Combination of low- or moderate-intensity statin and ezetimibe versus high-intensity statin monotherapy on primary prevention of cardiovascular disease and all-cause death: A propensity-matched nationwide cohort study.

AIMS: This study aims to compare the preventive effect of low- or moderate-statin with ezetimibe combination therapy and high-intensity statin monotherapy on cardiovascular disease (CVD) and all-cause death in a real-world setting. METHODS AND RESULTS: Using the Korean National Health Insurance Service datasets, two cohorts comparing high-intensity statin monotherapy with low- or moderate intensity statin and ezetimibe combination were constructed by 1:1 propensity score matching procedure. Primary outcome was a composite of myocardial infarction (MI), stroke, and all-cause death. Secondary outcome was an individual event. The study population was followed from baseline until the date of events, or the last health check-ups, whichever came first.Compared to high-intensity statin monotherapy, moderate-intensity statin with ezetimibe combination significantly reduced the risk of composite outcome (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.77-0.92, P < 0.001) as well as individual MI (HR 0.81, 95% CI 0.71-0.94, P = 0.005) and stroke (HR 0.78, 95% CI 0.65-0.93, P = 0.005), but not all-cause death. Low-intensity statin with ezetimibe also significantly reduced the risk of the composite outcomes (HR 0.80, 95% CI 0.66-0.97, P = 0.024) compared to high-intensity statin monotherapy, but the risk of individual outcome did not differ between two groups. Statin and ezetimibe combination demonstrated consistent effect across various subgroups. CONCLUSIONS: Among people without pre-existing CVD, moderate-intensity statin with ezetimibe combination was superior to high-intensity statin monotherapy in preventing composite outcomes as well as each of MI and stroke. In contrast, low-intensity statin with ezetimibe combination reduced the risk of composite but not individual outcomes.

We compared the preventive effect of low- or moderate-statin with ezetimibe combination and high-intensity statin monotherapy on cardiovascular disease and all-cause death.Low- or moderate-intensity statin with ezetimibe is beneficial for reducing a composite of MI, stroke, and all-cause death.Moderate-intensity statin with ezetimibe reduced 19% of MI and 22% of stroke, compared with high-intensity statin.Statin with ezetimibe combination might be attractive bypass for primary prevention, beyond an alternative to high-intensity statin.

Comparison of the Efficacy of Ezetimibe Combination Therapy and High-Intensity Statin Monotherapy in Type 2 Diabetes.

CONTEXT: Low-density lipoprotein cholesterol (LDL-C)-lowering therapy is considerably important in preventing cardiovascular disease (CVD) among patients with diabetes. Studies comparing CVD, stroke, and mortality outcomes of low- or moderate-intensity statins with ezetimibe combination therapy and high-intensity statin monotherapy in patients with diabetes remain lacking. OBJECTIVE: This study compared the primary prevention effect of myocardial infarction (MI), stroke, and all-cause death between combination therapy of low- or moderate-intensity statins and ezetimibe and high-intensity statin monotherapy in patients with diabetes using the Korean National Health Insurance claims database. METHODS: Patients aged ≥20 years with type 2 diabetes and dyslipidemia were enrolled. The combination therapy of low- or moderate-intensity statin and ezetimibe was compared with high-intensity statin monotherapy after a propensity score-matched analysis. The incidence of composite outcomes consisting of MI, stroke, and all-cause death and each component were analyzed. RESULTS: In moderate-intensity statin therapy with ezetimibe combination therapy, LDL-C (74 ± 37.9 mg/dL vs 80.8 ± 38.8 mg/dL, P < .001) and the incidence of composite outcomes were lower (hazard ratio 0.85, 95% CI 0.74-0.98) than those in high-intensity statin monotherapy. Meanwhile, no significant difference was observed in the LDL-C levels and composite outcomes between low-intensity statins with ezetimibe combination therapy and high-intensity statin monotherapy. CONCLUSION: Adding ezetimibe to a moderate-intensity statin in patients with type 2 diabetes has a greater LDL-C-lowering effect and greater primary prevention of composite outcomes than that of high-intensity statin monotherapy.

Peroxisome proliferator-activated receptor γ activation ameliorates liver fibrosis-differential action of transcription factor EB and autophagy on hepatocytes and stellate cells.

BACKGROUND: Peroxisome proliferator-activated receptor γ (PPARγ) activation suppresses HSC activation and liver fibrosis. Moreover, autophagy is implicated in hepatic lipid metabolism. Here, we determined whether PPARγ activation ameliorates HSC activation by downregulating transcription factor EB (TFEB)-mediated autophagy. METHODS AND RESULTS: Atg7 or Tfeb knockdown in human HSC line LX-2 cells downregulated the expression of fibrogenic markers including α smooth muscle actin, glial fibrillary acidic protein, and collagen type 1. Conversely, Atg7 or Tfeb overexpression upregulated fibrogenic marker expression. Rosiglitazone (RGZ)-mediated PPARγ activation and/or overexpression in LX-2 cells and primary HSCs decreased autophagy, as indicated by LC3B conversion, total and nuclear-TFEB contents, mRFP-LC3 and BODIPY 493/503 colocalization, and GFP-LC3 and LysoTracker colocalization. RGZ treatment decreased liver fat content, liver enzyme levels, and fibrogenic marker expression in high-fat high-cholesterol diet-fed mice. Electron microscopy showed that RGZ treatment restored the high-fat high-cholesterol diet-mediated lipid droplet decrease and autophagic vesicle induction in primary HSCs and liver tissues. However, TFEB overexpression in LX-2 cells offset the aforementioned effects of RGZ on autophagic flux, lipid droplets, and fibrogenic marker expression. CONCLUSIONS: Activation of PPARγ with RGZ ameliorated liver fibrosis and downregulation of TFEB and autophagy in HSCs may be important for the antifibrotic effects of PPARγ activation.

Sarcopenia in youth.

Recent research has revealed causes other than aging that may induce sarcopenia in young people, contrary to the long-studied age-dependent reduction in muscular mass and function. The risk of sarcopenia begins in early adulthood, resulting in exaggerated muscle dysfunction in later life. Despite its clinical significance, research on youth-onset sarcopenia is still in its infancy. Due to a paucity of epidemiologic data and standardized criteria for sarcopenia in youth, determining the prevalence of sarcopenia in the young population remains challenging. Based on the evidence, >1 in every 10 young adults of most ethnicities is estimated to have sarcopenia. This review summarizes the possible etiologies of sarcopenia in young populations, including metabolic syndrome, physical inactivity, inadequate nutrition, inherent and perinatal factors, vitamin D deficiency, endocrinopathy, an imbalance of gut microbiota, neuromuscular diseases, organ failure, malignancy, and other inflammatory disorders. This is the first review of the current knowledge on the importance, prevalence, diagnosis, and causes of sarcopenia in youth.

Subtypes of type 2 diabetes and their association with outcomes in Korean adults - A cluster analysis of community-based prospective cohort.

BACKGROUND: Little is known about the subtypes of type 2 diabetes (T2D) and their association with clinical outcomes in Asians. METHODS: We performed data-driven cluster analysis in patients with newly diagnosed drug-naive T2D (n = 756) from the Korean Genome and Epidemiology Study. Clusters were based on five variables (age at diagnosis, BMI, HbA1c, and HOMA2 ß-cell function, and insulin resistance). RESULTS: We identified four clusters of patients with T2D according to k-means clustering: cluster 1 (22.4 %, severe insulin-resistant diabetes [SIRD]), cluster 2 (32.7 %, mild age-related diabetes [MARD]), cluster 3 (32.7 %, mild obesity-related diabetes [MOD]), and cluster 4 (12.3 %, severe insulin-deficient diabetes [SIDD]). During 14 years of follow-up, individuals in the SIDD cluster had the highest risk of initiation of glucose-lowering therapy compared to individuals in the other three clusters. Individuals in the MARD and SIDD clusters showed the highest risk of chronic kidney disease and cardiovascular disease, and individuals in the MOD clusters showed the lowest risk after adjusting for other risk factors (P < 0.05). CONCLUSIONS: Patients with T2D can be categorized into four subgroups with different glycemic deterioration and risks of diabetes complications. Individualized management might be helpful for better clinical outcomes in Asian patients with different T2D subgroups.

An Integrated Digital Health Care Platform for Diabetes Management With AI-Based Dietary Management: 48-Week Results From a Randomized Controlled Trial.

OBJECTIVE: We investigated the efficacy of an integrated digital health care platform with artificial intelligence (AI)-based dietary management in adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: In this 48-week, open-label, randomized, multicenter clinical trial, overweight or obese adults with T2D were randomly assigned to one of three groups in a 1:1:1 ratio: group A received routine diabetes care; group B used the digital integrated health care platform by themselves; and group C used the platform with feedback from medical staff and intermittently applied personal continuous glucose monitoring. The primary end point was the difference of change in HbA1c from baseline to 24 weeks between groups A and B, while secondary end points included changes in HbA1c from baseline to 48 weeks and changes in body weight during follow-up. RESULTS: A total of 294 participants were randomly assigned to group A (n = 99), B (n = 97), or C (n = 98). The decreases in HbA1c from baseline to 24 and 48 weeks in group B (-0.32 ± 0.58% to 24 weeks and -0.28 ± 0.56% to 48 weeks) and group C (-0.49 ± 0.57% to 24 weeks and -0.44 ± 0.62% to 48 weeks) were significantly larger than those in group A (-0.06 ± 0.61% to 24 weeks and 0.07 ± 0.78% to 48 weeks). Groups B and C exhibited greater weight loss than group A from baseline to 24 weeks, and group C demonstrated more weight loss than group A from baseline to week 48. CONCLUSIONS: Among adults with T2D, use of an integrated digital health care platform with AI-driven dietary management resulted in better glycemia and more weight loss.

High physical activity alleviates the adverse effect of higher sedentary time on the incidence of chronic kidney disease.

BACKGROUND: Low physical activity (PA) increases the prevalence of chronic kidney disease (CKD). This study aimed to investigate the effects of PA and sedentary time (ST) on the changes in renal function and the development of CKD in the middle-aged Korean population. METHODS: From the Korean Genome and Epidemiology Study Database, 7988 participants in their 40s and 60s were identified and stratified by (1) PA: high-PA (>24 MET-h/day), moderate-PA (9-24 MET-h/day) and low-PA (<9 MET-h/day); and (2) ST: high-ST (>6 h/day), moderate-ST (3-6 h/day) and low-ST (<3 h/day). Incident CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 following the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: The mean age of the participants was 52.0 years. The overall incidence of CKD was 16.8 per 1000 person-years over a median of 12 years. The lower the PA and the higher the ST, the lower the baseline eGFR. Relative to the high-PA, the coefficients of the annual eGFR decline were -0.12 (95% confidence interval [CI]: -0.26 to 0.001, P = 0.081) and -0.13 (95% CI: -0.27 to 0.01, P = 0.078) in the moderate- and low-PA groups, respectively. Similarly, relative to the low-ST, the coefficients of annual eGFR decline were -0.07 (59% CI: -0.19 to 0.05, P = 0.236) and -0.14 (95% CI: -0.28 to -0.01, P = 0.039) in the moderate- and high-ST groups, respectively. Incident CKD was higher with lower PA (hazard ratio: high-PA 1.00, moderate-PA 1.13 [1.00, 1.28, P = 0.056] and low-PA 1.25 [1.11, 1.24, P < 0.001]) and higher ST (hazard ratio: low-ST 1.00, moderate-ST 1.04 [0.94, 1.16, P = 0.440] and high-ST 1.19 [1.05, 1.34, P = 0.007]). The high-PA reduced the risk for the CKD development irrespective of the amount of ST. CONCLUSIONS: Low-PA and high-ST are risk factors for the development of CKD in the middle-aged Korean population. High-PA recovers high-ST, inducing a harmful effect on the occurrence of CKD.

Association between carotid atherosclerosis and presence of intracranial atherosclerosis using three-dimensional high-resolution vessel wall magnetic resonance imaging in asymptomatic patients with type 2 diabetes.

AIMS: Carotid atherosclerosis (CAS) is associated with a high risk of cardiovascular diseases. We aimed to investigate whether CAS is associated with the presence of intracranial atherosclerosis (ICAS). METHODS: A total of 69 asymptomatic patients with type 2 diabetes (36 with CAS and 33 without CAS) who were free of cerebrovascular disease were enrolled in this case-control study. CAS was defined as a mean carotid intima-media thickness ≥ 1.0 mm or carotid plaque. The presence of ICAS was identified using three-dimensional high-resolution vessel wall magnetic resonance imaging. RESULTS: There was no difference between the case and control groups in baseline characteristics, such as age, the proportion of men, duration of diabetes, and other cardiometabolic risk factors. The prevalence of ICAS was significantly higher in patients with CAS than those without CAS (72.2 % vs 48.5 %, P = 0.044). CAS was significantly associated with the presence of ICAS, even after adjusting other covariates (odds ratio [OR], 3.19; 95 % confidence interval [CI] 1.09-9.33, P = 0.034). In addition, CAS was significantly associated with the presence of multiple ICAS lesions (OR, 5.57; 95 % CI 1.75-17.78, P = 0.004). CONCLUSIONS: CAS is significantly and independently associated with the presence and extent of ICAS in asymptomatic patients with type 2 diabetes.

Delayed diagnosis of pseudohypoparathyroidism type 1a with rare hypothyroidism since childhood.

Pseudohypoparathyroidism (PHP) is a rare disorder that associates with resistance to parathyroid hormone (PTH). A 21-year old man visited outpatient clinic to treat previously diagnosed hypothyroidism and vitamin D deficiency. Despite daily 150 mcg of levothyroxine supplement, thyroid-stimulating hormone level was elevated, but thyroid autoantibodies were not detected. He showed features of Albright Hereditary Osteodystrophy and elevated serum PTH level with normal albumin-corrected calcium and phosphorus level. The Ellsworth-Howard test proved the blunted response of urinary phosphorus and cyclic adenosine monophosphate after the infusion of the exogenous PTH, suggesting PTH resistance. DNA analysis revealed a heterozygous mutation in the GNAS gene (c.478C > T). Herein, we report a case of PHP type 1a confirmed by clinical, biochemical and molecular analyses. Establishing correct diagnosis of PHP is necessary for efficient therapeutic management.

Evaluating Triglyceride and Glucose Index as a Simple and Easy-to-Calculate Marker for All-Cause and Cardiovascular Mortality.

OBJECTIVE: The triglyceride and glucose (TyG) index is a useful marker of insulin resistance and is a predictor of several metabolic diseases. The aim of this study was to evaluate the association between the TyG index and all-cause or cardiovascular mortality using a large population-based cohort study database. METHODS: A total of 255,508 subjects in the Kangbuk Samsung Health Study cohort were enrolled. Cox proportional hazards models were used to analyze the risk of mortality. RESULTS: During a median 5.7-year follow-up, the cumulative all-cause and cardiovascular mortality was 0.47% and 0.07%. There was a nonlinear relationship between the TyG index and death, and moving from moderate to high, the TyG index levels were associated with an increase in the risk of death. The hazard ratio (HR) for all-cause and cardiovascular mortality of the TyG index was 1.21 [95% confidence interval (CI) 1.14-1.28] and 1.45 (95% CI 1.26-1.66) in the unadjusted model, respectively. After adjustment for covariates, the association between the TyG index and all-cause and cardiovascular mortality was attenuated. In the multivariable-adjusted model, the TyG index was associated with an elevated risk of all-cause mortality in women (HR 1.13, 95% CI 1.02-1.26) and a decreased risk in men (HR 0.92, 95% CI 0.85-0.99). The association between cardiovascular mortality and the TyG index was not statistically significant among either men or women in the multivariable-adjusted model. CONCLUSIONS: The TyG index in a young, relatively healthy, population is associated with an elevated risk of all-cause and cardiovascular mortality. This association between the TyG index and all-cause mortality persists in women after multivariable adjustment.

Trends in the Prevalence of Obesity and Its Phenotypes Based on the Korea National Health and Nutrition Examination Survey from 2007 to 2017 in Korea.

This study used data from the Korea National Health and Nutrition Examination Survey IV-VII from 2007 to identify the prevalence of obesity and its phenotypes (metabolically unhealthy obesity [MUO] and metabolically healthy obesity [MHO]) and their secular changes. The prevalence of obesity in Korea increased with significant secular changes observed (ß=0.326, P trend <0.01) between 2007 and 2017, and especially in men (ß=0.682, P trend <0.001) but not in women. The changes in the prevalence of obesity during the study period were different between men and women (P=0.001). The prevalence of MUO significantly increased only in men (ß=0.565, P trend <0.01), while that of MHO increased only in women (ß=0.179, P<0.05), especially in the younger age group (ß=0.308, P<0.01).

The efficacy and safety of Dendropanax morbifera leaf extract on the metabolic syndrome: a 12-week, placebo controlled, double blind, and randomized controlled trial.

BACKGROUND/OBJECTIVES: The extract from Dendropanax morbifera exhibited diverse therapeutic potentials. We aimed to evaluate the efficacy and safety of D. morbifera leaf extract for improving metabolic parameters in human. SUBJECTS/METHODS: A 12-week, double blind, placebo-controlled and randomized trial included a total of 74 adults, and they were assigned to the placebo group (n = 38) or 700 mg/day of D. morbifera group (n = 36). The efficacy endpoints were changes in glycemic, lipid, obesity, and blood pressure (BP) parameters, in addition to the prevalence of metabolic syndrome (MetS) and the numbers of MetS components. Safety was assessed by monitoring adverse events (AEs). RESULTS: After 12 weeks of treatment, the hemoglobin A1c (HbA1c) level significantly decreased in the D. morbifera group compared to that of the placebo group (difference: -0.13 ± 0.20% vs. 0.00 ± 0.28%, P = 0.031; % of change: -2.27 ± 3.63% vs. 0.10 ± 5.10%, P = 0.025). The homeostatic model assessment for insulin resistance level also decreased significantly from its baseline in the D. morbifera group. The systolic BP of D. morbifera group decreased significantly than that of placebo group (difference: -3.9 ± 9.8 mmHg vs. 3.3 ± 11.7 mmHg, P = 0.005; % of change: -2.8 ± 7.7% vs. 3.3 ± 10.2%, P = 0.005). However, the lipid parameters and body composition including body weight did not differ between the groups. The prevalence of MetS (36.8% vs. 13.9%, P = 0.022) and the incidence of MetS (10.5% vs. 13.9%, P = 0.027) at 12 weeks was significantly lower in the D. morbifera group than it was in the placebo group. No serious AEs occurred in either group. CONCLUSIONS: Supplementation with D. morbifera extracts over a 12-week period improved metabolic parameters such as HbA1c and BP and reduced the prevalence of MetS. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0004672.

Effects of Teneligliptin on HbA1c levels, Continuous Glucose Monitoring-Derived Time in Range and Glycemic Variability in Elderly Patients with T2DM (TEDDY Study).

BACKGROUND: To evaluate the effects of teneligliptin on glycosylated hemoglobin (HbA1c) levels, continuous glucose monitoring (CGM)-derived time in range, and glycemic variability in elderly type 2 diabetes mellitus patients. METHODS: This randomized, double-blinded, placebo-controlled study was conducted in eight centers in Korea (clinical trial registration number: NCT03508323). Sixty-five participants aged ≥65 years, who were treatment-naïve or had been treated with stable doses of metformin, were randomized at a 1:1 ratio to receive 20 mg of teneligliptin (n=35) or placebo (n=30) for 12 weeks. The main endpoints were the changes in HbA1c levels from baseline to week 12, CGM metrics-derived time in range, and glycemic variability. RESULTS: After 12 weeks, a significant reduction (by 0.84%) in HbA1c levels was observed in the teneligliptin group compared to that in the placebo group (by 0.08%), with a between-group least squares mean difference of -0.76% (95% confidence interval [CI], -1.08 to -0.44). The coefficient of variation, standard deviation, and mean amplitude of glycemic excursion significantly decreased in participants treated with teneligliptin as compared to those in the placebo group. Teneligliptin treatment significantly decreased the time spent above 180 or 250 mg/dL, respectively, without increasing the time spent below 70 mg/dL. The mean percentage of time for which glucose levels remained in the 70 to 180 mg/dL time in range (TIR70-180) at week 12 was 82.0%±16.0% in the teneligliptin group, and placebo-adjusted change in TIR70-180 from baseline was 13.3% (95% CI, 6.0 to 20.6). CONCLUSION: Teneligliptin effectively reduced HbA1c levels, time spent above the target range, and glycemic variability, without increasing hypoglycemia in our study population.

Statin use for primary prevention in patients with type 2 diabetes: Can it benefit all ages? - A nationwide propensity-matched cohort study.

AIMS: This study aims to investigate whether statin use is associated with a reduction in CVD and mortality in patients with type 2 diabetes without pre-existing CVD. METHODS: A propensity score-matched cohort analysis using retrospective data was created. Statin users received at least a 90-day prescription, and never used statin before initiation of the study. Statin non-users never received statin throughout the study. Primary outcome was a composite of myocardial infarction (MI), stroke, and all-cause death, and secondary outcome was an individual event. RESULTS: The propensity score matched cohort included 168,045 statin users and 168,045 non-users (mean age 57 years; median follow-up 5.0 years). Compared to statin non-users, the hazard ratio (HR) was 0.72 (95% confidence interval [CI] 0.70-0.73; P < 0.001) for composite outcomes, 0.80 (0.76-0.84; P < 0.001) for MI, 0.74 (0.71-0.76; P < 0.001) for stroke, and 0.68 (0.66-0.70; P < 0.001) for all-cause death in statin users. The risk reduction was most prominent in subjects aged 40-74 years, attenuated but significant in those aged ≥75 years, and not significant in those aged <40 years. CONCLUSIONS: Statin showed a protective effect against CVD and all-cause death in type 2 diabetes; this effect was reduced beyond the age of 75 years and disappeared in young patients aged <40 years.

Lower High-Density Lipoprotein Cholesterol Concentration Is Independently Associated with Greater Future Accumulation of Intra-Abdominal Fat.

BACKGROUND: Both intra-abdominal fat (IAF) and high-density lipoprotein cholesterol (HDL-C) are known to be associated with cardiometabolic health. We evaluated whether the accumulation of computed tomography (CT)-measured IAF over 5 years was related to baseline HDL-C concentration in a prospective cohort study. METHODS: All participants were Japanese-Americans between the ages of 34 and 74 years. Plasma HDL-C concentration and CT measurements of IAF, abdominal subcutaneous fat (SCF), and thigh SCF cross-sectional areas were assessed at baseline and at 5-year follow-up visits. RESULTS: A total of 397 subjects without diabetes were included. The mean±standard deviation HDL-C concentration was 51.6±13.0 mg/dL in men and 66.0±17.0 mg/dL in women, and the IAF was 91.9±48.4 cm2 in men and 63.1±39.5 cm2 in women. The baseline plasma concentration of HDL-C was inversely associated with the change in IAF over 5 years using multivariable regression analysis with adjustment for age, sex, family history of diabetes, weight change over 5 years, and baseline measurements of body mass index, IAF, abdominal SCF, abdominal circumference, thigh SCF, and homeostatic model assessment for insulin resistance. CONCLUSION: These results demonstrate that HDL-C concentration significantly predicts future accumulation of IAF over 5 years independent of age, sex, insulin sensitivity, and body composition in Japanese-American men and women without diabetes.

Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway.

Excess fructose consumption contributes to development obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). Uric acid (UA), a metabolite of fructose metabolism, may have a direct role in development of NAFLD, with unclear mechanism. This study aimed to evaluate role of fructose and UA in NAFLD and explore mechanisms of allopurinol (Allo, a UA lowering medication) on NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a high fructose diet (HFrD), with Long-Evans Tokushima Otsuka (LETO) rats used as a control. There were six groups: LETO, LETO-Allo, OLETF, OLETF-Allo, OLETF-HFrD, and OLETF-HFrD-Allo. HFrD significantly increased body weight, epididymal fat weight, and serum concentrations of UA, cholesterol, triglyceride, HbA1c, hepatic enzymes, HOMA-IR, fasting insulin, and two hour-glucose after intraperitoneal glucose tolerance tests, as well as NAFLD activity score of liver, compared to the OLETF group. Allopurinol treatment significantly reduced hepatic steatosis, epididymal fat, serum UA, HOMA-IR, hepatic enzyme levels, and cholesterol in the OLETF-HFrD-Allo group. Additionally, allopurinol significantly downregulated expression of lipogenic genes, upregulated lipid oxidation genes, downregulated hepatic pro-inflammatory cytokine genes, and decreased ER-stress induced protein expression, in comparison with the OLETF-HFrD group. In conclusion, allopurinol ameliorates HFrD-induced hepatic steatosis through modulation of hepatic lipid metabolism, inflammation, and ER stress pathway. UA may have a direct role in development of fructose-induced hepatic steatosis, and allopurinol could be a candidate for prevention or treatment of NAFLD.

Fenofibrate, a PPARα agonist, reduces hepatic fat accumulation through the upregulation of TFEB-mediated lipophagy.

BACKGROUND: Recent studies have shown that dysregulation of autophagy is involved in the development of nonalcoholic fatty liver disease (NAFLD). Transcription factors E3 (TFE3) and EB (TFEB) are master regulators of the transcriptional response of basic cellular processes such as lysosomal biogenesis and autophagy. Here, we investigated the role of fenofibrate, a PPARα agonist, in promotion of intracellular lipid clearance by upregulation of TFEB/TFE3. METHODS: We investigated whether the effects of fenofibrate on livers were dependent on TFEB in high fat diet (HFD)-fed mice and in vivo Tfeb knockdown mice. These mice were analyzed for characteristics of obesity and diabetes; the effects of fenofibrate on hepatic fat content, glucose sensitivity, insulin resistance, and autophagy functional dependence on TFEB were investigated. HepG2, Hep3B, TSC2+/+ and tsc2-/- MEFs, tfeb wild type- and tfeb knockout-HeLa cells were used for in vitro experiments. RESULTS: Fenofibrate treatment activated autophagy and TFEB/TFE3 and reduced hepatic fat accumulation in an mTOR-independent manner. Knockdown of TFEB offset the effects of fenofibrate on autophagy and hepatic fat accumulation. In addition, fenofibrate treatment induced lysosomal Ca2+ release through mucolipin 1, activated calcineurin and the CaMKKß-AMPK-ULK1 pathway, subsequently promoted TFEB and TFE3 dephosphorylation and nuclear translocation. Treatment with calcium chelator or knockdown of mucolipin 1 in hepatocytes offset the effects of fenofibrate treatment on autophagy and hepatic fat accumulation. CONCLUSION: Activation of PPARα ameliorates hepatic fat accumulation via activation of TFEB and lipophagy induction. Lysosomal calcium signaling appears to play a critical role in this process. In addition, activation of TFEB by modulating nuclear receptors including PPARα with currently available drugs or new molecules might be a therapeutic target for treatment of NAFLD and other cardiometabolic diseases.

Additive effect of low skeletal muscle mass and abdominal obesity on coronary artery calcification.

OBJECTIVE: We aimed to investigate the interaction of reduced skeletal muscle mass and abdominal obesity on coronary artery calcification (CAC). DESIGN AND METHODS: A total of 19 728 adults free of cardiovascular disease (CVD) who contemporaneously underwent cardiac tomography and bioelectrical impedance analysis were enrolled in a cross-sectional and longitudinal cohort. Skeletal muscle mass index (SMI) was calculated using the following formula: SMI (%) = total appendicular muscle mass (kg)/body weight (kg) × 100 according to sex. CAC presence or incidence was defined as CAC score > 0, and CAC progression was defined as √CAC score (follow-up) - √CAC score (baseline)>2.5. Pre-sarcopenia was defined as SMI ≤ -1.0 s.d. of the sex-specific mean of a young reference group. Abdominal obesity was defined as waist circumference ≥ 90 cm for men and ≥85 cm for women. All individuals were further classified into four groups: normal, abdominal obesity alone, pre-sarcopenia alone, and pre-sarcopenic obesity. RESULTS: Individuals with pre-sarcopenic obesity showed the highest adjusted odds ratio (AOR) for CAC presence (AOR 2.16, 95% CI : 1.98-2.36, P < 0.001) as well as total CAC incidence and progression (adjusted hazard ratio: 1.54, 95% CI: 1.37-1.75, P < 0.001), compared with normal individuals. Pre-sarcopenic obesity significantly increased CAC incidence and progression compared to either pre-sarcopenia or abdominal obesity alone. CONCLUSION: Pre-sarcopenia and abdominal obesity together were significantly associated with a higher CAC presence and increased risk of CAC incidence and progression, independent of traditional CVD risk factors.

Low Skeletal Muscle Mass Is Associated With the Presence, Incidence, and Progression of Coronary Artery Calcification.

BACKGROUND: Low skeletal muscle mass (SMM) is an emerging risk factor of cardiovascular disease (CVD). We investigated the association between SMM and coronary artery calcification (CAC). METHODS: We enrolled 19,728 adults free of CVD who underwent computed tomographic estimation of Agatston CAC scores for cross-sectional analysis. Among them, 5,401 subjects who had at least 2 follow-up CAC scores were included in longitudinal analysis. Relative SMM is presented as the skeletal muscle mass index [SMI (%) = total appendicular muscle mass (kg)/body weight (kg) × 100]. CAC presence and incidence were defined as CAC score > 0, and CAC progression was defined as √CAC score (follow-up) - √CAC score (baseline) > 2.5. RESULTS: Among all of the subjects (mean age 53.4 years, 80.8% male), the prevalence of CAC was 36.7%. The incidence of CAC was 17.4% during a mean of 3.6 years, and the progression of CAC was 49.9% during a mean of 2.3 years. The lowest SMI quartile was significantly associated with an increased risk of CAC presence (adjusted odds ratio 2.75, 95% confidence interval [CI] 2.45-3.05; P < 0.001), incidence (adjusted hazard ratio [AHR] 1.99, 95% CI 1.36-2.91; P < 0.001), and progression (AHR 1.48, 95% CI 1.25-1.77; P < 0.001) compared with the highest quartile. SMI as a continuous value was also significantly inversely associated with CAC. SMI was the best parameter to be related to CAC among other quantitative indices such as height or body mass index adjusted. CONCLUSIONS: Low SMM is significantly associated with an elevated risk of CAC, independently of other cardiometabolic parameters.

Increased Visit-to-Visit Liver Enzyme Variability Is Associated with Incident Diabetes: A Community-Based 12-Year Prospective Cohort Study.

BACKGROUND: Fatty liver and/or increased liver enzyme values have been reported to be associated with incident diabetes. We sought to determine whether increased visit-to-visit liver enzyme variability is associated with incident diabetes. METHODS: Study participants were recruited from the Korean Genome and Epidemiologic Study (KoGES). A total of 4,151 people aged 40 to 69 years was recruited and tested every 2 years for up to 12 years. Visit-to-visit aspartate aminotransferase (AST) and alanine aminotransferase (ALT) variability was evaluated in first the 6-year period through the use of various variability measurements: standard deviation (SD), average successive variability, coefficient of variation (CV), and variation independent of mean (VIM). Oral glucose tolerance test was performed at every visit. RESULTS: During the 6-year follow-up appointments, 13.0% (538/4,151) of people developed incident diabetes. Visit-to-visit AST variability was associated with an increased risk of diabetes independent of conventional risk factors for diabetes (hazard ratio per 1-SD increment [95% confidence interval]: 1.06 [1.00 to 1.11], 1.12 [1.04 to 1.21], and 1.13 [1.04 to 1.22] for SD, CV, and VIM, respectively; all P<0.05); however, no such associations were observed in the visit-to-visit ALT variability. According to alcohol consumption status, both AST and ALT variability were independent predictors for incident diabetes in subjects with heavy alcohol consumption; however, neither AST nor ALT variability was associated with diabetes risk in subjects who did not drink alcohol heavily. CONCLUSION: Visit-to-visit liver enzyme variability is an independent predictor of incident diabetes. Such association was more evident in those who consumed significant amounts of alcohol.