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Skeletal muscle is the most abundant tissue and constitutes about 40% of total body mass. Herein, we report that crude water extract (CWE) of G. uralensis enhanced myoblast proliferation and differentiation. Pretreatment of mice with the CWE of G. uralensis prior to cardiotoxin-induced muscle injury was found to enhance muscle regeneration by inducing myogenic gene expression and downregulating myostatin expression. Furthermore, this extract reduced nitrotyrosine protein levels and atrophy-related gene expression. Of the five different fractions of the CWE of G. uralensis obtained, the ethyl acetate (EtOAc) fraction more significantly enhanced myoblast proliferation and differentiation than the other fractions. Ten bioactive compounds were isolated from the EtOAc fraction and characterized by GC-MS and NMR. Of these compounds (4-hydroxybenzoic acid, liquiritigenin, (R)-(-)-vestitol, isoliquiritigenin, medicarpin, tetrahydroxymethoxychalcone, licochalcone B, liquiritin, liquiritinapioside, and ononin), liquiritigenin, tetrahydroxymethoxychalcone, and licochalcone B were found to enhance myoblast proliferation and differentiation, and myofiber diameters in injured muscles were wider with the liquiritigenin than the non-treated one. Computational analysis showed these compounds are non-toxic and possess good drug-likeness properties. These findings suggest that G. uralensis-extracted components might be useful therapeutic agents for the management of muscle-associated diseases.

Background Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes and is associated with cardiovascular risk. We investigated whether the degree of NAFLD was associated with myocardial dysfunction related to impaired myocardial glucose uptake in patients with type 2 diabetes. Methods In total, 131 patients with type 2 diabetes from a tertiary care hospital were included. Myocardial glucose uptake was assessed using [18F]-fluorodeoxyglucose-positron emission tomography. Hepatic steatosis and fibrosis were determined using transient liver elastography. Echocardiography was performed to evaluate cardiac structure and function. Results Patients with NAFLD revealed cardiac diastolic dysfunction with higher left ventricular filling pressure (E/e’ ratio) and left atrial volume index (LAVI) than patients without NAFLD (all p p r2 = 0.409; p = 0.041) and a higher degree of fibrosis (r2 = 0.423; p = 0.009) were independent determinants for a higher E/e’ ratio even after adjusting for confounding factors. Decreased myocardial glucose uptake was associated with a higher degree of steatosis (p for trend = 0.084) and fibrosis (p for trend = 0.012). In addition, decreased myocardial glucose uptake was an independent determinant factor for a higher E/e’ ratio (r2 = 0.409; p = 0.04). Conclusions Hepatic steatosis and fibrosis are significantly associated with diastolic heart dysfunction in patients with type 2 diabetes coupled with impaired myocardial glucose uptake.

Background: Non-alcoholic steatohepatitis is closely associated with the progression of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). We investigated whether urinary N-acetyl-β-D-glucosaminidase (u-NAG), an early renal tubular damage biomarker in DKD, could be related to the degree of hepatic fibrosis in patients with T2DM.Methods: A total of 300 patients with T2DM were enrolled in this study. Hepatic steatosis and fibrosis were determined using transient elastography. The levels of urinary biomarkers, including u-NAG, albumin, protein, and creatinine, and glucometabolic parameters were measured.Results: Based on the median value of the u-NAG to creatinine ratio (u-NCR), subjects were divided into low and high u-NCR groups. The high u-NCR group showed a significantly longer duration of diabetes, worsened hyperglycemia, and a more enhanced hepatic fibrosis index. A higher u-NCR was associated with a greater odds ratio for the risk of higher hepatic fibrosis stage (F2: odds ratio, 1.99; 95% confidence interval [CI], 1.04 to 3.82). Also, u-NCR was an independent predictive marker for more advanced hepatic fibrosis, even after adjusting for several confounding factors (β=1.58, P

BackgroundNon-alcoholic fatty liver disease (NAFLD) and obesity are independently associated with increased risk for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality in patients with NAFLD. Many NAFLD patients are lean, but their ASCVD risk compared to obese subjects with NAFLD is unclear.MethodsData from the 2008–2011 Korean National Health and Nutrition Examination Surveys database were analysed (n = 4,786). NAFLD was defined as a comprehensive NAFLD score of ≥40 or a liver fat score of ≥–0.640. ASCVD risk was evaluated using the American College of Cardiology/American Heart Association guidelines. A high probability of ASCVD was defined as an ASCVD risk of >10%.ResultsThe frequency of subjects without NAFLD, with obese NAFLD, and with lean NAFLD was 62.4% (n = 2,987), 26.6% (n = 1,274), and 11.0% (n = 525), respectively. Subjects with lean NAFLD had a significantly higher ASCVD score and prevalence of a high ASCVD risk (mean 15.6 ± 14.0 and 51.6%) than those with obese NAFLD and without NAFLD (mean 11.2 ± 11.4 and 39.8%; 7.9 ± 10.9 and 25.5%, all P < 0.001). Subjects with lean NAFLD and significant liver fibrosis showed a significantly higher odds ratio for a high risk for ASCVD than those with obese NAFLD with or without significant liver fibrosis (odds ratio = 2.60 vs. 1.93; P = 0.023).ConclusionsDespite a more favourable metabolic profile, subjects with lean NAFLD had a significantly higher ASCVD score and prevalence of high ASCVD risk than those with obese NAFLD. Similarly, lean subjects with significant liver fibrosis had a higher probability of ASCVD than obese subjects in the subpopulation with NAFLD.

Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.

Background & Aims An international expert panel proposed a new definition for metabolic dysfunction–associated fatty liver disease (MAFLD) as a name change from nonalcoholic fatty liver disease (NAFLD). The clinical impact of this change on the assessment of cardiovascular disease (CVD) risk is yet unknown. We evaluated the prevalence of fatty liver disease (FLD) and the associated CVD risk using each of these definitions. Methods From a nationwide health screening database, we included 9,584,399 participants (48.5% male) aged 40-64 years between 2009 and 2010. Participants were categorized by presence of NAFLD and MAFLD, separately, and by the combination of the 2 definitions—Neither-FLD, NAFLD-only, MAFLD-only, or Both-FLD. The primary outcome was a composite CVD event, including myocardial infarction, ischemic stroke, heart failure, or CVD-related death. Results The prevalence of NAFLD and MAFLD was 28.0% and 37.3%, respectively. After excluding those with prior CVD, 8,962,813 participants were followed for a median of 10.1 years. NAFLD and MAFLD were each associated with significantly higher risk for CVD events. When the Neither-FLD group was the reference, multivariable-adjusted hazard ratios (95% confidence interval) for CVD events were 1.09 (1.03-1.15) in the NAFLD-only group, 1.43 (1.41-1.45) in the MAFLD-only group, and 1.56 (1.54-1.58) in the Both-FLD group. Conclusions A considerable proportion of middle-aged Korean adults have MAFLD without satisfying the former definition of NAFLD. The change from NAFLD to MAFLD criteria may identify a greater number of individuals with metabolically complicated fatty liver and increased risk for CVD.

INTRODUCTION: Clinical studies have produced conflicting results on the effects of metformin on gastrointestinal cancer development. We aimed to investigate the association between metformin use and stomach, colon, liver, and pancreatic cancer development among patients with newly diagnosed, drug-naïve type 2 diabetes. METHODS: This retrospective study evaluated propensity score-matched patients with newly diagnosed type 2 diabetes from the Korean National Health Insurance Service database. Metformin users were categorized into tertiles according to the cumulative dose or duration of metformin treatment, and the risks of gastrointestinal cancers were compared. RESULTS: Metformin users had reduced risks of developing stomach cancer (hazard ratio [HR]: 0.841, 95% confidence interval [CI]: 0.797–0.887), colon cancer (HR: 0.865, 95% CI: 0.822–0.91), and liver cancer (HR: 0.709, 95% CI: 0.675–0.746; P < 0.001). However, metformin users did not have a reduced overall risk of pancreatic cancer (HR: 1.335, 95% CI: 1.209–1.475; P < 0.001). The risks tended to decrease at higher cumulative doses and durations of metformin use, with significantly reduced risks of all 4 cancers at the highest cumulative dose (≥1,200,000 mg) and the longest duration (≥2,000 days) of metformin use. DISCUSSION: This population-based data suggest that metformin could be associated with reductions in the risks of stomach, colon, and liver cancers, as well a reduced risk of pancreatic cancer in some subgroups. Metformin has benefit as a first-line treatment for type 2 diabetes mellitus. A further role in cancer risk reduction could be studied in controlled trials.

Previous studies have indicated that liver cirrhosis is associated with hypoglycemia, but there have been no studies investigating the association between nonalcoholic fatty liver disease (NAFLD) and hypoglycemia in noncirrhotic populations with type 2 diabetes.To explore the association of NAFLD with severe hypoglycemia among patients with type 2 diabetes.This nationwide population-based retrospective cohort study using the National Health Insurance System of South Korea included individuals aged 20 years or older who had undergone a medical health examination between January 1, 2009, and December 31, 2012, and were diagnosed with type 2 diabetes. Participants were followed up until December 31, 2015. Data analyses were performed between January 1, 2019, and February 2, 2021.The baseline fatty liver index (FLI) was used as a surrogate marker for NAFLD.The outcome of interest, severe hypoglycemia, was measured using hospital admission and emergency department visit records with a primary diagnosis of hypoglycemia.Among 1 946 581 individuals with type 2 diabetes, 1 125 187 (57.8%) were male. During a median (IQR) follow-up of 5.2 (4.1-6.1) years, 45 135 (2.3%) experienced 1 or more severe hypoglycemia events. Participants with severe hypoglycemia, vs those without severe hypoglycemia, were older (mean [SD] age, 67.9 [9.9] years vs 57.2 [12.3] years; P .001) and had lower mean (SD) body mass index (24.2 [3.43] vs 25.1 [3.4]; P .001). Patients with NAFLD tended to have less severe hypoglycemia without consideration of obesity status. However, after adjustment of multiple clinical covariates, including body mass index, there was a J-shaped association between FLI and severe hypoglycemia (5th decile: adjusted hazard ratio [aHR], 0.86; 95% CI, 0.83-0.90; 9th decile: aHR, 1.02; 95% CI, 0.96-1.08; 10th decile: aHR, 1.29; 95% CI, 1.22-1.37), and the estimated risk of hypoglycemia was higher in participants with NAFLD (aHR, 1.26; 95% CI, 1.22-1.30). The association was more prominent in female participants (aHR, 1.29; 95% CI, 1.23-1.36) and those with underweight (aHR, 1.71; 95% CI, 1.02-2.88).In this study, NAFLD was associated with a higher risk of severe hypoglycemia in patients with type 2 diabetes independent of obesity status. Presence of NAFLD should be considered when evaluating vulnerability to hypoglycemia in patients with type 2 diabetes.

OBJECTIVES: The purpose of this study was (1) to examine whether the addition of resting heart rate (RHR) to the existing undiagnosed diabetes mellitus (UnDM) prediction model would improve predictability, and (2) to develop and validate UnDM prediction models by using only easily assessable variables such as gender, RHR, age, and waist circumference (WC).METHODS: Korea National Health and Nutrition Examination Survey (KNHANES) 2010, 2012, 2014, 2016 data were used to develop the model (model building set, n=19,675), while the data from 2011, 2013, 2015, 2017 were used to validate the model (validation set, n=19,917). UnDM was defined as a fasting glucose level ≥126 mg/dL or glycated hemoglobin ≥6.5%; however, doctors have not diagnosed it. Statistical package for the social sciences logistic regression analysis was used to determine the predictors of UnDM.RESULTS: RHR, age, and WC were associated with UnDM. When RHR was added to the existing model, sensitivity was reduced (86 vs. 73%), specificity was increased (49 vs. 65%), and a higher Youden index (35 vs. 38) was expressed. When only gender, RHR, age, and WC were used in the model, a sensitivity, specificity, and Youden index of 70%, 67%, and 37, respectively, were observed.CONCLUSIONS: Adding RHR to the existing UnDM prediction model improved specificity and the Youden index. Furthermore, when the prediction model only used gender, RHR, age, and WC, the outcomes were not inferior to those of the existing prediction model.

Ginsenosides have offered a wide array of beneficial roles in the pharmacological regulation of hepatic metabolic syndromes, including non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and obesity. Of the numerous ginsenosides, Rg3 has been widely investigated, but there have been few studies of gypenosides (Gyp). Particularly, no study on Gyp LXXV has been reported to date. Here, to firstly explore the pharmacological effects of Gyp LXXV against NASH and the related mechanism, methionine- and choline-deficient (MCD) diet-induced NASH mice and hepatic cells (stellate cells, hepatic macrophages, and hepatocytes) were selected. Gyp LXXV exhibited markedly alleviated MCD diet-induced hepatic injury, inflammation, and fibrosis by down-regulating hepatic fibrosis markers such as &alpha, smooth muscle actin(&alpha, SMA), collagen1, transforming growth factors-&beta, (TGF-&beta, 1), tumor necrosis factor-&alpha, (TNF-&alpha, ), MCP-1, interleukin (IL)-1&beta, nuclear factor &kappa, B (NF&kappa, B), and GRP78. Remarkably, histopathological studies confirmed that 15 mg/kg of Gyp LXXV administration to MCD diet-induced mice led to effective prevention of liver injury, lipid accumulation, and activation of hepatic macrophages, indicating that Gyp LXXV might be a potential anti-NASH drug.

The association between non-alcoholic fatty liver disease (NAFLD) and diabetic kidney disease assessed using either albuminuria or proteinuria remains controversial. This study aimed to investigate the association between hepatic steatosis or fibrosis and albuminuria or proteinuria in Korean patients with type 2 diabetes mellitus (T2D). We enrolled 1108 patients with T2D and categorized as 3 groups; non-proteinuria (NP), isolated non-albumin proteinuria (iNAP), and albuminuria. Urinary albumin and protein levels were assessed as urinary albumin-to-creatinine ratio (uACR) and urinary protein-to-creatinine ratio (uPCR), respectively. Hepatic steatosis and fibrotic burden were assessed using the NAFLD liver fat score, Fibrosis-4 calculator (FIB-4) index, and NAFLD fibrosis score (NFS). The prevalence of significant steatosis was similar among groups (NP: 74.6% vs iNAP: 70.3% vs albuminuria: 79.9%, P = .085). The prevalence of significant fibrosis was significantly higher in the iNAP (18.7%) and albuminuria (16.5%) groups than in the NP group (9.5%, P = .001). Both uPCR and uACR showed a correlation with NFS (uPCR: r = 0.123, P

Hydroformylation, a reaction which installs both a C–H bond and an aldehyde group across an unsaturated substrate, is one of the most important catalytic reactions both in industry and academia. Given the synthetic importance of creating new C–C bonds, and the widespread academic and industrial impact of hydroformylation, the development of carboformylation reactions, wherein a new C–C bond is formed instead of a C–H bond, would bear enormous synthetic potential to rapidly increase molecular complexity in the synthesis of valuable aldehydes. However, the demanding complexity inherent in a four-component reaction, utilizing an exogenous CO source, has made the development of a direct carboformylation reaction a formidable challenge. Here, we describe a molecular shuffling strategy featuring the use of readily available aroyl chlorides as a carbon electrophile and CO source, in tandem with a sterically congested hydrosilane, to perform a stereoselective carboformylation of alkynes under palladium catalysis. An extension of this protocol to four chemodivergent carbonylations further highlights the creative opportunity offered by this molecular shuffling strategy in carbonylation chemistry.

Skeletal muscle is an essential tissue that attaches to bones and facilitates body movements. Insulin-like growth factor-1 (IGF-1) is a hormone found in blood that plays an important role in skeletal myogenesis and is importantly associated with muscle mass entity, strength development, and degeneration and increases the proliferative capacity of muscle satellite cells (MSCs). IGF-1R is an IGF-1 receptor with a transmembrane location that activates PI3K/Akt signaling and possesses tyrosine kinase activity, and its expression is significant in terms of myoblast proliferation and normal muscle mass maintenance. IGF-1 synthesis is elevated in MSCs of injured muscles and stimulates MSCs proliferation and myogenic differentiation. Mechanical loading also affects skeletal muscle production by IGF-1, and low IGF-1 levels are associated with low handgrip strength and poor physical performance. IGF-1 is potentially useful in the management of Duchenne muscular dystrophy, muscle atrophy, and promotes neurite development. This review highlights the role of IGF-1 in skeletal muscle, its importance during myogenesis, and its involvement in different disease conditions.

The skeletal muscle provides movement and support to the skeleton, controls body temperature, and regulates the glucose level within the body. This is the core tissue of insulin-mediated glucose uptake via glucose transporter type 4 (GLUT4). The extracellular matrix (ECM) provides a scaffold for cells, controlling biological processes, and providing structural as well as mechanical support to surrounding cells. Disruption of ECMhomeostasis results in several pathological conditions. Various ECM components are typicallyfound to be augmented in the skeletal muscle of obese and/or diabetic humans. A better understanding of the importance of skeletal muscle ECM remodeling, integrin signaling,and other factors that regulate insulin activity may help in the development of novel therapeutics formanaging diabetes and other metabolic disorders.

Introduction Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed for type 2 diabetes (T2D) and their glycemic control effects are well studied. However, information regarding the effects of switching DPP-4 inhibitors is limited, especially in older patients. Research Design and Methods We investigated whether switching from linagliptin to teneligliptin decreases blood glucose in older (≥65 years) T2D patients. In total, 164 patients with T2D who switched from linagliptin to teneligliptin for >12 weeks were included and the primary outcome was glycemic changes. Results Switching from linagliptin to teneligliptin ameliorated fasting blood glucose (148.1 ± 47.1 to 139.6 ± 43.4 mg/dL), glycated hemoglobin (HbA1c; 7.9 ± 1.3 to 7.5 ± 1.2%), and postprandial blood glucose (224.8 ± 77.4 to 205.8 ± 70.8 mg/dL) levels (all P < 0.05). Low-density lipoprotein cholesterol concentration was reduced while liver and kidney functions were maintained. Subgroup analysis showed that glucose control improved more in patients with uncontrolled hyperglycemia (HbA1c > 8.0%) and chronic kidney disease (estimated glomerular filtration rate

Background There is increasing concern regarding cardiovascular risk in individuals with non-alcoholic fatty liver disease. This study was conducted to evaluate whether hepatic steatosis with or without fibrosis is associated with the progression of carotid atherosclerosis in patients with type 2 diabetes. Methods From a longitudinal cohort, we enrolled 1120 patients with type 2 diabetes who underwent repeated carotid artery ultrasonography every 1–2 years. Ultrasonographic findings at baseline and after 6–8 years were compared. Presence of hepatic steatosis was mainly assessed by abdominal ultrasonography; patients with hepatic steatosis were further evaluated for hepatic fibrosis according to fibrosis-4 index. We investigated the association between liver status and atherosclerosis progression. Results Of 1120 patients, 636 (56.8%) were classified as having hepatic steatosis at baseline. After 6–8 years, 431 (38.5%) showed atherosclerosis progression. Hepatic steatosis was significantly associated with atherosclerosis progression (adjusted odds ratio[AOR]: 1.370, 95% CI 1.025–1.832; p p p p Conclusions Hepatic steatosis with fibrosis is independently associated with the progression of carotid atherosclerosis in patients with type 2 diabetes.

Background: Recent studies investigated the association between nonalcoholic fatty liver disease (NAFLD) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM) but the results are inconclusive. Here we aimed to investigate the effect of obesity on the association between NAFLD and DKD in a large cohort of participants with T2DM. Methods: In this cross-sectional study, a total of 3,439 patients (1,710 men and 1,729 women) with T2DM were recruited from the Seoul Metabolic Syndrome cohort between 2003 and 2016. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver diseases. Advanced fibrosis was defined as FIB4 index ≥ 1.45. DKD was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2. Obesity was defined as body mass index (BMI) ≥ 25 kg/m2. Results: The mean age was 57.4 ± 10.3 years and duration of diabetes was 7.7 ± 7.1 years. Two hundred and fifty subjects (7.3%) had DKD and 1869 (54.3%) subjects had NAFLD. The prevalence of DKD were 7.0%, 4.5% and 11.9% in no-NAFLD group, liver steatosis only group and advanced fibrosis group respectively (p Conclusion: This study suggests that advanced liver fibrosis, a severe form of NAFLD, was independently associated with increased risk of DKD in non-obese patients with T2DM. Disclosure D. Seo: None. Y. Cho: None. S. Ahn: None. S. Hong: None. Y. Lee: None. Y. Choi: None. B. Huh: None. K. Huh: None. S. Kim: None.

This study aimed to assess how to enhance the value of 18F-Fluorodeoxyglucose (FDG) PET/CTs for glioma grading and better delineation of the tumor boundary by glucose loading. In mouse models of brain tumor using U87MG cells, 18F-FDG-PET images were obtained after fasting and after glucose loading. There was a significant difference in the tumor-to-normal cortex-uptake ratio (TNR) between the fasting and glucose-loading scans. 14C-2-Deoxy-D-glucose (14C-DG) uptake was measured in vitro using U87MG, U373MG and primary neurons cultured with different concentrations of glucose. The tumor-to-neuron ratio of 14C-DG uptake increased with up to 10 mM of glucose. Finally, 10 low-grade and 17 high-grade glioma patients underwent fasting and glucose loading 18F-FDG PET/CT and the TNR was compared between scans. The effect of glucose loading was significant in high-grade but not in low-grade gliomas. The receiver operating characteristic curve analyses with a cut-off TNR of 0.81 showed a higher area under the curve after glucose loading than fasting for differentiating low-grade versus high-grade gliomas. In addition, the glucose loading PET/CT was more useful than the fasting PET/CT for the discrimination of oligodendrogliomas from IDH-wildtype glioblastomas. Glucose loading resulted in a greater reduction in 18F-FDG uptake in the normal cortex than in tumors, which increases the usefulness of 18F-FDG PET/CT for grading.

The extracellular matrix (ECM) provides a scaffold for cells, controlling biological processes and providing structural as well as mechanical support to surrounding cells. Disruption of ECM homeostasis results in several pathological conditions. Skeletal muscle ECM is a complex network comprising collagens, proteoglycans, glycoproteins, and elastin. Recent therapeutic approaches targeting ECM remodeling have been extensively deliberated. Various ECM components are typically found to be augmented in the skeletal muscle of obese and/or diabetic humans. Skeletal muscle ECM remodeling is thought to be a feature of the pathogenic milieu allied with metabolic dysregulation, obesity, and eventual diabetes. This narrative review explores the current understanding of key components of skeletal muscle ECM and their specific roles in the regulation of metabolic diseases. Additionally, we discuss muscle-specific integrins and their role in the regulation of insulin sensitivity. A better understanding of the importance of skeletal muscle ECM remodeling, integrin signaling, and other factors that regulate insulin activity may help in the development of novel therapeutics for managing diabetes and other metabolic disorders.

Neither lowering of blood lipid levels nor treatment with statins definitively improves renal outcomes. Ezetimibe, a non-statin antilipidemic agent, is known to not only decrease blood lipid levels but also reduce inflammatory response and activate autophagy. We evaluated the effect of adding ezetimibe to a statin on renal outcome compared with statin monotherapy by analyzing longitudinal data of 4537 patients treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) for more than 180 days. A propensity-score-based process was used to match baseline characteristics, medical history, and estimated glomerular filtration rate (eGFR) between S + E and S groups. Changes in serum creatinine and incidence of renal events, defined as doubling of serum creatinine to &ge, 1.5 mg/dL or occurrence of end-stage renal disease after the first day of treatment initiation, were compared between the groups. Among 3104 well-matched patients with a median follow-up of 4.2 years, the S + E group showed a significantly lower risk of renal events than the S group (hazard ratio 0.58, 95% CI 0.35-0.95, P = 0.032). In addition, the S + E group tended to preserve renal function compared with the S group throughout follow-up, as assessed by serum creatinine changes (P-values for time&ndash, group interactions &lt, 0.001). These data support the beneficial effects on renal function when combining ezetimibe with a statin.

OBJECTIVE To assess the effects of empagliflozin, a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics. RESEARCH DESIGN AND METHODS Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate–corrected P < 0.05) was discerned through Ingenuity Pathway Analysis. RESULTS Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid–binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and β2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration. CONCLUSIONS SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design.

The association of specific urinary proteins other than albumin with cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) has been shown. In this respect, CV outcomes may differ in non-albuminuric T2D patients who were considered as a low risk group, according to the presence of proteinuria. We investigated the association between proteinuria and atherosclerosis assessed by carotid artery intima-media thickness (CIMT) in non-albuminuric T2D patients. 2047 T2D patients whose urine albumin-to-creatinine ratio was below 30 mg/g were recruited and classified into a non-proteinuria (NP, uPCR &lt, 150 mg/g, n = 1865) group and a non-albuminuric proteinuria (NAP, uPCR &ge, 150 mg/g, n = 182) group. CIMT was compared between the two groups and logistic regression analysis was conducted to verify whether proteinuria could predict deteriorated CIMT status. In this cross-sectional study, mean CIMT of the NAP group were significantly thicker than those of the NP group (0.73 &plusmn, 0.16 vs. 0.70 &plusmn, 0.14, p = 0.016). The presence of proteinuria is associated with deteriorated CIMT after the adjustment for conventional risk factors (odds ratio, 2.342, 95% confidence interval, 1.082&ndash, 5.070, p = 0.030) in regression analysis. We postulated that the measurement of urinary protein in conjunction with albumin might be helpful for predicting atherosclerosis, especially for non-albuminuric patients.

Despite the benefits of pioglitazone in the treatment of non-alcoholic fatty liver disease (NAFLD), many treated patients continue to experience disease progression. We aimed to investigate the additive effect of ipragliflozin on NAFLD in patients with type 2 diabetes treated with metformin and pioglitazone. In this 24-week randomized controlled trial, 44 patients with type 2 diabetes and comorbid NAFLD were either randomized to receive 50 mg/day of ipragliflozin as an add-on treatment (n = 29) or maintained on metformin and pioglitazone (n = 15). The fatty burden was assessed using the fatty liver index, NAFLD liver fat score, and controlled attenuation parameter (CAP). Changes in fat and muscle depots were measured by dual-energy x-ray absorptiometry and abdominal computed tomography scans. The enrolled patients were relatively controlled (mean baseline glycated hemoglobin of 6.6% &plusmn, 0.6%) and centrally obese (mean waist circumference of 101.6 &plusmn, 10.9 cm). At week 24, patients in the ipragliflozin add-on group exhibited reduced hepatic fat content (fatty liver index: &minus, 9.8 &plusmn, 1.9, p = 0.002, NAFLD liver fat score: &minus, 0.5 &plusmn, 0.2, p = 0.049, CAP: &minus, 8.2 &plusmn, 7.8 dB/m2, p = 0.133). Ipragliflozin add-on therapy also reduced whole-body visceral fat and the ratio of visceral to subcutaneous fat (change in whole-body visceral fat: &minus, 69.6 &plusmn, 21.5 g, change in abdominal visceral fat: &minus, 26.2 &plusmn, 3.7 cm2, abdominal visceral to subcutaneous fat ratio: &minus, 0.15 &plusmn, 0.04, all p &lt, 0.05). In conclusion, ipragliflozin treatment significantly ameliorates liver steatosis and reduces excessive fat in euglycemic patients with type 2 diabetes and NAFLD taking metformin and pioglitazone.

We describe a general strategy for the intermolecular synthesis of polysubstituted cyclopentenones using palladium catalysis. Overall, this reaction is achieved via a molecular shuffling process involving an alkyne, an alpha,beta-unsaturated acid chloride, which serves as both the alkene and carbon monoxide source, and a hydrosilane to create three new C-C bonds. This new carbon monoxide-free pathway delivers the products with excellent yields. Furthermore, the regioselectivity is complementary to conventional methods for cyclopentenone synthesis. In addition, a set of regio- and chemodivergent reactions are presented to emphasize the synthetic potential of this novel strategy., Journal of the American Chemical Society, 142 (50), ISSN:0002-7863, ISSN:1520-5126

Lipotoxicity, induced by saturated fatty acid (SFA)-mediated cell death, plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The KEAP1 (kelch like ECH associated protein 1)-NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) pathway is a pivotal defense mechanism against lipotoxicity. We previously reported that SQSTM1/p62 has a cytoprotective role against lipotoxicity through activation of the noncanonical KEAP1- NFE2L2 pathway in hepatocytes. However, the underlying mechanisms and physiological relevance of this pathway have not been clearly defined. Here, we demonstrate that NFE2L2-mediated induction of SQSTM1 activates the noncanonical KEAP1-NFE2L2 pathway under lipotoxic conditions. Furthermore, we identified that SQSTM1 induces ULK1 (unc-51 like autophagy activating kinase 1) phosphorylation by facilitating the interaction between AMPK (AMP-activated protein kinase) and ULK1, leading to macroautophagy/autophagy induction, followed by KEAP1 degradation and NFE2L2 activation. Accordingly, the activity of this SQSTM1-mediated noncanonical KEAP1-NFE2L2 pathway conferred hepatoprotection against lipotoxicity in the livers of conventional sqstm1- and liver-specific sqstm1-knockout mice. Moreover, this pathway activity was evident in the livers of patients with nonalcoholic fatty liver. This axis could thus represent a novel target for NAFLD treatment. Abbreviations: ACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; BafA1: bafilomycin A1; CM-H2DCFDA:5-(and-6)-chloromethyl-2ʹ,7ʹ-dichlorodihydrofluorescein diacetate; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; FASN: fatty acid synthase; GSTA1: glutathione S-transferase A1; HA: hemagglutinin; Hepa1c1c7: mouse hepatoma cells; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch like ECH associated protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC: N-acetyl-L-cysteine; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PA: palmitic acid; PARP: poly (ADP-ribose) polymerase 1; PRKAA1/2: protein kinase AMP-activated catalytic subunits alpha1/2; RBX1: ring-box 1; ROS: reactive oxygen species; SESN2: sestrin 2; SFA: saturated fatty acid; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; TBK1: TANK binding kinase 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; ULK1: unc-51 like autophagy activating kinase.

The Axion Resonant InterAction Detection Experiment (ARIADNE) is a collaborative effort to search for the QCD axion using nuclear magnetic resonance (NMR), where the axion acts as a mediator of spin-dependent forces between an unpolarized tungsten source mass and a sample of polarized helium-3 gas. Since the experiment involves precision measurement of a small magnetization, it relies on limiting ordinary magnetic noise with superconducting magnetic shielding. In addition to the shielding, proper characterization of the noise level from other sources is crucial. We investigate one such noise source in detail: the magnetic noise due to impurities and Johnson noise in the tungsten source mass.

Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T4) complex, which consecutively induces the intracellular triiodothyronine (T3) level, followed by T3 secretion out of the cell through the exosomes. The decrease in T3 with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle. Subsequent studies, including microarray analysis, demonstrated that T3-regulated genes, such as FNDC5 (Fibronectin type III domain containing 5, irisin) and RXR&gamma, (Retinoid X receptor gamma), are influenced by TTR knockdown, implying that thyroid hormones and TTR coordinate with each other with respect to muscle growth and development. These results suggest that, in addition to utilizing T4, skeletal muscle also distributes generated T3 to other tissues and has a vital role in sensing the intracellular T4 level. Furthermore, the results of TTR function with T4 in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration.

Current methods for functional group interconversion have, for the most part, relied on relatively strong driving forces which often require highly reactive reagents to generate irreversibly a desired product in high yield and selectivity. These approaches generally prevent the use of the same catalytic strategy to perform the reverse reaction. Here we describe a catalytic functional group metathesis approach to interconvert, under CO-free conditions, two synthetically important classes of electrophiles that are often employed in the preparation of pharmaceuticals and agrochemicals-aroyl chlorides (ArCOCl) and aryl iodides (ArI). Our reaction design relies on the implementation of a key reversible ligand C-P bond cleavage event, which enables a non-innocent, metathesis-active phosphine ligand to mediate a rapid aryl group transfer between the two different electrophiles. Beyond enabling a practical and safer approach to the interconversion of ArCOCl and ArI, this type of ligand non-innocence provides a blueprint for the development of a broad range of functional group metathesis reactions employing synthetically relevant aryl electrophiles.

Aims Recent evidence has shown that renal tubulointerstitial injuries play an important role in diabetic nephropathy. In this study, we evaluated the association between urinary N-acetyl-β- d -glucosaminidase (uNAG), an early renal tubular damage marker, and carotid artery atherosclerosis in patients with type 1 diabetes (T1D). Methods This was a cross-sectional study of 88 patients with T1D. Demographic and laboratory data; urinary indices, including urinary NAG-to-creatinine ratio (uNCR), and albumin-to-creatinine ratio (uACR); and carotid ultrasonography were investigated. Results Eighty-eight subjects were divided into three groups based on uNCR tertiles. Subjects belonging to the highest tertile of uNCR had the highest average mean and maximum carotid intima-media thickness (IMT). An elevated uNCR was also significantly correlated with increased average mean and maximum carotid IMT, whereas an elevated uACR was not. Even after adjusting for confounding factors, uNCR continued to be a meaningful predictive marker for increased average mean and maximum IMT. Conversely, the uACR could not predict carotid IMT after adjustment for confounding factors. Conclusions Elevated levels of uNAG are significantly associated with carotid artery atherosclerosis in patients with T1D independently of albuminuria, a marker of glomerular damage.

Sung Woo Moon,1 Song Yee Kim,1 Ji Ye Jung,1 Young Ae Kang,1 Moo Suk Park,1 Young Sam Kim,1 Joon Chang,1 Jun Soo Ro,2 Yong-Ho Lee,3 Sang Hoon Lee1,4 1Division of Pulmonary Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea; 2Center for Preventive Medicine and Public Health, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea; 3Division of Endocrinology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea; 4Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea Purpose: Previous studies have shown that progressive forms of non-alcoholic fatty liver disease (NAFLD) occur frequently in patients with obstructive lung disease (OLD). However, few studies have written about this relationship. This study aimed to investigate the relationship between OLD and NAFLD. Subjects and methods: The Korea National Health and Nutrition Examination Survey is a national population-based, cross-sectional surveillance program that was initiated to assess the health and nutritional status of the Korean population. From 2007 to 2010, 11,738 subjects were enrolled. The subjects were defined as having NAFLD when they had scores higher than -0.640 in a NAFLD liver fat score prediction model, which was a previously validated prediction score. Individuals with forced expiratory volume in one second/forced vital capacity&nbsp

Background A diabetes risk score in Korean adults was developed and validated. Methods This study used the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) of 359,349 people without diabetes at baseline to derive an equation for predicting the risk of developing diabetes, using Cox proportional hazards regression models. External validation was conducted using data from the Korean Genome and Epidemiology Study. Calibration and discrimination analyses were performed separately for men and women in the development and validation datasets. Results During a median follow-up of 10.8 years, 37,678 cases (event rate=10.4 per 1,000 person-years) of diabetes were identified in the development cohort. The risk score included age, family history of diabetes, alcohol intake (only in men), smoking status, physical activity, use of antihypertensive therapy, use of statin therapy, body mass index, systolic blood pressure, total cholesterol, fasting glucose, and γ glutamyl transferase (only in women). The C-statistics for the models for risk at 10 years were 0.71 (95% confidence interval [CI], 0.70 to 0.73) for the men and 0.76 (95% CI, 0.75 to 0.78) for the women in the development dataset. In the validation dataset, the C-statistics were 0.63 (95% CI, 0.53 to 0.73) for men and 0.66 (95% CI, 0.55 to 0.76) for women. Conclusion The Korean Diabetes Risk Score may identify people at high risk of developing diabetes and may be an effective tool for delaying or preventing the onset of condition as risk management strategies involving modifiable risk factors can be recommended to those identified as at high risk.

Metformin, the most widely used drug for type 2 diabetes, has recently attracted attention with regard to its antitumor activity. However, clinical studies have yielded conflicting results regarding the association between metformin and thyroid cancer development, despite its antitumor effect in preclinical studies.This is a retrospective cohort study using the Korean National Health Insurance claim database. Matched populations of 128,453 metformin users and 128,453 non-users were analyzed for thyroid cancer incidence. Metformin users were categorized into lowest, middle, and highest tertiles according to cumulative dose or duration of metformin therapy.Thyroid cancer developed in 340 (0.26%) metformin users and 487 (0.38%) non-users during a mean follow-up of 7.2 years (hazard ratio = 0.69 [confidence interval 0.60-0.79]; p 0.001). The incidence of thyroid cancer per 10Metformin appears to be associated with a preventive effect on thyroid cancer development in a nationwide population-based study, but is not effective in the early phase of treatment. Considering the increasing prevalence of obesity and the role of insulin resistance in the development of cancer, metformin might be the preferred treatment for its dual anti-diabetic and antitumor effects.

The effects of an intermittent fasting diet (IFD) in the general population are still controversial. In this study, we aimed to systematically evaluate the effectiveness of an IFD to reduce body mass index and glucose metabolism in the general population without diabetes mellitus. Cochrane, PubMed, and Embase databases were searched to identify randomized controlled trials and controlled clinical trials that compared an IFD with a regular diet or a continuous calorie restriction diet. The effectiveness of an IFD was estimated by the weighted mean difference (WMD) for several variables associated with glucometabolic parameters including body mass index (BMI) and fasting glucose. The pooled mean differences of outcomes were calculated using a random effects model. From 2814 studies identified through a literature search, we finally selected 12 articles (545 participants). Compared with a control diet, an IFD was associated with a significant decline in BMI (WMD, &minus, 0.75 kg/m2, 95% CI, &minus, 1.44 to &minus, 0.06), fasting glucose level (WMD, &minus, 4.16 mg/dL, 6.92 to &minus, 1.40), and homeostatic model assessment of insulin resistance (WMD, &minus, 0.54, 1.05 to &minus, 0.03). Fat mass (WMD, &minus, 0.98 kg, 2.32 to 0.36) tended to decrease in the IFD group with a significant increase in adiponectin (WMD, 1008.9 ng/mL, 95% CI, 140.5 to 1877.3) and a decrease in leptin (WMD, &minus, 0.51 ng/mL, 0.77 to &minus, 0.24) levels. An IFD may provide a significant metabolic benefit by improving glycemic control, insulin resistance, and adipokine concentration with a reduction of BMI in adults.

Two spotted spider mite, Tetranychus urticae, is a polyphagous pest to a variety of plants and they are hard to be controlled due to occurrence of resistance to acaricides. In this study, biochemical evaluation after ethyl formate (EF) and phosphine (PH3) fumigation towards T. urticae might help officials to control them in quarantine purposes. PH3 fumigation controlled eggs (LC50; 0.158 mg/L), nymphs (LC50; 0.030 mg/L), and adults (LC50; 0.059 mg/L) of T. urticae, and EF effectively affected nymphs (LC50; 2.826 mg/L) rather than eggs (LC50; 6.797 mg/L) and adults (LC50; 5.836 mg/L). In a longer exposure time of 20 h, PH3 fumigation was 94.2-fold more effective tool for control of T. urticae than EF fumigant. EF and PH3 inhibited cytochrome c oxidase (COX) activity differently in both nymphs and adults of T. urticae. It confirmed COX is one of target sites of these fumigants in T. urticae and COX is involved in the respiratory chain as complex IV. Molecular approaches showed that EF fumigation completely down-regulated the expression of cox11 gene at the concentration of LC10 value, while PH3 up-regulated several genes greater than twofold in T. urticae nymphs treated with the concentration of LC50 value. These increased genes by PH3 fumigation are ndufv1, atpB, para, and ace, responsible for the expression of NADH dehydrogenase [ubiquinone] flavoprotein 1, ATP synthase, and acetylcholinesterase in insects, respectively. Lipidomic analyses exhibited a significant difference between two fumigants-exposed groups and the control, especially an ion with 815.46 m/z was analyzed less than twofold in the fumigants-treated group. It was identified as PI(15:1/18:3) and it may be used as a biomarker to EF and PH3 toxicity. These findings may contribute to set an effective control strategy on T. urticae by methyl bromide alternatives such as EF and PH3 because they have shared target sites on the respiratory chain in the pest.

Aims We evaluated specific alterations in amino acids (AAs) profile in patients with type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) compared with healthy controls. In addition, we tried to find the mechanisms behind these AA alterations. Methods Twenty AAs, TNF-α, and IL-6 were analyzed in fasting serum samples from a total of 198 individuals (56 drug-naive patients with T2DM, 69 patients IFG, and 73 healthy controls). The C2C12 mouse myoblast cell lines were used to examine the changes of MAFbx and MuRF1 expressions, which are muscle specific E3 ligases acting as major mediators of skeletal muscle proteolysis, after development of insulin resistance induced by palmitate treatment. Results In addition to branched chain amino acids BCAAs, fasting serum AAs such as glutamic acid, lysine, phenylalanine, arginine, alanine, tyrosine, aspartic acid, were higher in patients with T2DM and intermediately elevated in patients with IFG compared with normoglycemic controls. These serum AA concentrations positively correlated with fasting glucose, homeostasis model assessment of insulin resistance (HOMA-IR), and pro-inflammatory cytokines. In addition, HOMA-IR and pro-inflammatory cytokines were two important independent predictors of serum AA levels. In vitro experiments showed that palmitate treatment in C2C12 myotubes induced insulin resistance, increased pro-inflammatory cytokine gene expression, and increased MAFbx gene and protein expression. Conclusions The increase in fasting serum AAs can be an early manifestation of insulin resistance. Increased muscle proteolysis induced by insulin resistance and inflammatory cytokines can be a possible mechanism for the rise in serum AA levels.

Objective: Studies have indicated that weight regain following weight loss predisposes obese individuals to metabolic disorders; however, the molecular mechanism of this potential adverse effect of weight regain is not fully understood. Here we investigated global transcriptome changes and the immune response in mouse white adipose tissue caused by weight regain. Design: We established a diet switch protocol to compare the effects of weight regain with those of weight gain without precedent weight loss, weight loss maintenance and chow diet. We conducted a time course analysis of global transcriptome changes in gonadal white adipose tissue (gWAT) during the weight fluctuation. Co-expression network analysis was used to identify functional modules associated with the weigh regain phenotype. Immune cell populations in gWAT were characterized by flow-cytometric immunophenotyping. Metabolic phenotypes were monitored by histological analysis of adipose tissue and liver, and blood-chemistry and body weight/composition analyses. Results: In total, 952 genes were differentially expressed in the gWAT in the weight regain vs the weight gain group. Upregulated genes were associated with immune response and leukocyte activation. Co-expression network analysis showed that genes involved in major histocompatibility complex I and II-mediated antigen presentation and T-cell activation function were upregulated. Consistent with the transcriptome analysis results, flow cytometry demonstrated significant increases in subsets of T cells and proinflammatory M1 macrophages in the gWAT in the weight regain as compared to the weight gain group. In addition, upregulation of adaptive immune responses was associated with high incidence of adipocyte death and upregulation of high mobility group box 1, a well-known component of damage-associated molecular patterns. Conclusions: Our global transcriptome analysis identified weight regain-induced activation of adaptive immune responses in mouse white adipose tissue. Results suggest that activation of adipocyte death-associated adaptive immunity in adipose tissue may contribute to unfavorable metabolic effects of weight regain following weight loss.

Background Ezetimibe-statin combination therapy has been found to reduce low density lipoprotein cholesterol levels and the risk of major adverse cardiovascular events (MACEs) in large trials. We sought to examine the differential effect of ezetimibe on MACEs when added to statins according to the presence of diabetes. Methods Randomized clinical trials with a sample size of at least 50 participants and at least 24 weeks of follow-up that compared ezetimibe-statin combination therapy with a statin- or placebo-controlled arm and reported at least one MACE, stratified by diabetes status, were included in the meta-analysis and meta-regression. Results A total of seven trials with 28,191 enrolled patients (mean age, 63.6 years; 75.1% men; 7,298 with diabetes [25.9%]; mean follow-up, 5 years) were analysed. MACEs stratified by diabetes were obtained from the published data (two trials) or through direct contact (five trials). No significant heterogeneity was observed among studies (I²=14.7%, P=0.293). Ezetimibe was associated with a greater reduction of MACE risk in subjects with diabetes than in those without diabetes (pooled relative risk, 0.84 vs. 0.93; P(heterogeneity)=0.012). In the meta-regression analysis, the presence of diabetes was associated with a greater reduction of MACE risk when ezetimibe was added to statins (β=0.87, P=0.038). Conclusion Ezetimibe-statin combination therapy was associated with greater cardiovascular benefits in patients with diabetes than in those without diabetes. Our findings suggest that ezetimibe-statin combination therapy might be a useful strategy in patients with diabetes at a residual risk of MACEs.

BACKGROUND To the authors' knowledge, relatively little is known regarding the interaction of risk factors for hepatocellular carcinoma (HCC) with age, sex, and liver disorder status. METHODS The authors followed 504,646 Korean patients aged 40 to 80 years who underwent routine health checkups between 2002 and 2003 until 2013 via linkage to national hospital discharge records. RESULTS HCC occurred in 2744 individuals. In the sex-adjusted and age-adjusted analysis, cirrhosis increased the incidence of HCC by 42-fold, followed by hepatitis B virus (21-fold), hepatitis C virus (HCV; 19-fold), male sex (4.3-fold), and each 5-year age increment (1.24-fold). In the multivariable adjusted analysis, diabetes increased the risk of HCC by 80%, alcohol consumption ≥80 g/day increased the risk by 75%, alcohol consumption of 40 to 79 g/day increased the risk by 37%, and being a current smoker increased the risk by 25%. The multivariable adjusted hazard ratios of male sex and HCV were 6.27 and 5.72, respectively, at age

Urinary N-acetyl-β-D-glucosaminidase (uNAG) predicted the progression of diabetic kidney disease (DKD) prior to development of albuminuria in diabetes patients. We sought whether uNAG level is associated with glycoalbumin-to-hemoglobin A1c ratio (G/A ratio), a marker of postprandial hyperglycemia and glycemic excursion, independent of albuminuria and kidney function. The association between uNAG excretion and G/A ratio was assessed in 204 consecutive subjects with type 1 diabetes (T1D) (mean age 43.9 years; 49.0% men). uNAG excretion level increased along with older age, hyperglycemia, and degree of albuminuria, but was not correlated with body mass index or estimated glomerular filtration rate (eGFR). Elevated uNAG showed robust association with higher G/A ratio (adjusted β = 0.103, P = 0.020) after adjustment for age, sex, body mass index, duration of diabetes, uACR, angiotensin blockers use, fasting plasma glucose, and hemoglobin level. uNAG showed better discriminatory performance for individuals with high G/A ratio than albuminuria (AUC 0.613 vs. 0.518, P = 0.038). Measurement of uNAG improved AUC for high G/A ratio from 0.699 to 0.748 (P = 0.043) when added to conventional risk factors (cutoff 5.24 U/g creatinine; sensitivity 62.5% and specificity 58.0%). In conclusion, Elevated uNAG was found to be associated with high G/A ratio in patients with T1D with early stage DKD, independent of age and albuminuria.