 1.91 ± 0.72 μol/L; P = 0.002) but not in the non-responder group. Conclusion The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.

The spheroid culture method is an effective strategy for ex vivo expansion of an autologous therapeutic cell population. We investigated if cotransplantation of bone marrow-derived spheroids (BM-spheroid) formed using 3D culture of BM-derived mononuclear cells (BM-MNCs) could improve the posttransplant outcome of islet grafts using a mouse syngeneic marginal mass renal subcapsular islet transplantation model. Using green fluorescent protein transgenic (GFP-Tg) mice, the role of the BM-spheroids and the contribution of vessels derived from donors and recipients in grafted areas were assessed by immunohistochemistry. Compared to fresh BM-MNCs and nonspheroid remnant cells (BM-nonspheroid), the BM-spheroids, mainly composed of CXCR4(+) CD14(+) myeloid cells, showed higher angiogenic capacity, such as in vitro self-formed vessel structures; increased expression of angiogenic and chemoattractive factors; and incorporation into new vessel formation in basement membrane matrix plugs. BM-spheroid cotransplantation with islets improved the posttransplant outcomes in terms of glucose tolerance, serum insulin level, and diabetes reversal rate when compared with cotransplantation of BM-nonspheroids. Immunohistochemistry revealed that cotransplantation of the BM-spheroids increased vessel density, area of grafted endocrine and non-endocrine tissue, and β cell proliferation. In conclusion, cotransplantation of islets and BM-spheroids improved islet function through facilitation of revascularization and an increase in cell proliferation and islet cell mass.