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Background: Myosteatosis, ectopic fat accumulation in skeletal muscle, is a crucial component of sarcopenia, linked to various cardiometabolic diseases. This study aimed to analyze the association between dyslipidemia and myosteatosis using abdominal computed tomography (CT) in a large population., Methods: This study included 11,823 patients not taking lipid-lowering medications with abdominal CT taken between 2012 and 2013. Total abdominal muscle area (TAMA), measured at the L3 level, was segmented into skeletal muscle area (SMA) and intramuscular adipose tissue. SMA was further classified into normal attenuation muscle area (NAMA: good quality muscle) and low attenuation muscle area (poor quality muscle). NAMA divided by TAMA (NAMA/TAMA) represents good quality muscle. Atherosclerotic dyslipidemia was defined as high-density lipoprotein cholesterol (HDL-C) less than 40 mg/dL in men and 50 mg/dL in women, low-density lipoprotein cholesterol (LDL-C) greater than 160 mg/dL, triglycerides (TG) greater than 150 mg/dL, small dense LDL-C (sdLDL-C) greater than 50.0 mg/dL, or apolipoprotein B/A1 (apoB/A1) greater than 0.08., Results: The adjusted odds ratios (ORs) of dyslipidemia according to the HDL-C and sdLDL definitions were greater in both sexes in the lower quartiles (Q1~3) of NAMA/TAMA compared with Q4. As per other definitions, the ORs were significantly increased in only women for LDL-C and only men for TG and ApoB/A1. In men, all lipid parameters were significantly associated with NAMA/TAMA, while TG and ApoB/A1 did not show significant association in women., Conclusion: Myosteatosis measured in abdominal CT was significantly associated with a higher risk of dyslipidemia. Myosteatosis may be an important risk factor for dyslipidemia and ensuing cardiometabolic diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Cho, Kim, Kim, Lee, Lee, Kim and Jung.)

Purpose: Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys and has proven efficacy and safety in patients with diabetic kidney disease. We aimed to evaluate the 1-year efficacy of dulaglutide in patients with diabetic kidney disease who have used the drug for more than 1 year., Methods: This retrospective, observational study comprised 131 patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m 2 who had received dulaglutide for more than one year between June 2016 and May 2023. The primary outcome measures were changes in glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and body weight from baseline to the 12-month follow-up, with assessments performed at six-month intervals. Subgroup analyses were conducted based on age, sex, baseline body mass index, FPG, and HbA1c, and insulin administration at baseline and last follow-up., Findings: The mean age was 60.0 ± 10.2 years, and 61.1% of the participants were males. Baseline HbA1c, FPG, and body weight were 9.1% (76.0 mmol/mol), 186.8 mg/dL, and 79.3 kg, respectively. Dulaglutide significantly reduced HbA1c, FPG, and body weight from baseline to the 12-month follow-up (mean ± standard error: -1.2 ± 0.1%, -34.8 ± 6.9 mg/dL, and -2.3 ± 0.5 kg, respectively; P < 0.001). Subgroup analysis revealed significant differences in HbA1c reduction based on baseline HbA1c., Implications: Dulaglutide exhibited sustained glucose-lowering and weight-reduction effects during the initial 1 year of treatment in patients with diabetic kidney disease. Altogether, dulaglutide could serve as a favorable long-term therapeutic option for patients with diabetic kidney disease in real-world clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to determine the efficacy and safety profile of pioglitazone compared with placebo (PBO) in patients with type 2 diabetes (T2D) inadequately controlled with metformin and dapagliflozin., Methods: In this prospective, multicenter, randomized, double-blind, PBO-controlled trial, 366 patients with T2D who did not meet glycemic targets (7.0% ≤ glycosylated hemoglobin [HbA 1c ] ≤ 10.5%), despite treatment with metformin ≥1000 mg and dapagliflozin 10 mg, received either a PBO, 15 mg of pioglitazone daily (PIO15), or 30 mg of pioglitazone daily (PIO30). The primary end point was the mean change in HbA 1c from baseline at 24 weeks across the groups., Findings: For the 366 participants (PBO, n = 124; PIO15, n = 118; PIO30, n = 124), the mean age was 55.6 years and mean duration of diabetes was 8.7 years, with a baseline HbA 1c of 7.9%. After 24 weeks, HbA 1c reduced significantly in the PIO15 and PIO30 groups from baseline, with intergroup differences of -0.38% and -0.83%, respectively, compared with the PBO group. The proportion of patients with HbA 1c levels <7% was significantly higher in the PIO15 and PIO30 groups than in the PBO group. The adverse event rates did not significantly differ across the groups, indicating favorable safety profiles for triple combination therapy using metformin, dapagliflozin, and pioglitazone., Implications: The addition of pioglitazone as a third oral antidiabetic medication is an appropriate option for patients with T2D inadequately controlled with metformin and dapagliflozin based on the resulting significant efficacy in glycemic control and favorable safety profile., Clinicaltrials: gov identifier: NCT04885712., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In 2023, the concept of metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced as an alternative to non-alcoholic fatty liver disease (NAFLD). We aimed to assess the quantity and quality of skeletal muscle using each of these diagnostic classifications., Methods: This cross-sectional study included 18 154 participants (11 551 [63.6%] men and 6603 [36.4%] women, mean age 53.0 ± 8.8). The participants were classified into four categories: neither steatotic liver disease (SLD), NAFLD only, MASLD only or both SLDs. An appendicular skeletal muscle mass adjusted for body mass index of <0.789 for men and <0.512 for women was defined as sarcopenia. The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area and intermuscular/intramuscular adipose tissue. Myosteatosis was defined by a T-score < -1.0 of the NAMA/TAMA index, which was calculated by dividing the NAMA by the TAMA and multiplying by 100., Results: Using subjects with neither SLD as a reference, the multivariable-adjusted odds ratios (ORs) for sarcopenia were significantly increased in those with MASLD, with adjusted ORs (95% confidence interval [CI]) of 2.62 (1.94-3.54) in the MASLD-only group and 2.33 (1.92-2.82) in the both SLDs group, while the association was insignificant in those with NAFLD only (adjusted OR [95% CI]: 2.16 [0.67-6.94]). The OR for myosteatosis was also elevated in the MASLD groups, with an OR (95% CI) of 1.75 (1.52-2.02) in subjects with MASLD only and 1.70 (1.57-1.84) in those with both SLDs, while it was slightly decreased in subjects with NAFLD only (0.52 [0.29-0.95])., Conclusions: Employing the MASLD concept rather than that of the NAFLD proved to be more effective in distinguishing individuals with reduced muscle mass and compromised muscle quality., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background and Aims: The estimated glucose disposal rate (eGDR) is an easily accessible clinical parameter for assessing insulin resistance in patients with diabetes mellitus. In this study, we aimed to investigate the link between eGDR and subclinical coronary atherosclerosis in an asymptomatic middle-aged Korean population., Methods and Results: This study involved 4004 subjects who underwent routine health checkups with coronary multidetector computed tomography (MDCT) at Asan Medical Center from 2007 to 2011, among whom 913 had a follow-up analysis through 2014. The eGDR was calculated using: 21.16 - (0.09 ∗ waist circumference [cm]) - (3.41 ∗ hypertension) - (0.55 ∗ glycated hemoglobin [%]). Patients were categorized into three groups according to the tertiles of eGDR. Subclinical coronary atherosclerosis was defined by significant coronary stenosis (≥50%), presence of plaques, coronary artery calcification (CAC) score, and its progression. As a result, a lower eGDR level was associated with higher prevalence of significant coronary stenosis, plaques, moderate to severe CAC, and CAC progression. Compared to other markers or risk scores, eGDR was superior to other biomarkers of insulin resistance but did not provide additional information beyond classic cardiovascular risk models like the Framingham Risk Score and Pooled Cohort Equations., Conclusion: Decreased eGDR values were significantly associated with higher subclinical coronary atherosclerosis burdens in an asymptomatic middle-aged Korean population. However, its clinical implications remain uncertain due to its weaker performance compared to established cardiovascular risk models., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: In this study, we aimed to evaluate the impact of overall cardiovascular disease (CVD) risk on the development of incident T2DM in patients with prediabetes., Methods: We retrospectively enrolled 5,908 subjects with prediabetes who underwent health check-ups at the Asan Medical Center. CVD risk was estimated using the Framingham Risk Score (FRS). We compared moderate- to high-risk groups with low-risk controls based on the FRS. Cox proportional hazards regressions were conducted to estimate the time-to-develop incident T2DM., Results: Among the 5908 subjects with prediabetes, 3031 (51.8 %) were identified to have either moderate or high CVD risk scores. During a median follow-up of 5.2 years, 278 (9.2 %) patients from the moderate- to high-risk group and 171 (5.9 %) from the low-risk group were diagnosed with T2DM. The covariate-adjusted hazard ratio for the incident T2DM was 1.30 (95 % CI, 1.06-1.60, p = 0.011) in the moderate- to high-risk group compared to the low-risk controls., Conclusion: Among patients with prediabetes, those with high CVD risk were more likely to develop incident T2DM, as determined by the FRS. CVD risk factors should be properly evaluated and managed in individuals with prediabetes to reduce the risk of both incident T2DM and associated cardiovascular complications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: Ectopic fat deposition in skeletal muscle, termed myosteatosis, is a key factor in developing insulin resistance., Objective: This work aimed to evaluate the association between insulin resistance and myosteatosis in a large Asian population., Methods: A total of 18 251 participants who had abdominal computed tomography were included in this cross-sectional study. Patients were categorized into 4 groups according to quartiles of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area (LAMA), and intermuscular adipose tissue (IMAT). The absolute values of TAMA, NAMA, LAMA, and IMAT and the ratios of NAMA/BMI, LAMA/BMI, and NAMA/TAMA were used as myosteatosis indices., Results: The absolute values of TAMA, NAMA, LAMA, and IMAT appeared to increase with higher HOMA-IR levels, and LAMA/BMI showed a similar upward trend. Meanwhile, the NAMA/BMI and NAMA/TAMA index showed downward trends. As HOMA-IR levels increased, the odds ratios (ORs) of the highest quartile of NAMA/BMI and NAMA/TAMA index decreased and that of LAMA/BMI increased. Compared with the lowest HOMA-IR group, the adjusted ORs (95% CI) in the highest HOMA-IR group for the lowest NAMA/TAMA quartile were 0.414 (0.364-0.471) in men and 0.464 (0.384-0.562) in women. HOMA-IR showed a negative correlation with NAMA/BMI (r = -0.233 for men and r = -0.265 for women), and NAMA/TAMA index (r = -0.211 for men and r = -0.214 for women), and a positive correlation with LAMA/BMI (r = 0.160 for men and r = 0.119 for women); P was less than .001 for all., Conclusion: In this study, a higher HOMA-IR level was significantly associated with a high risk of myosteatosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

With the increasing use of immune-checkpoint inhibitors (ICIs), such as anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and anti-programmed cell death-1 (PD-1), for the treatment of malignancies, cases of ICI-induced type 1 diabetes mellitus (ICI-T1DM) have been reported globally. This review focuses on the features and pathogenesis of this disease. T1DM is an immune-related adverse event that occurs following the administration of anti-PD-1 or anti-programmed death ligand-1 (PDL1) alone or in combination with anti-CTLA-4. More than half of the reported cases presented as abrupt-onset diabetic ketoacidosis. The primary mechanism of ICI-T1DM is T-cell stimulation, which results from the loss of interaction between PD-1 and PD-L1 in pancreatic islet. The similarities and differences between ICI-T1DM and classical T1DM may provide insights into this disease entity. ICI-T1DM is a rare but often life-threatening medical emergency that healthcare professionals and patients need to be aware of. Early detection of and screening for this disease is imperative. At present, the only known treatment for ICI-T1DM is insulin injection. Further research into the mechanisms and risk factors associated with ICI-T1DM development may contribute to a better understanding of this disease entity and the identification of possible preventive strategies.

Background: Contrary to the previously known concept of muscle mass decrease following bariatric metabolic surgery, changes in muscle strength have been poorly investigated in systematic reviews. In this meta-analysis, we evaluated changes in handgrip strength (HGS) and lean mass (LM) after undergoing bariatric metabolic surgery., Methods: A systematic literature review using the PubMed, Embase, and Cochrane Library databases was conducted in November 2022. Longitudinal studies reporting HGS change after bariatric metabolic surgery were eligible. Pooled estimates for changes in HGS, body mass index (BMI), LM, and fat mass (FM) were calculated. Changes from baseline to the point closest to 6 months postoperatively were analyzed in trials with multiple follow-up examinations. The risk of bias was assessed using the Joanna Briggs Institute critical appraisal checklist., Results: Three randomized controlled trials and seven prospective cohort studies involving 301 patients were included. Follow-up evaluations were conducted 6 months postoperatively in all trials except for two, whose follow-up visits were at 18 weeks and 12 months, respectively. Pooled analysis showed reduced BMI (- 10.8 kg/m 2 ; 95% confidence interval: - 11.6 to - 9.9 kg/m 2 ), LM (- 7.4 kg; - 9.3 to - 5.4 kg), and FM (- 22.3 kg; - 25.1 to - 19.6 kg) after bariatric metabolic surgery, whereas the change in HGS was not statistically significant (- 0.46 kg; - 1.76 to 0.84 kg)., Conclusion: Despite the decreased body composition parameters, including muscle mass, strength was not impaired after bariatric metabolic surgery; this indicates that bariatric metabolic surgery is an effective weight management intervention that does not compromise strength., (© 2023. The Author(s).)

Background/aims: To investigate whether non-alcoholic fatty liver disease (NAFLD) in individuals without generalized obesity is associated with visceral fat obesity (VFO), sarcopenia, and/or myosteatosis., Methods: This cross-sectional analysis included 14,400 individuals (7,470 men) who underwent abdominal computed tomography scans during routine health examinations. The total abdominal muscle area (TAMA) and skeletal muscle area (SMA) at the 3rd lumbar vertebral level were measured. The SMA was divided into the normal attenuation muscle area (NAMA) and low attenuation muscle area, and the NAMA/TAMA index was calculated. VFO was defined by visceral to subcutaneous fat ratio, sarcopenia by body mass index-adjusted SMA, and myosteatosis by the NAMA/TAMA index. NAFLD was diagnosed with ultrasonography., Results: Of the 14,400 individuals, 4,748 (33.0%) had NAFLD, and the prevalence of NAFLD among non-obese individuals was 21.4%. In regression analysis, both sarcopenia (men: odds ratio [OR] 1.41, 95% confidence interval [CI] 1.19-1.67, P<0.001; women: OR=1.59, 95% CI 1.40-1.90, P<0.001) and myosteatosis (men: OR=1.24, 95% CI 1.02-1.50, P=0,028; women: OR=1.23, 95% CI 1.04-1.46, P=0.017) were significantly associated with non-obese NAFLD after considering for VFO and other various risk factors, whereas VFO (men: OR=3.97, 95% CI 3.43-4.59 [adjusted for sarcopenia], OR 3.98, 95% CI 3.44-4.60 [adjusted for myosteatosis]; women: OR=5.42, 95% CI 4.53-6.42 [adjusted for sarcopenia], OR=5.33, 95% CI 4.51-6.31 [adjusted for myosteatosis]; all P<0.001) was strongly associated with non-obese NAFLD after adjustment with various known risk factors., Conclusion: In addition to VFO, sarcopenia and/or myosteatosis were significantly associated with non-obese NAFLD.

Glucagon-like peptide-1 (GLP-1) receptor agonists have been used extensively in the clinic and have an established safety profile in cardiovascular disease settings. For the treatment of peptide-secreting enteroendocrine cells, most research has focused on developing peptide multi-agonists as most of these cells are multihormonal. Among the various peptides secreted by enteroendocrine cells, the combination of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) is an attractive strategy for treating type 2 diabetes mellitus (T2DM) because both of these hormones have glucose-lowering actions. Tirzepatide, a synthetic peptide composed of 39 amino acids, functions as a dual receptor agonist of both the GIP and GLP-1 receptors. This unique mechanism of action has earned tirzepatide the nickname "twincretin." Tirzepatide's dual agonist activity may be the mechanism by which tirzepatide significantly reduces glycated hemoglobin levels and body weight in patients with T2DM as observed in phase 3 clinical trials. Besides its glucose-lowering and anti-obesity effects, tirzepatide has been reported to have potential cardiovascular benefits. In this review, we discuss the cardiovascular effects of tirzepatide based on the available preclinical and clinical data., Competing Interests: Conflict of Interest: Yun Kyung Cho is editor of Journal of LIpid and Atherosclerosis. However, she was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported., (Copyright © 2023 The Korean Society of Lipid and Atherosclerosis.)

Objective: This study assessed whether cholecystectomy is a risk factor for newly developed type 2 diabetes mellitus (T2DM) in the Korean population., Background: There is a lack of evidence that cholecystectomy is independently associated with insulin resistance and T2DM., Methods: This study included all patients aged more than 20 years who had undergone cholecystectomy from 2010 to 2015 (n=55,166) and age-matched and sex-matched control subjects without cholecystectomy (n=110,332) using the National Health Insurance Service database. They were followed up until the date of newly developed T2DM or study end and the incidence of T2DM was traced over a maximum observation period of 7 years., Results: Overall, 55,166 patients who underwent cholecystectomy and 110,332 age-matched and sex-matched controls were followed up for ∼4.7 years, during which, incident T2DM occurred in 5982 (3.61%) patients. Cholecystectomy was associated with 20% higher risk of T2DM after adjustment for all covariates. The cumulative incidence of T2DM also significantly increased in the cholecystectomy group for ∼7 years ( P <0.001). The adjusted hazard ratio (HR) for T2DM was the highest in the group with both cholecystectomy and obesity using the control without both cholecystectomy and obesity as a reference [HR=1.41, 95% confidence interval (CI): 1.29-1.56]. The group with cholecystectomy without obesity showed the comparable risk of incident T2DM compared with the group without cholecystectomy with obesity (HR=1.29, 95% CI: 1.20-1.40 for cholecystectomy without obesity and HR=1.24, 95% CI: 1.14-1.36 for control with obesity)., Conclusions: These results provide evidence that cholecystectomy is associated with an increased risk of newly developed T2DM in the Korean population. Further research is required to elucidate the mechanism of the association between cholecystectomy and incident diabetes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Backgruound: Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study., Methods: In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver., Results: Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis., Conclusion: Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.

Background: Cholecystectomy is a common surgical procedure to treat symptomatic gallstones; however, the long-term outcomes after cholecystectomy are unknown. Therefore, we aimed to investigate whether incident metabolic syndrome (MetS) is associated with cholecystectomy through a large, population-based, longitudinal study., Methods: Subjects aged ≥20 years who underwent cholecystectomy from 2010 to 2014 (n=76,485) and controls (n=76,485), matched for age and sex, were identified from the Korean National Health Insurance Corporation. Cox proportional hazards analyses were performed to evaluate the association between cases and incident MetS, and hazard ratios and 95% confidence intervals (CIs) were calculated., Results: A total of 152,970 patients were included. Mean age was 52.47±12.76 years, and 50.65% of participants were male. During the follow-up period, there were 38,979 (25.48%) newly diagnosed MetS cases in the study participants. The risk of MetS in the cholecystectomy group was approximately 20% higher than that in the control group [adjusted odds ratio (OR), 1.20; 95% CI: 1.17-1.23]. In the fully adjusted models, the corresponding ORs for new-onset high waist circumference (WC), low high-density lipoprotein cholesterol (HDL-C) levels, high triglycerides (TG) levels, high blood pressure (BP), and high blood glucose levels were 1.16 (1.13-1.19), 1.19 (1.16-1.22), 1.25 (1.22-1.28), 1.27 (1.23-1.31), and 1.21 (1.18-1.24), respectively. Cholecystectomy was an independent risk factor of incident MetS, after adjusting for potential confounding factors. In the subgroup analyses, the cholecystectomy group had a higher risk of MetS than the control group in subjects without hypertension or dyslipidemia, respectively., Conclusions: In this large, population-based study, cholecystectomy was associated with an increased risk of developing MetS, independent of other confounding factors. Therefore, careful monitoring of metabolic variables and long-term follow-up are required to evaluate MetS risk after cholecystectomy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-201/coif). JHH reports that this study was supported by Hallym University Research Fund 2021 (HURF-2021-45). JGK reports that this study was supported by National Research Foundation of Korea (NRF) grant funded by the Korea government (2017R1D1A1B03029575). The other authors have no conflicts of interest to declare., (2023 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is common and is associated with cardiovascular (CV) disease and mortality. The Framingham steatosis index (FSI) was recently proposed as a diagnostic marker of NAFLD and was calculated from age, body mass index, triglyceride, aspartate aminotransferase, alanine aminotransferase, diabetes history, and hypertension status. We aimed to evaluate the predictive ability of FSI for CV risk using a large-scale population dataset from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS)., Methods: Among 514,866 individuals in the NHIS-HEALS, we excluded those who died, had a history of admission due to a CV event, and were heavy drinkers. The final study cohort comprised 283,427 participants. We employed both unadjusted and covariate-adjusted models in Cox proportional hazards regression analyses to determine the association between FSI and major adverse cardiovascular events (MACEs), CV events, and CV mortality., Results: During a median follow-up of 5.9 years, we documented 9,674, 8,798, and 1,602 cases of MACEs, CV events, and CV mortality, respectively. The incidence of MACEs was 1.28%, 2.99%, 3.94%, and 4.82% in the first to fourth quartiles of FSI, respectively. The adjusted hazard ratios (95% confidence interval) for MACEs gradually and significantly increased with the FSI quartiles [1.302 (1.215-1.395) in Q2, 1.487 (1.390-1.590) in Q3, and 1.792 (1.680-1.911) in Q4], following an adjustment for conventional CV risk factors, including age, sex, smoking, drinking, physical activities, low-density lipoprotein cholesterol, estimated glomerular filtration rate, and waist circumference. Participants in the higher quartiles of FSI exhibited a noteworthy increase in the occurrence of CV event. However, upon adjusting for relevant risk factors, the association between FSI and CV mortality did not reach statistical significance., Conclusion: Our study suggests that the FSI, which is a surrogate marker of NAFLD, has a prognostic value for detecting individuals at higher risk of CV events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Cho, Kim, Kim, Jung, Lee and Park.)

Background: The association between body mass index (BMI) and mortality in patients with type 1 diabetes mellitus (T1DM) has been poorly examined and has never been systematically reviewed. This meta-analysis investigated the all-cause mortality risk for each BMI category among patients with T1DM., Methods: A systematic literature review of the PubMed, Embase, and Cochrane Library databases was performed in July 2022. Cohort studies comparing the mortality risk between BMI categories among patients with T1DM were eligible. Pooled hazard ratios (HRs) for all-cause mortality among underweight (BMI <18.5 kg/m 2 ), overweight (BMI, 25 to <30 kg/m 2 ), and obese (BMI ≥30 kg/m 2 ) individuals were calculated in reference to the normal-weight group (BMI, 18.5 to <25 kg/m 2 ). The Newcastle-Ottawa Scale was used to assess the risk of bias., Results: Three prospective studies involving 23,407 adults were included. The underweight group was shown to have a 3.4 times greater risk of mortality than the normal-weight group (95% confidence interval [CI], 1.67 to 6.85). Meanwhile, there was no significant difference in mortality risk between the normal-weight group and the overweight group (HR, 0.90; 95% CI, 0.66 to 1.22) or the obese group (HR, 1.36; 95% CI, 0.86 to 2.15), possibly due to the heterogeneous results of these BMI categories among the included studies., Conclusion: Underweight patients with T1DM had a significantly greater risk of all-cause mortality than their normal-weight counterparts. Overweight and obese patients showed heterogeneous risks across the studies. Further prospective studies on patients with T1DM are required to establish weight management guidelines.

Objective: This study evaluated whether sarcopenic obesity is closely associated with muscle quality using abdominal computed tomography., Methods: This cross-sectional study included 13,612 participants who underwent abdominal computed tomography. The cross-sectional area of the skeletal muscle was measured at the L3 level (total abdominal muscle area [TAMA]) and segmented into normal attenuation muscle area (NAMA, +30 to +150 Hounsfield units), low attenuation muscle area (-29 to +29 Hounsfield units), and intramuscular adipose tissue (-190 to -30 Hounsfield units). The NAMA/TAMA index was calculated by dividing NAMA by TAMA and multiplying by 100, and the lowest quartile of NAMA/TAMA index was defined as myosteatosis (<73.56 in men and <66.97 in women). Sarcopenia was defined using BMI-adjusted appendicular skeletal muscle mass., Results: The prevalence of myosteatosis was found to be significantly higher in participants with sarcopenic obesity (17.9% vs. 54.2%, p < 0.001) than the control group without sarcopenia or obesity. Compared with the control group, the odds ratio (95% CI) for having myosteatosis was 3.70 (2.87-4.76) for participants with sarcopenic obesity after adjusting for age, sex, smoking, drinking, exercise, hypertension, diabetes, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein., Conclusions: Sarcopenic obesity is significantly associated with myosteatosis, which is representative of poor muscle quality., (© 2023 The Obesity Society.)

Few studies have examined the relationship between myosteatosis and hypertension, and no studies have enrolled an Asian population. Existing studies also found discordant results, possibly due to the use of conventional myosteatosis indices that are not sufficiently reliable and representative. Therefore, we investigated the association between myosteatosis and hypertension in Asian individuals using novel, objective computed tomography (CT) markers. The total abdominal muscle area (TAMA) was determined from abdominal CT scans taken at the L3 level. Based on the mean CT attenuation, the TAMA was divided into intramuscular adipose tissue and skeletal muscle area (SMA), which was further segmented into normal attenuation muscle area (NAMA) and low attenuation muscle area (LAMA). Among SMA/body mass index (BMI), NAMA/BMI, LAMA/BMI, and the NAMA/TAMA index, NAMA/BMI was chosen through receiver operating characteristic curves as the best predictive marker for hypertension. The hypertension risk for each quartile of NAMA/BMI was calculated by logistic regression analysis. Among the 19,766 participants, 40.3% of men and 23.8% of women had hypertension. People with hypertension showed unhealthier myosteatosis profiles than normotensive controls. Similarly, a lower NAMA/BMI was significantly associated with a greater hypertension risk. The lowest quartile group of NAMA/BMI exhibited 2.3- and 2.6-fold higher risks of hypertension than the highest quartile in men and women, respectively. In conclusion, advanced myosteatosis assessed by abdominal CT was significantly correlated with a higher risk of hypertension. Improving myosteatosis may be a new approach for preventing cardiovascular diseases, including hypertension. Advanced myosteatosis measured by abdominal CT taken at the L3 level was significantly correlated with a higher risk of hypertension even after adjusting for health behaviors, intake of lipid-lowering drugs, plasma lipid levels, and other ectopic fat distribution., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Abdominal obesity has been suggested as a risk factor for glioma; however, it is unclear whether this association applies to people with diabetes. This study examined the association between abdominal obesity and the risk of developing gliomas in diabetic patients., Methods: We conducted a retrospective cohort study using the National Health Insurance System of South Korea from 2009 to 2012. The primary outcome was the incidence of newly diagnosed gliomas according to waist circumference (WC), and subgroup analyses were performed according to demographic characteristics and diabetes status including disease duration, number of oral hypoglycemic agents, and insulin use., Results: Of a total of 1,893,057 participants, 1,846 (0.10%) cases of gliomas occurred. After adjusting for confounding factors, WC ≥90 cm (men)/85 cm (women) was associated with significantly higher risks of gliomas (adjusted HR [95% CI]; 1.279 [1.053, 1.554], 1.317 [1.048, 1.655], and 1.369 [1.037, 1.807] in the WC <95 cm (men)/90 cm (women) group, WC <100 cm (men)/95 cm (women) group, and WC ≥100 cm (men)/95 cm (women) group, respectively). Subgroup analysis showed that patients with larger WC had a consistently higher incidence of glioma than their lean counterparts, except for insulin users (insulin user vs. nonuser, P for interaction = .03)., Conclusions: Abdominal obesity was associated with the development of gliomas in diabetic patients in a nationwide population-based database. Further study is needed in diabetic patients to stratify the risk for glioma development according to WC and to establish the underlying mechanism of carcinogenesis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Obesity is associated with an increased risk of developing type 2 diabetes mellitus (T2DM) and end-stage renal disease (ESRD). This study aimed to examine the effect of waist circumference (WC) on the risk for ESRD based on glycaemic status in a Korean population-based sample., Methods: This cohort study with a 9.2-year follow-up period used a population-based National Health Insurance Service health checkup database with approximately 10 585 852 participants who were followed up from 2009 to the time of ESRD diagnosis. WC was categorized into seven levels in 5-cm increments, with Level 4 as the reference group. Glycaemic status was categorized into the following groups: normal fasting glucose (NFG), impaired fasting glucose (IFG), newly diagnosed T2DM, T2DM treated with ≤2 oral hypoglycaemic agents (OHAs) and diabetes treated with ≥3 OHAs or insulin. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for ESRD according to WC values and glycaemic status of the participants., Results: The study finally included 10 177 245 patients with a mean age of 47.1 (13.8) years. The study population included 5 604 446 men (55.1%) and 4 572 799 women (45.9%). In total, 8.3% (n = 877 143) of the study population had diabetes. During the mean follow-up of 9.2 (1.0) years (93 554 951 person-years of follow-up), 23 031 individuals were newly diagnosed with ESRD. The ESRD risk increased in parallel with an increase in WC in participants without T2DM, that is, the NFG and IFG groups (adjusted HRs [95% CIs] of WC Levels 4, 5 and 6: 1.17 [1.09-1.26], 1.37 [1.25-1.51] and 1.84 [1.63-2.07] in the NFG group and 1.06 [0.97-1.16], 1.23 [1.10-1.38] and 1.80 [1.57-2.06] in the IFG group, respectively). In patients with T2DM, the risk for ESRD was significantly increased in those with a low WC (adjusted HRs [95% CIs] of WC Level 1: 2.23 [1.77-2.80], 3.18 [2.70-3.74] and 10.31 [9.18-11.59] in patients with newly diagnosed diabetes, patients on ≤2 OHAs and those on ≥3 OHAs or insulin, respectively). The association between WC and ESRD thus showed a J-shaped pattern in patients with newly diagnosed T2DM and a U-shaped pattern in those on ≤2 OHAs and on ≥3 OHAs or insulin., Conclusions: Central obesity substantially increases the risk of developing ESRD regardless of glycaemic status. The harmful effects of low WC only become significant with the progression of T2DM., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Purpose: Myosteatosis, which is associated with a variety of cardiometabolic illnesses, represents muscle quality, an important aspect of sarcopenia. A new laboratory marker for myosteatosis has been required to more readily identify it. We investigated whether serum gamma-glutamyl transferase (GGT) levels are associated with myosteatosis measured by computed tomography (CT)., Methods: The total abdominal muscle area (TAMA) of 13,452 subjects was measured at the L3 level with abdominal CT. TAMA was segmented into intramuscular adipose tissue and skeletal muscle area (SMA), which was further classified into normal attenuation muscle area (NAMA) and low attenuation muscle area (LAMA). The following variables were adopted as indicators of myosteatosis: SMA/body mass index (BMI), NAMA/BMI, LAMA/BMI, and NAMA/TAMA. Logistic regression analysis was used to examine the odds ratio (OR) of each GGT quartile for the highest quartile of myosteatosis indices in each sex., Results: The mean age and serum GGT levels were 53.7 years and 32.8 IU/L (standard deviation [SD], 37.6), respectively, in men, and 53.2 years and 18.4 IU/L (SD, 19.8) in women. In both sexes, the ORs of all myosteatosis indices differed significantly between GGT quartiles. Indices of good- and poor-quality muscle were negatively and positively correlated with GGT levels, respectively., Conclusion: Higher GGT levels were significantly associated with advanced myosteatosis defined by reliable CT indices. This result opens the possibility for using GGT as a cost-effective indicator of myosteatosis. Further prospective research on changes to GGT levels with myosteatosis alleviation will validate GGT as a monitoring marker., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier Inc.)

Background: Elevated remnant cholesterol (remnant-C) is considered a risk factor for cardiovascular disease (CVD); however, whether this notion applies to the East Asian population with type 2 diabetes (T2D) has not been established. This study investigated the association between remnant-C concentrations and the risk of CVD in Korean patients with T2D., Methods: By using the Korean National Health Insurance Service database, 1,956,452 patients with T2D and without atherosclerotic CVD who underwent regular health checks between 2009 and 2012 were included. Cox regression analyses were conducted to assess the association between remnant-C concentrations and incident CVD comprising myocardial infarction (MI) and ischemic stroke., Results: In total, 50,120 (2.56%) cases of MI and 73,231 (3.74%) cases of ischemic strokes occurred during a median follow-up of 8.1 years. The adjusted hazard ratios for MI and stroke in the highest remnant-C quartile were 1.281 (95% confidence interval [CIs], 1.249-1.314) for MI and 1.22 (1.195-1.247) for ischemic stroke, compared to those in the lowest quartiles. The results were similar, based on stratified analysis by age, sex, use of statin or fibrate, and levels of other cholesterol. The increased risk of CVD in the highest remnant-C quartile was profound in patients who had a longer T2D duration. A remnant-C concentration ≥ 30 mg/dL differentiated patients who were at a higher risk of CVD, compared to patients with a lower concentrations, regardless of whether LDL-C levels were or were not on target at ≤ 100 mg/dL., Conclusion: In Korean patients with T2D, remnant-C was associated with CVD, independent of the LDL-C level or other conventional CVD risk factors. Our finding confirmed evidence of the causal role of remnant-C on CVD, as a residual risk of CVD, in East Asian patients with T2D., (© 2022. The Author(s).)

Introduction: Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease requiring lifelong treatment, and durable medication is essential for maintaining stable glycemic control. This study aimed to evaluate the long-term efficacy of dulaglutide in participants who have continued the drug for more than one year., Methods: We conducted a retrospective study on 605 participants, who used dulaglutide for over one year between 2016 and 2020. Changes in glycosylated hemoglobin (HbA1c), fasting plasma glucose, and bodyweight from baseline to last prescription day were assessed. Adherence was evaluated by the proportion of days covered (PDC), and a PDC value ≥ 0.80 was considered adherent., Results: The mean age was 54.0 ± 11.1 years, and 46.1% were female. The mean baseline HbA1c, bodyweight, and duration of diabetes were 8.8% (72.7 mmol/mol), 75.6 kg, and 12.2 years, respectively. During the mean follow-up of 33.1 months, HbA1c and bodyweight decreased by 1.28% (14 mmol/mol, P &lt; 0.001) and by 3.19 kg (P &lt; 0.001), respectively. The participants were highly adherent with PDC ≥ 0.80 in 92.4% of the participants., Conclusion: In T2DM patients, long-term dulaglutide treatment was effective in maintaining HbA1c and weight reduction. Dulaglutide could be a favorable option of long-term treatment in real-world clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Cho, Kim, Jung, Park and Lee.)

Purpose: This study evaluated the association between metabolic health status and incident kidney cancer among obese participants., Materials and Methods: A total of 514,866 individuals were included from the Korean National Health Insurance Service-National Health Screening Cohort. Changes in metabolic health status and obesity from the baseline examination in 2009-2010 to the next biannual examination in 2011-2012 were determined. Based on the status change, obese participants were divided into four groups: stable metabolically healthy obesity, metabolically healthy obesity to metabolically unhealthy obesity, metabolically unhealthy obesity to metabolically healthy obesity, and stable metabolically unhealthy obesity., Results: The stable metabolically healthy obesity phenotype did not confer an increased risk of incident kidney cancer, compared to the stable metabolically healthy non-obese group. In contrast, the metabolically healthy obesity to metabolically unhealthy obesity group had a significantly higher risk of incident kidney cancer than the stable metabolically healthy non-obese group. Among patients with metabolically unhealthy obesity at baseline, those who transitioned to the metabolically healthy obese group had no increased risk of kidney cancer, whereas those who remained in metabolically unhealthy obesity status had a higher risk of incident kidney cancer than the stable metabolically healthy non-obese group. The transition or maintenance of metabolic health was a decisive factor for kidney cancer in obese patients., Conclusions: Maintaining or restoring metabolic health should be stressed upon in obese patients to reduce the risk of kidney cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cho, Kim, Park, Lee, Kim and Jung.)

The increasing prevalence of obesity is a worldwide health concern. Although obesity primarily affects the development of cardiometabolic disorders, it has also been closely linked to chronic kidney disease (CKD). However, potential causal relationships between obesity and CKD remain unclear, as obesity and CKD share a number of common risk factors. Accordingly, the risk of incident CKD in obese people without metabolic abnormalities, also called "metabolically healthy obesity" (MHO), has been a matter of interest. Recent investigations found that MHO was related to increased risk of incident CKD; however, the conclusions were based primarily on the static state. According to previous publications, approximately one-half of people initially identified as MHO became metabolically unhealthy, while one-tenth reduced their body weight to normal range while remaining metabolically healthy. It is essential to consider these transitions in obese-metabolic health status when analyzing obesity-related outcomes. This review discusses research on obesity and metabolic health in patients with CKD. Furthermore, we summarize recent reports on the implications of obesity and metabolic health in CKD and discuss the possible mechanisms of their relationship with CKD.

Although obesity is commonly associated with numerous cardiometabolic pathologies, some people with obesity are resistant to detrimental effects of excess body fat, which constitutes a condition called "metabolically healthy obesity" (MHO). Metabolic features of MHO that distinguish it from metabolically unhealthy obesity (MUO) include differences in the fat distribution, adipokine types, and levels of chronic inflammation. Murine models are available that mimic the phenotype of human MHO, with increased adiposity but preserved insulin sensitivity. Clinically, there is no established definition of MHO yet. Despite the lack of a uniform definition, most studies describe MHO as a particular case of obesity with no or only one metabolic syndrome components and lower levels of insulin resistance or inflammatory markers. Another clinical viewpoint is the dynamic and changing nature of MHO, which substantially impacts the clinical outcome. In this review, we explore the pathophysiology and some murine models of MHO. The definition, variability, and clinical implications of the MHO phenotype are also discussed. Understanding the characteristics that differentiate people with MHO from those with MUO can lead to new insights into the mechanisms behind obesity-related metabolic derangements and diseases.

Background: This study assesses the prognostic value of the triglyceride-glucose (TyG) index for cardiovascular (CV) risk in subgroups based on metabolic health and obesity status., Methods: Originally, 514,866 participants were enrolled from the Korean National Health Insurance Service-National Health Screening Cohort. The study participants were categorized into four groups: metabolically healthy non-obese (MHNO), metabolically unhealthy non-obese (MUNO), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). The TyG index was calculated using the following formula: ln (fasting triglyceride [mg/dL]×fasting plasma glucose [mg/dL]/2). Participants were followed from 2009 to 2015 for CV events and CV mortality according to the TyG index., Results: After exclusions, the final study cohort contained 292,206 people. During the follow-up, 9,138 CV events and 1,163 CV deaths were documented. When the high and low TyG groups were compared, the high TyG group had a substantially increased risk of CV events among the MUNO and MUO participants (multivariable-adjusted hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.07-1.30 and 1.27 [1.14-1.42], respectively). In participants with MUO status, CV mortality was also significantly increased in the high TyG group compared with the corresponding low TyG group (multivariable-adjusted HR, 1.48; 95% CI, 1.13-1.93). In contrast, a high TyG index was not related to CV mortality in the MHNO, MHO, and MUNO groups., Conclusion: The predictive value of the TyG index can vary across populations. Among MUO participants, the TyG index was significantly and positively correlated with unfavorable CV outcomes.

Background: The atherogenic index of plasma (AIP) is composed of triglycerides and high-density lipoprotein cholesterol and is a novel marker for assessing the risk of atherogenicity and cardiometabolic health. An association between AIP and greater frequency of major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus and high cardiovascular (CV) disease risk has been reported. However, only few studies have examined the correlation between AIP and CV risk in general populations. We thus aimed to evaluate the relationship between AIP and CV diseases using a large-scale population dataset from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS)., Methods: A total of 514,866 participants were enrolled from the NHIS-HEALS and classified according to the AIP quartiles. We performed univariate and multivariate Cox proportional hazards regression analyses to determine the association between AIP and MACEs, CV events, and CV mortality., Results: During follow-up, we documented 12,133, 11,055, and 1942 cases of MACEs, CV events, and CV mortality, respectively. The multivariate-adjusted hazard ratios [HRs; 95% confidence interval (CI)] for MACEs gradually and significantly increased with the AIP quartiles [1.113 (1.054-1.175) in Q2, 1.175 (1.113-1.240) in Q3, and 1.278 (1.209-1.350) in Q4], following an adjustment for the conventional CV risk factors, including age, sex, body mass index, smoking, alcohol drinking, physical activities, household income, fasting glucose, systolic blood pressure, low-density lipoprotein cholesterol, and estimated glomerular filtration rate. In subgroup analyses, the association of AIP with MACEs and CV events was particularly outstanding in patients with diabetes., Conclusions: AIP was significantly associated with CV risks after adjusting for the traditional risk factors. Therefore, it may be used as an effective mass screening method to identify patients at a high risk of CV events., (© 2022. The Author(s).)

Objective: The triglyceride-glucose (TyG) index, the product of fasting triglycerides and glucose, is a useful and cost-effective marker of insulin resistance (IR). Furthermore, the TyG index is a known IR screening tool in healthy young adults but not in those with atherosclerotic cardiovascular disease (CVD). Thus, this study aimed to evaluate the TyG index as a predictor of CVD in healthy young adults., Methods: This study enrolled 6,675,424 adults aged 20-39 years without CVD from the National Health Information Database. We categorized them by TyG index quartile from 2009-2017. The study outcomes were stroke, myocardial infarction (MI), and mortality. All outcomes were analyzed by Cox proportional hazards regression analysis while controlling for baseline covariates., Results: During a mean 7.4 years of follow-up, 8,506 cases of stroke, 12,312 cases of MI, and 22,667 deaths were recorded. Multivariable-adjusted hazard ratios (HRs) for participants in the highest TyG index quartile demonstrated that they were at higher risk for stroke (HR, 1.253; 95% confidence interval [CI], 1.167-1.346), MI (HR, 1.258; 95% CI, 1.187-1.334), and mortality (HR, 1.151; 95% CI, 1.104-1.200) than those in the lowest TyG index quartile independent of age, sex, smoking, alcohol consumption, physical activity, income, body mass index, blood pressure, and total cholesterol. The HRs for outcomes in the highest quartiles were higher when the TyG index was applied than when triglyceride or fasting glucose alone was applied., Conclusion: TyG index, a simple measure reflecting IR, can predict CVD and mortality in young and healthy populations., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (Copyright © 2022 The Korean Society of Lipid and Atherosclerosis.)

Background & Aims: Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear., Methods: We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n -octylphenyl)ethyl]-1,3- propanediol hydrochloride)-like sphingolipid-focused library., Results: The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1pr4. Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1pr4 +/- mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca ++ release and deactivated the Nod-like receptor pyrin domain-containning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate-receptor-dependent [Ca ++ ] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1pr4 +/- mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome., Conclusions: S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to evaluate the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors for managing obesity in non-diabetic overweight or obese patients., Methods: For purposes of this study, PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched through May 2021. Randomized controlled trials published in English that compared SGLT2 inhibitors with placebo in overweight and obese patients without diabetes were included in the primary analysis. The random effects standardized mean difference ±95% confidence interval (95% CI) was calculated as the effect size., Results: Five randomized controlled trials were included to evaluate body weight change, four trials to assess body mass index (BMI), and three trials to assess waist circumference were included. Results showed that the mean body weight loss on SGLT2 inhibitors in obese patients without diabetes was -1.62 kg (95% CI, -2.38 to -0.85 kg) when compared with placebo. Treatment with SGLT2 inhibitors was also associated with a greater reduction in BMI than placebo (weighted mean difference, -0.47 kg/m 2 ; 95% CI, -0.62 to -0.31 kg/m 2 ). The mean reduction in waist circumference with SGLT2 inhibitors versus placebo was 1.29 cm (95% CI, -2.62 to 0.04 cm), which was not statistically significant. There were no significant changes in fat mass, blood pressure, low-density lipoprotein cholesterol or high-density lipoprotein cholesterol with SGLT2 inhibitor treatment., Conclusion: A meta-analysis demonstrated that although the weight lowering effect was mild, SGLT2 inhibitors significantly reduced body weight in obese patients without diabetes.

The triglyceride glucose (TyG) index has been suggested as a marker for insulin resistance; however, few studies have investigated the clinical implications of markers that combine obesity markers with the TyG index. This study aimed to investigate the associations between non-alcoholic fatty liver disease (NAFLD) and TyG-related markers in healthy subjects in Korea. We enrolled 21,001 asymptomatic participants who underwent hepatic ultrasonography. The homeostasis model assessment of insulin resistance (HOMA-IR), TyG index, TyG-body mass index, and TyG-waist circumference (WC) were subsequently analyzed. NAFLD was diagnosed using hepatic ultrasonography. A multiple logistic regression analysis was performed to evaluate the associations between the quartiles of each parameter and the risk of NAFLD. The increase in the NAFLD risk was most evident when the TyG-WC quartiles were applied; the multivariate-adjusted odds ratios for NAFLD were 4.72 (3.65-6.10), 13.28 (10.23-17.24), and 41.57 (31.66-54.59) in the 2nd, 3rd, and 4th TyG-WC quartiles, respectively, when compared with the lowest quartile. The predictability of the TyG-WC for NAFLD was better than that of the HOMA-IR using the area under the curve. The TyG-WC index was superior to the HOMA-IR for identifying NAFLD in healthy Korean adults, especially in the non-obese population.

Background: Metabolically healthy obese (MHO) phenotype is metabolically heterogeneous in terms of type 2 diabetes (T2D). Previously, the triglyceride and glucose (TyG) index has been considered for identifying metabolic health and future risk of T2D. This study aimed to evaluate the risk of incident T2D according to obesity status and metabolic health, categorized by four different criteria and the TyG index., Methods: The study included 39,418 Koreans without T2D at baseline. The risk of T2D was evaluated based on four different definitions of metabolic health and obesity status and according to the baseline TyG index within each metabolic health and obesity group., Results: During the median follow-up at 38.1 months, 726 individuals developed T2D. Compared with the metabolically healthy non-obese (MHNO) group with low TyG index, the MHO group with high TyG index showed increased risk of T2D in all four definitions of metabolic health with multivariate-adjusted hazard ratios of 2.57 (95% confidence interval [CI], 1.76 to 3.75), 3.72 (95% CI, 2.15 to 6.43), 4.13 (95% CI, 2.67 to 6.38), and 3.05 (95% CI, 2.24 to 4.15), when defined by Adult Treatment Panel III, Wildman, Karelis, and homeostasis model assessment (HOMA) criteria, respectively., Conclusion: MHO subjects with high TyG index were at an increased risk of developing T2D compared with MHNO subjects, regardless of the definition of metabolic health. TyG index may serve as an additional factor for predicting the individual risk of incident T2D in MHO subjects.

Objective: Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH., Design: Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4)., Results: HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis., Conclusion: SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We evaluated the association of metabolic health and obesity phenotypes with the risk of Alzheimer's disease (AD). This study enrolled 136,847 elderly participants aged 60 or above from the Korean National Health Insurance System. At baseline examinations in 2009 and 2010, subjects were categorized into four groups: the metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO) groups. Based on the phenotypic transition after 2 years, the subjects were further categorized into 16 subgroups. They were followed from 2009 to 2015 to monitor for AD development. The MHO phenotype protected subjects from AD, relative to the MHNO phenotype (HR, 0.73; 95% CI, 0.65-0.81). Among subjects initially classified as MHO, 41.8% remained MHO, with a significantly lower risk of AD compared with the stable MHNO group (HR, 0.62; 95% CI, 0.50-0.77). Among MUO subjects at baseline, those who changed phenotype to MUNO were at higher risk of AD (HR, 1.47; 95% CI, 1.28-1.70), and the transition to the MHO phenotype protected subjects from AD (HR, 0.62; 95% CI, 0.50-0.78). The MHO phenotype conferred a decreased risk of AD. Maintenance or recovery of metabolic health might mitigate AD risk among obese individuals.

Background: Metabolically healthy obese (MHO) individuals and their association with cardiometabolic diseases have remained controversial. We aimed to explore the risk of incident heart failure (HF) based on the baseline metabolic health and obesity status as well as their transition over 2 years., Methods: The Korean National Health Insurance Service-National Health Screening Cohort data of 514,886 participants were analyzed. Obesity was defined as BMI ≥25 kg/m 2 according to the Korean Centers for Disease Control and Prevention. The metabolic health and obesity status were evaluated at baseline and after two years. Study participants were followed to either the date of newly diagnosed HF or the last follow-up visit, whichever occurred first., Results: The MHO group comprised 9.1% of the entire population and presented a better baseline metabolic profile than the metabolically unhealthy non-obese (MUNO) and metabolicavlly unhealthy obese (MUO) groups. During the median 71.3 months of follow-up, HF developed in 5,406 (1.5%) participants. The adjusted hazard ratios [HRs (95% CI)] of HF at baseline compared with the metabolically healthy non-obese (MHNO) group were 1.29 [1.20-1.39], 1.37 [1.22-1.53], and 1.63 [1.50-1.76] for MUNO, MHO, and MUO groups, respectively. With the stable MHNO group as reference, transition into metabolically unhealthy status (MUNO and MUO) increased the risk of HF, regardless of the baseline status. Subjects who were obese at both baseline and follow-up showed an increased risk of HF, regardless of their metabolic health status., Conclusions: Metabolic health and obesity status and their transition can predict the risk of incident HF. Losing metabolic health in baseline non-obese and obese individuals and remaining obese in baseline obese individuals showed a significantly increased risk of incident HF. Maintaining good metabolic health and a lean body may prevent the development of HF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kim, Lee, Cho, Park, Lee, Kim and Jung.)

Autophagy is an important process in the pathogenesis of atherosclerosis. C1q/tumor necrosis factor-related protein 9 (CTRP9) is the closest adiponectin paralog. CTRP9 has anti-aging and anti-atherogenic effects, but its roles in autophagy and endothelial senescence are currently unknown. This study aimed to evaluate whether CTRP9 prevents palmitic acid (PA)-induced endothelial senescence by promoting autophagy. After no treatment or pre-treatment of human umbilical vein endothelial cells with CTRP9 prior to PA treatment, the level of senescence was measured by senescence associated acidic β-galactosidase staining and the level of hyperphosphorylated pRB protein. Autophagy was evaluated by LC3 conversion and the level of p62/SQSTM1, a protein degraded during autophagy. Autophagosome-lysosome fusion was detected by fluorescence microscopy. Pre-treatment with CTRP9 attenuated PA-induced endothelial senescence. CTRP9 increased the conversion of LC3-I to LC3-II and decreased p62 levels in a time- and dose-dependent manner. Although both CTRP9 and PA treatment increased LC3 conversion, treatment with PA increased the expression level of p62 and decreased the fusion of autophagosomes and lysosomes, which represented decreased autophagic flux. However, pre-treatment with CTRP9 recovered the autophagic flux inhibited by PA. AMP-activated kinase (AMPK) activation was involved in LC3 conversion and decreased p62 levels induced by CTRP9. CTRP9 inhibits PA-induced endothelial senescence by recovering autophagy and autophagic flux through AMPK activation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The association of the risk of colorectal cancer (CRC) with obesity or obesity-induced metabolic disturbances remains controversial. We assessed the association of metabolic health status with incident CRC among subjects with obesity., Methods: This study included 319,397 subjects from the Korean National Health Insurance Service-National Health Screening Cohort. Transitions in metabolic health status and obesity were examined during 2009-2010 and 2011-2012. We categorized subjects with obesity into four separate groups according to their dynamic metabolic health status: metabolically healthy obesity (MHO), MHO to metabolically unhealthy obesity (MUO), MUO to MHO, and stable MUO. Subjects were followed up from 2009 to 2015 for incident CRC., Results: The stable MHO group showed no increased risk of incident CRC (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.83-1.14). However, the MHO to MUO group had a higher risk of incident CRC than the stable metabolically healthy nonobese (MHNO) group (HR, 1.34; 95% CI, 1.15-1.57). Among patients with MUO at baseline, those in the subgroup who transitioned to MHO group were not at increased risk of CRC (HR, 1.06; 95% CI, 0.91-1.25), whereas those who remained in the stable MUO group had a higher risk of incident CRC than those in the stable MHNO group (HR, 1.29; 95% CI, 1.19-1.41)., Conclusions: The transition of metabolic health was a determining factor for CRC among subjects with obesity. Hence, maintenance or recovery of metabolic health should be addressed to prevent CRC in individuals with obesity., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The triglyceride glucose (TyG) index, a product of triglyceride and fasting glucose, is a reliable marker for insulin resistance. We aimed to investigate the association between the TyG-related markers and coronary artery calcification (CAC) progression. We enrolled 1145 asymptomatic participants who underwent repeated CAC score measurements during routine health examinations. Homeostasis model assessment of insulin resistance (HOMA-IR), TyG index, TyG-BMI (body mass index), and TyG-WC (waist circumference) were calculated. Progression of CAC was defined as (1) incident CAC in a CAC-free population, or an (2) increase of ≥2.5 units between the baseline and final square root of the CAC scores in participants with detectable CAC. According to the quartiles of parameters, we stratified the subjects into four groups. The prevalence of progression increased with the TyG-WC quartile (15.0%, 24.1%, 31.0%, and 32.2% for each of the groups; p < 0.001). The multivariate-adjusted odds ratio (95% confidence interval) for CAC score progression was 1.66 (1.01-2.77) when the highest and lowest TyG-WC index quartiles were compared. Furthermore, the predictability of TyG-WC for CAC progression was better than the other indices in terms of the area under the curve. The TyG-WC index predicted CAC progression better than other indices and could be a potential marker of future coronary atherosclerosis.

Background/aim: Heat shock protein 90 (HSP90) controls maturation of oncogenic client proteins of cancer cells, and thus we studied the effect of HSP 90 inhibitors on cell survival and survival-related mediators in thyroid carcinoma cells., Materials and Methods: Human TPC-1 and SW1736 thyroid carcinoma cells were utilized. Cell viability, cytotoxic activity and apoptosis were estimated using CCK-8 assay, cytotoxicity assay and FACS analysis, respectively., Results: AUY922, BIIB021 and SNX5422 decreased cell viability, and increased cytotoxic activity and the proportion of apoptotic cells. The protein levels of cleaved PARP, cleaved caspase-3, Bax and Bim were elevated, and Bcl2 protein levels were reduced. Knockdown of Bax did not change cell viability, cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. Meanwhile, knockdown of Bim enhanced cell viability, and diminished cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. AUY922, BIIB021 and SNX5422 increased the protein levels of phospho-AMPK, and decreased those of phospho-ERK1/2, and total and phospho-AKT., Conclusion: AUY922, BIIB021 and SNX5422 induce cytotoxicity by modulating Bim and ERK1/2, AKT and AMPK signaling in thyroid carcinoma cells., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Advanced liver fibrosis and coronary artery calcification (CAC) progression has been reported to correlate with cardiovascular disease. This study investigated the association between noninvasive liver fibrosis score and CAC progression in patients with nonalcoholic fatty liver disease (NAFLD). We included 1173 asymptomatic adults with CAC scores from 2007-2013. CAC progression was defined as newly incident CAC or a ≥ 2.5-unit increase in the final CAC score square root. Liver fibrosis was assessed using fibrosis-4 index (FIB-4) score and NAFLD fibrosis score (NFS). A total of 293 (25.0%) subjects developed CAC. Mean baseline FIB-4 score was significantly higher in subjects with CAC. CAC progressed in 20.5% of subjects without NAFLD, 27.5% of those with NAFLD and low FIB-4 scores, and 35.9% of those with NAFLD and intermediate/high FIB-4 scores. On multivariate logistic regression analysis, the odds ratio for CAC progression was 1.70 (95% confidence interval, 1.12-2.58) for subjects with NAFLD plus intermediate/high FIB-4 scores versus those without NAFLD. In the sensitivity analysis, the odds ratio for CAC progression was 1.57 (95% confidence interval, 1.02-2.44) for subjects with NAFLD plus an intermediate/high NFS versus those without NAFLD. Advanced liver fibrosis stage assessed using noninvasive markers is associated with a higher risk of CAC progression in subjects with NAFLD.

Introduction: We aimed to evaluate the effectiveness of quadruple oral therapy in patients with inadequately controlled type 2 diabetes (T2D) with the use of three types of oral hypoglycemic agents., Methods: Medical records of 318 patients with T2D who were prescribed quadruple therapy in the Asan Medical Center were reviewed. Changes in glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels from baseline were assessed. The regimens of quadruple oral therapy included the following: (1) thiazolidinedione (TZD) add-on to metformin (MET) + sulfonylurea (SU) + dipeptidyl peptidase 4 inhibitor (DPP4i), (2) sodium-glucose cotransporter 2 inhibitor (SGLT2i) add-on to MET + SU + DPP4i, and (3) DPP4i add-on to MET + SU + TZD., Results: The TZD add-on significantly reduced HbA1c levels by 1.1% (from 9.0 ± 1.1 to 7.9 ± 1.1%, P < 0.001) and FPG levels by 41.4 mg/dL (from 188.9 ± 45.9 to 147.4 ± 51.3 mg/dL, P < 0.001). The SGLT2i add-on changed the mean HbA1c level from 8.9 ± 1.0 to 7.8 ± 1.0%, a reduction of 1.1% (P < 0.001) and changed the mean FPG level from 193.4 ± 46.2 to 152.6 ± 37.0 mg/dL, a reduction of 40.8 mg/dL (P < 0.001). Finally, the DPP4i add-on reduced HbA1c levels by 1.3% (from 9.1 ± 1.3 to 7.8 ± 1.4%, P < 0.001) and FPG levels by 39.3 mg/dL (from 190.7 ± 45.3 to 151.4 ± 41.6 mg/dL, P < 0.001). Patients with higher baseline HbA1c levels (≥ 9.0%) showed a better response to quadruple therapy than those with baseline HbA1c levels lower than 9.0% for all three regimens., Conclusion: Quadruple oral hypoglycemic therapy can be a feasible option in patients with T2D.

Background/aims: The use of complementary and alternative medicine (CAM) is a global phenomenon, including inflammatory bowel disease (IBD) patients. We aimed to assess the change in prevalence and patterns of CAM use, and attitudes towards CAM over an 8-year time interval (2006 vs. 2014) among IBD patients in Korea., Methods: A total of 221 IBD patients (CD=142, UC=79) were asked to complete a questionnaire regarding CAM at two time points: at enrollment (2006) and 8 years later (2014/2015)., Results: The proportion of patients ever using CAM increased significantly from 60.2% in 2006 to 79.6% in 2014 (P<0.001), while the proportion of current CAM users increased slightly (35.7% to 38.0%, P=0.635); 21.7% used CAM consistently at both time points. The proportion of patients who felt CAM was less effective (P<0.001) and more expensive (P=0.04) than conventional treatments increased over time. Also, the proportion among ever CAM users who perceived a positive effect from CAM significantly decreased in 2014 compared to 2006 (P=0.004). Higher education (adjusted odds ratio [aOR], 2.10), prior side effects to conventional therapies (aOR, 2.23), and prior use of corticosteroids (aOR, 2.51) were associated with CAM use. Interestingly, use of CAM before IBD diagnosis (aOR, 2.73) was significantly associated with consistent CAM use., Conclusions: Although the attitudes toward CAM have become less favorable, the majority of IBD patients have experienced CAM with an overall increase of current CAM users over time. Moreover, more than half of current CAM users used CAM consistently over time.

Context: Metabolically healthy obesity (MHO) is a dynamic condition., Objective: To evaluate the risk of chronic kidney disease (CKD) among people with MHO according to its longitudinal change., Design: Observational study., Setting: A nationwide population-based cohort., Participants: A total of 514 866 people from the Korean National Health Insurance Service-National Sample Cohort., Intervention: The initial presence and changes of obesity (using body mass index [BMI] and waist circumference [WC]) and metabolic health status., Main Outcome Measure: Incident CKD from 2011 to 2015., Results: Of the people classified as MHO at baseline (BMI criteria), 47.6% remained as MHO in 2011 and 2012, whereas 12.1%, 5.5%, and 34.8% were classified as metabolically healthy, non-obese (MHNO), metabolically unhealthy, non-obese, and metabolically unhealthy, obese, respectively. The risk of incident CKD in the baseline MHO group was higher than that in the MHNO group (hazard ratio, 1.23; 95% confidence interval, 1.12-1.36). However, when transition was taken into account, people who converted to MHNO were not at increased risk (hazard ratio, 0.98; 95% confidence interval, 0.72-1.32), whereas the stable MHO group and the groups that evolved to metabolically unhealthy status had a higher risk of incident CKD than the stable MHNO group. When the risk was analyzed using WC criteria, it showed a similar pattern to BMI criteria except for the stable MHO group., Conclusions: MHO was a dynamic condition, and people with MHO constituted a heterogeneous group. Although the MHO phenotype was generally associated with incident CKD, maintenance of metabolic health and weight reduction might alleviate the risk of CKD., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

X-linked adrenoleukodystrophy (X-ALD) occurs due to mutations in the ABCD1 gene that encodes the peroxisomal membrane protein peroxisomal transporter ATP-binding cassette sub-family D member 1 (ABCD1). Degradation of very long-chain fatty acids in peroxisomes is impaired owing to ABCD dysfunction, subsequently leading to adrenomyeloneuropathy, cerebral adrenoleukodystrophy, and adrenal insufficiency. X-ALD frequently induces idiopathic Addison's disease in young male patients. Here, we confirmed the diagnosis of X-ALD in a young male patient with primary adrenal insufficiency, and identified a novel ABCD1 gene mutation (p.Trp664*, c.1991 G>A)., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020 Korean Endocrine Society.)