Association of the atherogenic index of plasma with cardiovascular risk beyond the traditional risk factors: a nationwide population-based cohort study.

BACKGROUND: The atherogenic index of plasma (AIP) is composed of triglycerides and high-density lipoprotein cholesterol and is a novel marker for assessing the risk of atherogenicity and cardiometabolic health. An association between AIP and greater frequency of major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus and high cardiovascular (CV) disease risk has been reported. However, only few studies have examined the correlation between AIP and CV risk in general populations. We thus aimed to evaluate the relationship between AIP and CV diseases using a large-scale population dataset from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). METHODS: A total of 514,866 participants were enrolled from the NHIS-HEALS and classified according to the AIP quartiles. We performed univariate and multivariate Cox proportional hazards regression analyses to determine the association between AIP and MACEs, CV events, and CV mortality. RESULTS: During follow-up, we documented 12,133, 11,055, and 1942 cases of MACEs, CV events, and CV mortality, respectively. The multivariate-adjusted hazard ratios [HRs; 95% confidence interval (CI)] for MACEs gradually and significantly increased with the AIP quartiles [1.113 (1.054-1.175) in Q2, 1.175 (1.113-1.240) in Q3, and 1.278 (1.209-1.350) in Q4], following an adjustment for the conventional CV risk factors, including age, sex, body mass index, smoking, alcohol drinking, physical activities, household income, fasting glucose, systolic blood pressure, low-density lipoprotein cholesterol, and estimated glomerular filtration rate. In subgroup analyses, the association of AIP with MACEs and CV events was particularly outstanding in patients with diabetes. CONCLUSIONS: AIP was significantly associated with CV risks after adjusting for the traditional risk factors. Therefore, it may be used as an effective mass screening method to identify patients at a high risk of CV events.

Switching from insulin to dulaglutide therapy in patients with type 2 diabetes: A real-world data study.

AIM: Patients with type 2 diabetes (T2DM) who require injectable therapy have been conventionally treated with insulin. A glucagon-like peptide 1 receptor agonist was recently recommended as first-line injectable treatment, but few studies have investigated the effects of switching from insulin to dulaglutide. This study investigated the clinical efficacy and parameters affecting responses to dulaglutide as an alternative to insulin in patients with T2DM in a real-world clinical setting. METHODS: Ninety-eight patients with T2DM who were switched from insulin to dulaglutide therapy were retrospectively evaluated. Changes in HbA1c concentrations were assessed after 6 months of consistent treatment with dulaglutide. Multiple linear regression analysis was performed to evaluate parameters affecting the response to dulaglutide treatment. RESULTS: After treatment with dulaglutide for 6 months, patients experienced changes in HbA1c of -0.95% (95% confidence interval [CI]: -1.30% to -0.59%, P < 0.001) and in body weight of -1.75 kg (95% CI: -2.42 to -1.08 kg, P < 0.001). Multiple linear regression analysis showed that higher baseline HbA1c was significantly associated with a greater reduction in HbA1c. The most frequent adverse events were gastrointestinal symptoms. CONCLUSION: Switching from insulin to dulaglutide can lead to significant improvement in HbA1c levels and body weight ​reduction in T2DM patients over 6 months. Higher baseline HbA1c is associated with a better clinical response to dulaglutide.

The Use of Mobile Personal Health Records for Hemoglobin A1c Regulation in Patients With Diabetes: Retrospective Observational Study.

BACKGROUND: The effectiveness of personal health records (PHRs) in diabetes management has already been verified in several clinical trials; however, evidence of their effectiveness in real-world scenarios is also necessary. To provide solid real-world evidence, an analysis that is more accurate than the analyses solely based on patient-generated health data should be conducted. OBJECTIVE: This study aimed to conduct a more accurate analysis of the effectiveness of using PHRs within electronic medical records (EMRs). The results of this study will provide precise real-world evidence of PHRs as a feasible diabetes management tool. METHODS: We collected log data of the sugar function in the My Chart in My Hand version 2.0 (MCMH 2.0) app from Asan Medical Center (AMC), Seoul, Republic of Korea, between December 2015 and April 2018. The EMR data of MCMH 2.0 users from AMC were collected and integrated with the PHR data. We classified users according to whether they were continuous app users. We analyzed and compared their characteristics, patterns of hemoglobin A1c (HbA1c) levels, and the proportion of successful HbA1c control. The following confounders were adjusted for HbA1c pattern analysis and HbA1c regulation proportion comparison: age, sex, first HbA1c measurement, diabetes complications severity index score, sugar function data generation weeks, HbA1c measurement weeks before MCMH 2.0 start, and generated sugar function data count. RESULTS: The total number of MCMH 2.0 users was 64,932, with 7453 users having appropriate PHRs and diabetes criteria. The number of continuous and noncontinuous users was 133 and 7320, respectively. Compared with noncontinuous users, continuous users were younger (P<.001) and had a higher male proportion (P<.001). Furthermore, continuous users had more frequent HbA1c measurements (P=.007), shorter HbA1c measurement days (P=.04), and a shorter period between the first HbA1c measurement and MCMH 2.0 start (P<.001). Diabetes severity-related factors were not statistically significantly different between the two groups. Continuous users had a higher decrease in HbA1c (P=.02) and a higher proportion of regulation of HbA1c levels to the target level (P=.01). After adjusting the confounders, continuous users had more decline in HbA1c levels than noncontinuous users (P=.047). Of the users who had a first HbA1c measurement higher than 6.5% (111 continuous users and 5716 noncontinuous users), continuous users had better regulation of HbA1c levels with regard to the target level, 6.5%, which was statistically significant (P=.04). CONCLUSIONS: By integrating and analyzing patient- and clinically generated data, we demonstrated that the continuous use of PHRs improved diabetes management outcomes. In addition, the HbA1c reduction pattern was prominent in the PHR continuous user group. Although the continued use of PHRs has proven to be effective in managing diabetes, further evaluation of its effectiveness for various diseases and a study on PHR adherence are also required.

The haemoglobin glycation index is associated with nonalcoholic fatty liver disease in healthy subjects.

OBJECTIVES: The hemoglobin glycation index (HGI) quantifies interindividual variations in glycated hemoglobin (HbA1c) and is associated with diabetic complications and metabolic diseases. However, information on the association between HGI and non-alcoholic fatty liver disease (NAFLD) in healthy subjects is limited, particularly in Asian populations. This study aimed to investigate the association between HGI and NAFLD in a healthy Korean cohort. DESIGN: Subjects were stratified in quartiles according to their HGI level. NAFLD was diagnosed by hepatic ultrasonography, hepatic steatosis index and fatty liver index. Multiple logistic regression analysis was performed to evaluate the association between HGI quartiles and the risk of NAFLD. PATIENTS: Data from subjects without diabetes who underwent liver ultrasonography during routine health examinations were retrospectively reviewed. RESULTS: Data from 14 465 subjects were included in the analysis. The prevalence of NAFLD increased significantly with each HGI quartile (24.8%, 29.7%, 32.6% and 40.6% in quartiles 1-4, respectively; P < 0.001). In comparison with the lowest HGI quartile group, the highest quartile exhibited worse metabolic parameters, including body weight, waist circumference, body mass index and lipid profiles. Multiple logistic regression analysis adjusted for multiple factors showed that the odds ratio of having NAFLD was 1.564 (95% CI: 1.350-1.813, P < 0.001) in the highest HGI quartile. CONCLUSIONS: Elevated HGI levels are independently associated with NAFLD in a healthy Asian population.

Effect of SFRP5 (Secreted Frizzled-Related Protein 5) on the WNT5A (Wingless-Type Family Member 5A)-Induced Endothelial Dysfunction and Its Relevance With Arterial Stiffness in Human Subjects.

OBJECTIVE: SFRP5 (secreted frizzled-related protein 5) is an endogenous inhibitor of WNT5A (wingless-type family member 5a), which has been implicated in atherosclerosis. However, contradictory results have been reported about the role of SFRP5 in atherosclerosis. We aimed to investigate whether SFRP5 could restore WNT5A-induced endothelial dysfunction in vitro and ex vivo. In addition, we sought to determine whether the serum concentration of SFRP5 is associated with atherosclerosis in humans. APPROACH AND RESULTS: We measured endothelium-dependent vasorelaxation in the isolated thoracic aorta of Sprague-Dawley rats. In addition, we measured intracellular nitric oxide (NO) in human endothelial cells. The protein abundance of total and phosphorylated JNK (c-Jun N-terminal kinase), AKT (protein kinase B), and endothelial NO synthase was analyzed in human endothelial cells. Circulating SFRP5 and WNT5A levels and brachial-ankle pulse wave velocity were measured in 282 human subjects with type 2 diabetes mellitus. SFRP5 dose dependently restored Wnt5-induced impaired vasorelaxation in rat thoracic aorta by an endothelial NO synthase-dependent mechanism. SFRP5 treatment restored the WNT5A-induced reduction of NO production via endothelial NO synthase in human endothelial cells. WNT5A-induced changes in the phosphorylation of JNK, AKT, and endothelial NO synthase were ameliorated with SFRP5 administration. In humans with type 2 diabetes mellitus, the serum SFRP5 concentration positively correlated with brachial-ankle pulse wave velocity (r=0.146; P=0.024). Multivariate linear regression analysis demonstrated that the serum SFRP5 concentration was independently associated with brachial-ankle pulse wave velocity after adjustment for potential confounders [B (SE)=7.40 (3.35); P=0.028]. CONCLUSIONS: Our data suggest the possible compensatory action of SFRP5 against atherosclerosis under conditions of metabolic dysfunction.

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice.

Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing sterol regulatory element-binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator-activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat+/- mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. CONCLUSION: Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416-431).

Improved trends in cardiovascular complications among subjects with type 2 diabetes in Korea: a nationwide study (2006-2013).

BACKGROUND: Representative data on the secular trends in cardiovascular disease (CVD) are limited in Asian populations with diabetes. We aimed to estimate the temporal trends in cardiovascular complications using Korean nationwide whole population-based claims data in subjects with and without diabetes. METHODS: Type 2 diabetes was defined as a current medication history of anti-diabetic drugs and the presence of International Classification of Diseases (ICD)-10 codes (E11-E14) as diagnosis. We compared the 8-year rates of six cardiovascular complications [i.e., ischemic heart disease, acute myocardial infarction (AMI), ischemic stroke, hemorrhagic stroke, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG)] in Korean adults aged 30 years and older using data from four consecutive nationwide databases (2006-2007, 2008-2009, 2010-2011, and 2012-2013) of Korean national health insurance service. RESULTS: A total of 1,645,348, 1,971,559, 2,291,247, and 2,562,612 subjects with type 2 diabetes were found in the year of 2006-2007, 2008-2009, 2010-2011, and 2012-2013, respectively. Age and gender standardized rates of the six predefined cardiovascular complications decreased in Korean adults with type 2 diabetes during the study period. The greatest relative reductions were observed for hospitalization due to AMI (-37.28%), followed by hospitalizations due to ischemic stroke (-36.98%). In the overall population without type 2 diabetes, the greatest relative reductions were observed for hospitalization for hemorrhagic stroke (-29.47%), followed by hospitalization due to ischemic stroke (-28.92%). Relative decreases in all six predefined cardiovascular complications were generally more profound in adults with diabetes than in those without diabetes, which led to significant decrease in the relative risks of all six cardiovascular complications in subjects with diabetes over the past 8 years. However, people with diabetes still had a two- to sixfold higher risk of hospitalization for major CVD events and interventions than people without diabetes. CONCLUSIONS: Our findings suggest a significant reduction in the rate of people affected by CVD within the diabetic population. However, as the number of people with diabetes rises, the absolute burden of CVD will still be high in Korea.

Impact of diabetes duration and degree of carotid artery stenosis on major adverse cardiovascular events: a single-center, retrospective, observational cohort study.

BACKGROUND: We aimed to investigate the impact of diabetes duration and carotid artery stenosis (CAS) on the occurrence of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) without clinical cardiovascular disease. METHODS: A total of 2006 patients with T2DM, without clinical cardiovascular disease, aged >50 years, and who underwent baseline carotid Doppler ultrasound screening with regular follow-ups at the outpatient clinic of our diabetes center, were stratified into four subgroups according to diabetes duration and CAS degree. The primary outcomes included the occurrence of MACE, defined as fatal or nonfatal stroke and myocardial infarction, and all-cause mortality. RESULTS: The difference in the MACE incidence was significantly greater in patients with a longer diabetes duration (≥10 years) and significant CAS (50-69% luminal narrowing) (p < 0.001). Analysis of individual MACE components indicated a trend towards an increased incidence of stroke (p < 0.001), parallel to a longer diabetes duration and significant CAS. In contrast, the risk of myocardial infarction was significantly higher in patients with a diabetes duration <10 years and significant CAS (p = 0.039). Multivariate regression analysis showed that patients with both a longer diabetes duration and significant CAS demonstrated additive and very high risks of MACE (hazard ratio [HR], 2.07; 95% confidence interval [CI] 1.17-3.66; p = 0.012) and stroke (HR, 3.38; 95% CI 1.54-7.44; p = 0.002). CONCLUSIONS: The risk of MACE is significantly greater in patients with T2DM, without clinical cardiovascular disease, who have both a longer diabetes duration and significant CAS, compared with those who have a shorter duration and/or nonsignificant CAS.

The association of incident hypertension with metabolic health and obesity status: definition of metabolic health does not matter.

OBJECTIVE: Metabolically healthy obese (MHO) phenotype refers to obese individuals with a favourable metabolic profile. Its prognostic value remains controversial and may partly depend on differences in how the phenotype is defined. We aimed to investigate whether the MHO phenotype is associated with future development of incident hypertension in a Korean population according to various definitions of metabolic health. SUBJECTS AND METHODS: The study population comprised 31 033 Koreans without hypertension. Participants were stratified into metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) by body mass index (cut-off value, 25·0 kg/m(2) ) and metabolic health state, using four different definitions: Adult Treatment Panel (ATP)-III, Wildman, Karelis and the homoeostasis model assessment (HOMA) criteria. RESULTS: Over the median follow-up period of 35·0 months (range, 4·5-81·4 months), 4589 of the 31 033 individuals (14·8%) developed incident hypertension. Compared with the MHNO group, the MHO group showed increased association with incident hypertension with multivariate-adjusted odds ratios of 1·56 (95% confidence interval [CI], 1·41-1·72), 1·58 (95% CI 1·42-1·75), 1·52 (95% CI 1·35-1·71) and 1·46 (95% CI 1·33-1·61), when defined by ATP-III, Wildman, Karelis and HOMA criteria, respectively. CONCLUSION: MUO individuals showed the highest association with the incident hypertension (adjusted odds ratios up to 2·00). MHO subjects showed an approximately 1·5-fold higher association with incident hypertension than their nonobese counterpart regardless of the definition of metabolic health used. Thus, considering both metabolic health and obesity is important for the assessment of potential cardiovascular outcomes.

Mortality and causes of death in a national sample of type 2 diabetic patients in Korea from 2002 to 2013.

BACKGROUND: We aimed to investigate the mortality rate (MR), causes of death and standardized mortality ratio (SMR) in Korean type 2 diabetic patients from 2002 to 2013 using data from the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC). METHODS: From this NHIS-NSC, we identified 29,807 type 2 diabetic subjects from 2002 to 2004. Type 2 diabetes was defined as a current medication history of anti-diabetic drugs and the presence of International Classification of Diseases (ICD)-10 codes (E11-E14) as diagnosis. Specific causes of death were recorded according to ICD-10 codes as the following: diabetes, malignant neoplasm, disease of the circulatory system, and other causes. RESULTS: A total of 7103 (23.8 %) deaths were recorded. The MR tended to increase with age. In particular, the ratio of MR for men versus women was the highest in their 40s-50s. The overall SMR was 2.32 and the SMRs attenuated with increasing age. The causes of death ascribed to diabetes, malignant neoplasm, ischemic heart disease, cerebrovascular disease, and other causes were 22.0, 24.8, 6.2, 11.2 and 31.3 %, respectively. The SMRs according to each cause of death were 9.73, 1.76, 2.60, 2.04 and 1.89, respectively. CONCLUSIONS: The MRs among type 2 diabetic subjects increased with age, and diabetic men exhibited a higher mortality risk than diabetic women in Korea. Subjects with type 2 diabetes exhibited an excess mortality when compared with the general population. Approximately 78.0 % of the diabetes-related deaths was not ascribed to diabetes, and malignant neoplasm was the most common cause of death among those not recorded as diabetes.

Which Users Should Be the Focus of Mobile Personal Health Records? Analysis of User Characteristics Influencing Usage of a Tethered Mobile Personal Health Record.

BACKGROUND: This study was conducted to analyze the usage pattern of a hospital-tethered mobile personal health records (m-PHRs) application named My Chart in My Hand (MCMH) and to identify user characteristics that influence m-PHR usage. MATERIALS AND METHODS: Access logs to MCMH and its menus were collected for a total of 18 months, from August 2011 to January 2013. Usage patterns between users without a patient identification number (ID) and users with a patient ID were compared. Users with a patient ID were divided into light and heavy user groups by the median number of monthly access. Multiple linear regression models were used to assess MCMH usage pattern by characteristics of MCMH user with a patient ID. RESULTS: The total number of MCMH logins was 105,603, and the median number of accesses was 15 times. Users (n = 7,096) mostly accessed the "My Chart" menu, but "OPD [outpatient department] Service Support" and "Health Management" menus were also frequently used. Patients with chronic diseases, experience of hospital visits including emergency room and OPD, and age group of 0-19 years were more frequently found among users with a patient ID (n = 2,186) (p < 0.001). A similar trend was found in the heavy user group (n = 1,123). Submenus of laboratory result, online appointment, and medication lists that were accessed mostly by users with a patient ID were associated with OPD visit and chronic diseases. CONCLUSIONS: This study showed that focuses on patients with chronic disease and more hospital visits and empowerment functions in a tethered m-PHR would be helpful to pursue the extensive use.

The risk of chronic kidney disease in a metabolically healthy obese population.

Obesity has become an important risk factor for chronic kidney disease (CKD). The metabolically healthy obese (MHO) phenotype refers to obese individuals with a favorable metabolic profile. However, its prognostic value remains controversial and may depend on the health outcome being investigated. To assess this, we examined the risk of MHO phenotype with incident CKD in a Korean population of 41,194 people without CKD. Individuals were stratified by body mass index (cutoff value, 25.0 kg/m(2)) and metabolic health state (assessed using Adult Treatment Panel-III criteria). Incident CKD was defined as a glomerular filtration rate of <60 ml/min per 1.73 m(2) calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Over the median follow-up period of 38.7 months, 356 of the individuals developed incident CKD. Compared with the metabolically healthy nonobese (MHNO) group, the MHO group showed increased risk of incident CKD with a multivariate-adjusted hazard ratio of 1.38 (95% CI, 1.01-1.87). Nonobese but metabolically unhealthy individuals were at an increased risk of incident CKD (multivariate-adjusted hazard ratio, 1.37 (95% CI, 1.02-1.93)) than the MHNO group. Metabolically unhealthy obese individuals were at the highest risk of incident CKD. Thus, a healthy metabolic profile does not protect obese adults from incident CKD. Hence, it is important to consider metabolic health along with obesity when evaluating CKD risk.

Radicicol induces intracellular accumulation of glycan-deficient clusterin variant.

Proteostasis regulation using naturally occurring small molecules has been considered as a promising strategy for manipulating cancer sensitivity and therapy. Here, we identify a small molecule Hsp90 inhibitor radicicol that induces intracellular accumulation of cytotoxic clusterin variant. In the mechanistic basis, this variant proved to be a product disposed from the stressed ER. During this process, inhibitory effect of radicicol on protein degradation results in cytosolic accumulation of glycan-deficient clusterin variant that signals cell death. These results provide a therapeutic insight into the targeted proteostasis perturbation of clusterin as an anti-cancer strategy.

Association of serum angiopoietin-like protein 2 with carotid intima-media thickness in subjects with type 2 diabetes.

BACKGROUND: Although recent animal studies have suggested that angiopoietin-like protein 2 (ANGPTL2), a novel inflammatory adipokine, is likely to be involved in the pathogenesis of atherosclerosis, in rodents, little is known regarding whether serum ANGPTL2 level is also associated with atherosclerosis in humans, especially in patients with type 2 diabetes. The aim of this study was to investigate whether serum ANGPTL2 concentration is associated with atherosclerosis by measuring carotid intima-media thickness (IMT) in subjects with type 2 diabetes without previous history of cardiovascular diseases. In addition, we examined the clinical and biochemical variables associated with serum ANGPLT2 concentration. METHODS: We measured the circulating ANGPTL2 level in 166 subjects (92 men and 74 women; mean age of 60.0 years) with type 2 diabetes. Measurements of carotid IMT were performed in all subjects. RESULTS: Serum ANGPTL2 concentration was positively correlated with carotid IMT (r = 0.220, p = 0.004). In multiple linear regression, serum ANGPTL2 concentration was independently associated with increased carotid IMT along with older age, male gender, and higher systolic blood pressure. Higher levels of hemoglobin A1c and high-sensitivity C-reactive protein were significantly associated with elevated serum ANGPTL2 concentration in subjects with type 2 diabetes. CONCLUSIONS: Serum ANGPTL2 concentration was significantly and positively associated with carotid atherosclerosis in patients with type 2 diabetes, suggesting that ANGPTL2 may be important in the atherosclerosis in humans.

A randomized, double-blind, placebo-controlled, phase II clinical trial to investigate the efficacy and safety of oral DA-1229 in patients with type 2 diabetes mellitus who have inadequate glycaemic control with diet and exercise.

BACKGROUND: DA-1229 is a novel, potent and selective dipeptidyl peptidase-4 (DPP-IV) inhibitor that is orally bioavailable. We aimed to evaluate the optimal dose, efficacy and safety of DA-1229, in Korean subjects with type 2 diabetes mellitus suboptimally controlled with diet and exercise. METHODS: We enrolled 158 patients (mean age, 53 years and a mean BMI, 25.6 kg/m(2) ). The mean baseline fasting plasma glucose level, HbA1c and duration of diabetes were 8.28 mmol/L, 7.6% (60 mmol/mol) and 3.9 years, respectively. After 2 or 6 weeks of an exercise and diet program followed by 2 weeks of a placebo period, the subjects were randomized into one of four groups for a 12-week active treatment period: placebo, 2.5, 5 or 10 mg of DA-1229. RESULTS: All three doses of DA-1229 significantly reduced HbA1c from baseline compared to the placebo group (-0.09 in the placebo group vs. -0.56, -0.66 and -0.61% in 2.5, 5 and 10-mg groups, respectively) but without any significant differences between the doses. Insulin secretory function, as assessed by homeostasis model assessment ß-cell, the insulinogenic index, 2-h oral glucose tolerance test (OGTT) C-peptide and post-OGTT C-peptide area under the curve (AUC)0-2h, significantly improved with DA-1229 treatment. The incidence of adverse events was similar between the treatment groups and DA-1229 did not affect body weight or induce hypoglycaemic events. CONCLUSIONS: DA-1229 monotherapy (5 mg for 12 weeks) improved HbA1c, fasting plasma glucose level, OGTT results and ß-cell function. This drug was well tolerated in Korean subjects with type 2 diabetes mellitus.

Serum Triglyceride Levels and Cardiovascular Disease Events in Koreans.

OBJECTIVES: Hypercholesterolemia, especially elevated levels of LDL-cholesterol, is a well-known risk factor for cardiovascular disease (CVD). However, the role of triglycerides in CVD risk remains controversial. METHODS: We enrolled 86,476 individuals who had undergone a general health checkup at Asan Medical Center between January 2007 and June 2011. After exclusion criteria were applied to the total cohort, 76,434 participants were included. CVD events and death were gathered from the nationwide health insurance claims database and death certificates using ICD-10 codes. RESULTS: Age- and sex-adjusted odds ratios (ORs) of the higher triglyceride group were significantly increased: 1.52 (95% CI: 1.27-1.82) for major CVD events, 1.53 (95% CI: 1.24-1.88) for major ischemic heart disease events, and 1.49 (95% CI: 1.37-1.63) for overall CVD events. After adjustment for multiple risk factors including HDL-cholesterol, ORs for overall CVD events were significantly increased in the higher triglyceride group. When the analysis was stratified according to BMI, hypertension, and glycemic status at baseline, age- and sex-adjusted ORs for the outcomes were significantly increased in the higher triglyceride group with nonobese, normotensive, or nondiabetic subjects. CONCLUSIONS: Hypertriglyceridemia is independently associated with an increased risk for CVD, especially in nonobese, normotensive, or nondiabetic individuals.

Statin therapy is associated with the development of new-onset diabetes after transplantation in liver recipients with high fasting plasma glucose levels.

New-onset diabetes after transplantation (NODAT) and dyslipidemia are important metabolic complications after liver transplantation (LT) that can adversely affect both allograft and patient survival. Statins are used as first-line therapies for dyslipidemia because of their effectiveness and safety profile. However, it has recently been reported that statin therapy is associated with new-onset diabetes in the nontransplant population. The aim of this study was to investigate the association between statin therapy and the development of NODAT in LT recipients. Three hundred sixty-four LT recipients who underwent transplantation between the ages of 20 and 75 years without a previous history of diabetes were enrolled in this study. We evaluated the incidence of NODAT with respect to statin use as well as other risk factors. The incidence of NODAT was significantly higher in the statin group (31.7%) versus the control group (17.6%, P = 0.03). The mean follow-up period was 37.8 ± 19.0 months for the statin group and 42.7 ± 16.0 months for the control group (P = 0.07). Statin use was significantly associated with NODAT development after adjustments for other risk factors [hazard ratio (HR) = 2.32, 95% confidence interval (CI) = 1.23-4.39, P = 0.01]. Impaired fasting glucose before transplantation was also a risk factor for NODAT development (HR = 2.21, 95% CI = 1.36-3.62, P = 0.001). There were no significant differences in age, body mass index, cumulative corticosteroid dose, or fasting plasma glucose (FPG) levels between the groups. Patients with high FPG levels were more likely to develop NODAT when they were placed on statins after LT (P = 0.002). In conclusion, statin treatment could contribute to the development of NODAT in LT recipients, especially if they have high baseline FPG levels.

Vaspin inhibits cytokine-induced nuclear factor-kappa B activation and adhesion molecule expression via AMP-activated protein kinase activation in vascular endothelial cells.

BACKGROUND: Vaspin is an adipocytokine that was recently identified in the visceral adipose tissue of diabetic rats and has anti-diabetic and anti-atherogenic effects. We hypothesized that vaspin prevents inflammatory cytokine-induced nuclear factor-kappa B (NF-κB) activation by activating AMP-activated protein kinase (AMPK) in vascular endothelial cells. METHODS: We examined the effects of vaspin on NF-κB activation and the expression of the NF-κB-mediated genes intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1). Human aortic endothelial cells (HAECS) were used. Tumor necrosis factor alpha (TNFα) was used as a representative proinflammatory cytokine. RESULTS: Treatment with vaspin significantly increased the phosphorylation of AMPK and acetyl-CoA carboxylase, the down-stream target of AMPK. Furthermore, treatment with vaspin significantly decreased TNFα-induced activation of NF-κB, as well as the expression of the adhesion molecules ICAM-1, VCAM-1, E-selectin, and MCP-1. These effects were abolished following transfection of AMPKα1-specific small interfering RNA. In an adhesion assay using THP-1 cells, vaspin reduced TNFα-induced adhesion of monocytes to HAECS in an AMPK-dependent manner. CONCLUSIONS: Vaspin might attenuate the cytokine-induced expression of adhesion molecule genes by inhibiting NF-κB following AMPK activation.

Cotransin induces accumulation of a cytotoxic clusterin variant that cotranslationally rerouted to the cytosol.

Although clusterin (CLU) was originally identified as a secreted glycoprotein that plays cytoprotective role, several intracellular CLU variants have been recently identified in the diverse pathological conditions. The mechanistic basis of these variants is now believed to be alternative splicing and retrotranslocation. Here, we uncovered, an unglycosylated and signal sequence-unprocessed, CLU variant in the cytosol. This variant proved to be a product that cotranslationally rerouted to the cytosol during translocation. Cytosolic CLU was prone to aggregation at peri-nuclear region of cells and induced cell death. Signal sequence is shown to be an important determinant for cytosolic CLU generation and aggregation. These results provide not only a new mechanistic insight into the cytosolic CLU generation but also an idea for therapeutic mislocalization of CLU as a strategy for cancer treatment.

Specific inhibition of hamster prion protein translocation by the dodecadepsipeptide valinomycin.

Regulating the entry of secretory and membrane proteins into the ER is shown to be an important physiological process, in terms of controlling quantity, localization and therefore function of target proteins. However, few small molecule modulators are available to pharmacologically regulate translocation of a specific protein. Here, we identified a small molecule that specifically inhibits pathogenic PrP biosynthesis using a highly sensitive and reproducible assay based on the fluorogenic substrate reporter PrP. This molecule specifically destabilized the signal peptide of PrP, leading to cotranslational rerouting of a significant amount of nascent PrP to proteasome-dependent degradation pathway in the cytosol. This study suggests that regulating differential translocation efficiency attributable to sequence diversity in signal peptides of disease-causing secretory and membrane proteins using cell-permeable small molecules may be a potential therapeutic approach for diseases associated with impaired protein biogenesis.