Endocrinology and Metabolism

Original Articles

Diabetes, obesity and metabolism
Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells: Seok-Woo Hong, Jinmi Lee, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2024;39(2):353-363. Published online January 23, 2024; DOI: https://doi.org/10.3803/EnM.2023.1809

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Abstract PDF Supplementary Material PubReader ePub: Background
Polyunsaturated fatty acids (PUFAs) reportedly have protective effects on pancreatic β-cells; however, the underlying mechanisms are unknown.
Methods
To investigate the cellular mechanism of PUFA-induced cell protection, mouse insulinoma 6 (MIN6) cells were cultured with palmitic acid (PA) and/or docosahexaenoic acid (DHA), and alterations in cellular signaling and apoptosis were examined.
Results
DHA treatment remarkably repressed caspase-3 cleavage and terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL)-positive red dot signals in PA-treated MIN6 cells, with upregulation of autophagy, an increase in microtubule- associated protein 1-light chain 3 (LC3)-II, autophagy-related 5 (Atg5), and decreased p62. Upstream factors involved in autophagy regulation (Beclin-1, unc51 like autophagy activating kinase 1 [ULK1], phosphorylated mammalian target of rapamycin [mTOR], and protein kinase B) were also altered by DHA treatment. DHA specifically induced phosphorylation on S2448 in mTOR; however, phosphorylation on S2481 decreased. The role of G protein-coupled receptor 120 (GPR120) in the effect of DHA was demonstrated using a GPR120 agonist and antagonist. Additional treatment with AH7614, a GPR120 antagonist, significantly attenuated DHA-induced autophagy and protection. Taken together, DHA-induced autophagy activation with protection against PA-induced apoptosis mediated by the GPR120/mTOR axis.
Conclusion
These findings indicate that DHA has therapeutic effects on PA-induced pancreatic β-cells, and that the cellular mechanism of β-cell protection by DHA may be a new research target with potential pharmacotherapeutic implications in β-cell protection.

Diabetes, obesity and metabolism
Inhibition of Sodium-Glucose Cotransporter-2 during Serum Deprivation Increases Hepatic Gluconeogenesis via the AMPK/AKT/FOXO Signaling Pathway: Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Yu-Mi Lim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2024;39(1):98-108. Published online January 3, 2024; DOI: https://doi.org/10.3803/EnM.2023.1786

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Abstract PDF Supplementary Material PubReader ePub: Background
Sodium-dependent glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in the renal proximal tubules, and SGLT2 inhibitors are used as therapeutic agents for treating type 2 diabetes mellitus. This study aimed to elucidate the effects and mechanisms of SGLT2 inhibition on hepatic glucose metabolism in both serum deprivation and serum supplementation states.
Methods
Huh7 cells were treated with the SGLT2 inhibitors empagliflozin and dapagliflozin to examine the effect of SGLT2 on hepatic glucose uptake. To examine the modulation of glucose metabolism by SGLT2 inhibition under serum deprivation and serum supplementation conditions, HepG2 cells were transfected with SGLT2 small interfering RNA (siRNA), cultured in serum-free Dulbecco’s modified Eagle’s medium for 16 hours, and then cultured in media supplemented with or without 10% fetal bovine serum for 8 hours.
Results
SGLT2 inhibitors dose-dependently decreased hepatic glucose uptake. Serum deprivation increased the expression levels of the gluconeogenesis genes peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), glucose 6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (PEPCK), and their expression levels during serum deprivation were further increased in cells transfected with SGLT2 siRNA. SGLT2 inhibition by siRNA during serum deprivation induces nuclear localization of the transcription factor forkhead box class O 1 (FOXO1), decreases nuclear phosphorylated-AKT (p-AKT), and p-FOXO1 protein expression, and increases phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK) protein expression. However, treatment with the AMPK inhibitor, compound C, reversed the reduction in the protein expression levels of nuclear p- AKT and p-FOXO1 and decreased the protein expression levels of p-AMPK and PEPCK in cells transfected with SGLT2 siRNA during serum deprivation.
Conclusion
These data show that SGLT2 mediates glucose uptake in hepatocytes and that SGLT2 inhibition during serum deprivation increases gluconeogenesis via the AMPK/AKT/FOXO1 signaling pathway.

Diabetes, obesity and metabolism
Coronary Artery Calcium Score as a Sensitive Indicator of Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus: A Long-Term Cohort Study: Dae-Jeong Koo, Mi Yeon Lee, Sun Joon Moon, Hyemi Kwon, Sang Min Lee, Se Eun Park, Cheol-Young Park, Won-Young Lee, Ki Won Oh, Sung Rae Cho, Young-Hoon Jeong, Eun-Jung Rhee; Endocrinol Metab. 2023;38(5):568-577. Published online October 10, 2023; DOI: https://doi.org/10.3803/EnM.2023.1770

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Abstract PDF Supplementary Material PubReader ePub: Background
Coronary artery calcium score (CACS) has become an important tool for evaluating cardiovascular disease (CVD). This study evaluated the significance of CACS for future CVD through more than 10 years of follow-up in asymptomatic Korean populations with type 2 diabetes mellitus (T2DM) known to have a relatively low CACS burden.
Methods
We enrolled 981 asymptomatic T2DM patients without CVD at baseline who underwent CACS evaluation using multidetector computed tomography between January 2008 and December 2014. They were grouped into five predefined CACS categories based on Agatston scores and followed up by August 2020. The primary endpoint was incident CVD events, including coronary, cerebrovascular, and peripheral arterial disease.
Results
The relative risk of CVD was significantly higher in patients with CACS ≥10, and the significance persisted after adjustment for known confounders. A higher CACS category indicated a higher incidence of future CVD: hazard ratio (95% confidence interval) 4.09 (1.79 to 9.36), 12.00 (5.61 to 25.69), and 38.79 (16.43 to 91.59) for 10≤ CACS <100, 100≤ CACS <400, and CACS ≥400, respectively. During the 12-year follow-up period, the difference in event-free survival more than doubled as the category increased. Patients with CACS below 10 had very low CVD incidence throughout the follow-up. The receiver operating characteristic analysis showed better area under curve when the CACS cutoff was 10 than 100.
Conclusion
CACS can be a sensitive marker of CVD risk. Specifically, CACS above 10 is an indicator of CVD high-risk requiring more intensive medical treatment in Koreans with T2DM.

Editorial

Thyroid
The Current Status of Hyperthyroidism in Korea: Hyemi Kwon; Endocrinol Metab. 2023;38(4):392-394. Published online August 25, 2023; DOI: https://doi.org/10.3803/EnM.2023.401

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Special Article

Miscellaneous
Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society: Hyemi Kwon, Eun Roh, Chang Ho Ahn, Hee Kyung Kim, Cheol Ryong Ku, Kyong Yeun Jung, Ju Hee Lee, Eun Heui Kim, Sunghwan Suh, Sangmo Hong, Jeonghoon Ha, Jun Sung Moon, Jin Hwa Kim, Mi-kyung Kim, The Committee of Clinical Practice Guideline of the Korean Endocrine Society; Endocrinol Metab. 2022;37(6):839-850. Published online December 26, 2022; DOI: https://doi.org/10.3803/EnM.2022.1627

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Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.

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Pembrolizumab plus lenvatinib for radically unresectable or metastatic renal cell carcinoma in the Japanese population
Ryo Fujiwara, Takeshi yuasa, kenichi kobayashi, tetsuya yoshida, susumu kageyama
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Incidence of Endocrine-Related Dysfunction in Patients Treated with New Immune Checkpoint Inhibitors: A Meta-Analysis and Comprehensive Review
Won Sang Yoo, Eu Jeong Ku, Eun Kyung Lee, Hwa Young Ahn
Endocrinology and Metabolism.2023; 38(6): 750. CrossRef

Original Articles

Diabetes, Obesity and Metabolism
Dulaglutide Ameliorates Palmitic Acid-Induced Hepatic Steatosis by Activating FAM3A Signaling Pathway: Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2022;37(1):74-83. Published online February 9, 2022; DOI: https://doi.org/10.3803/EnM.2021.1293

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Background
Dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has been shown to reduce body weight and liver fat content in patients with type 2 diabetes. Family with sequence similarity 3 member A (FAM3A) plays a vital role in regulating glucose and lipid metabolism. The aim of this study was to determine the mechanisms by which dulaglutide protects against hepatic steatosis in HepG2 cells treated with palmitic acid (PA).
Methods
HepG2 cells were pretreated with 400 μM PA for 24 hours, followed by treatment with or without 100 nM dulaglutide for 24 hours. Hepatic lipid accumulation was determined using Oil red O staining and triglyceride (TG) assay, and the expression of lipid metabolism-associated factor was analyzed using quantitative real time polymerase chain reaction and Western blotting.
Results
Dulaglutide significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells. However, exendin-(9-39), a GLP-1R antagonist, reversed the expression of FAM3A, and fatty acid oxidation-associated factors increased due to dulaglutide. In addition, inhibition of FAM3A by siRNA attenuated the reducing effect of dulaglutide on TG content and its increasing effect on regulation of fatty acid oxidation.
Conclusion
These results suggest that dulaglutide could be used therapeutically for improving nonalcoholic fatty liver disease, and its effect could be mediated in part via upregulation of FAM3A expression through a GLP-1R-dependent pathway.

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GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD
Haoran Jiang, Linquan Zang
Current Pharmaceutical Design.2024; 30(2): 100. CrossRef
GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives
Riccardo Nevola, Raffaella Epifani, Simona Imbriani, Giovanni Tortorella, Concetta Aprea, Raffaele Galiero, Luca Rinaldi, Raffaele Marfella, Ferdinando Carlo Sasso
International Journal of Molecular Sciences.2023; 24(2): 1703. CrossRef
FAM3A mediates the phenotypic switch of human aortic smooth muscle cells stimulated with oxidised low-density lipoprotein by influencing the PI3K-AKT pathway
Lei Yang, Baoshun Du, Shitao Zhang, Maode Wang
In Vitro Cellular & Developmental Biology - Animal.2023; 59(6): 431. CrossRef
ATP Secretion and Metabolism in Regulating Pancreatic Beta Cell Functions and Hepatic Glycolipid Metabolism
Jing Li, Han Yan, Rui Xiang, Weili Yang, Jingjing Ye, Ruili Yin, Jichun Yang, Yujing Chi
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Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)
Xiaohan Xu, Kyle L. Poulsen, Lijuan Wu, Shan Liu, Tatsunori Miyata, Qiaoling Song, Qingda Wei, Chenyang Zhao, Chunhua Lin, Jinbo Yang
Signal Transduction and Targeted Therapy.2022;[Epub] CrossRef

Diabetes, Obesity and Metabolism
Changes in Insulin Resistance Index and the Risk of Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease without Diabetes: Kangbuk Samsung Health Study: Dae-Jeong Koo, Mi Yeon Lee, Inha Jung, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2021;36(5):1016-1028. Published online October 21, 2021; DOI: https://doi.org/10.3803/EnM.2021.1110

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Background
Fibrosis is the most important prognostic factor for nonalcoholic fatty liver disease (NAFLD). Insulin resistance plays a key role of fibrosis progression. We evaluated the association between changes in homeostasis model assessment of insulin resistance (HOMA-IR) values and changes in fibrosis status in NAFLD.
Methods
We analyzed the data of 15,728 participants with NAFLD (86% men, mean age 40.5 years) who had no diabetes at baseline and visited our centers for health check-ups both in 2012 and 2016. The participants were classified into four groups according to the degree of change in HOMA-IR values from baseline to the end of follow-up: G1 (<0), G2 (0–0.50), G3 (0.51–1.00), and G4 (>1.00). NAFLD was assessed by ultrasonography, and fibrosis status was evaluated by the NAFLD fibrosis score (NFS) and the aspartate aminotransferase to platelet ratio index (APRI).
Results
After the 4-year follow-up, the multivariable-adjusted odds ratio (OR) for progression of fibrosis probability increased with increasing HOMA-IR values (OR, 2.25; 95% confidence interval [CI], 1.87 to 2.71 for NFS; and OR, 2.55; 95% CI, 2.05 to 3.18 for APRI, G4). This tendency remained consistent throughout the subgroup analyses, except in those for female sex and a body mass index <25 kg/m². The OR for regression of fibrosis probability decreased with increasing HOMA-IR values (OR, 0.33; 95% CI, 0.25 to 0.43 for NFS, G4).
Conclusion
Changes in HOMA-IR values were associated with changes in fibrosis status in patients with NAFLD without diabetes, which underscores the role of insulin resistance in liver fibrosis.

Citations

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Insulin Resistance/Sensitivity Measures as Screening Indicators of Metabolic-Associated Fatty Liver Disease and Liver Fibrosis
Mohammad E. Khamseh, Mojtaba Malek, Soodeh Jahangiri, Sohrab Nobarani, Azita Hekmatdoost, Marieh Salavatizadeh, Samira Soltanieh, Haleh Chehrehgosha, Hoda Taheri, Zeinab Montazeri, Fereshteh Attaran, Faramarz Ismail-Beigi, Fariba Alaei-Shahmiri
Digestive Diseases and Sciences.2024; 69(4): 1430. CrossRef
Association between nonalcoholic fatty liver disease and left ventricular diastolic dysfunction: A 7-year retrospective cohort study of 3,496 adults using serial echocardiography
Gyuri Kim, Tae Yang Yu, Jae Hwan Jee, Ji Cheol Bae, Mira Kang, Jae Hyeon Kim
Diabetes & Metabolism.2024; : 101534. CrossRef
Factors Associated with Liver Fibrosis in Chinese Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease
Yu Luo, Cuiyu Wang, Tian Zhang, Xiaoyu He, Jianan Hao, Andong Shen, Hang Zhao, Shuchun Chen, Luping Ren
International Journal of General Medicine.2023; Volume 16: 293. CrossRef
Impact of COVID-19 Lockdown on Non-Alcoholic Fatty Liver Disease and Insulin Resistance in Adults: A before and after Pandemic Lockdown Longitudinal Study
Ángel Arturo López-González, Bárbara Altisench Jané, Luis Masmiquel Comas, Sebastiana Arroyo Bote, Hilda María González San Miguel, José Ignacio Ramírez Manent
Nutrients.2022; 14(14): 2795. CrossRef
Metabolic Score for Insulin Resistance Is Inversely Related to Incident Advanced Liver Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease
Jun-Hyuk Lee, Yu-Jin Kwon, Kyongmin Park, Hye Sun Lee, Hoon-Ki Park, Jee Hye Han, Sang Bong Ahn
Nutrients.2022; 14(15): 3039. CrossRef
Machine learning models including insulin resistance indexes for predicting liver stiffness in United States population: Data from NHANES
Kexing Han, Kexuan Tan, Jiapei Shen, Yuting Gu, Zilong Wang, Jiayu He, Luyang Kang, Weijie Sun, Long Gao, Yufeng Gao
Frontiers in Public Health.2022;[Epub] CrossRef
The crosstalk between insulin resistance and nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease: a culprit or a consequence?
Dae-Jeong Koo, Won-Young Lee
Cardiovascular Prevention and Pharmacotherapy.2022; 4(4): 132. CrossRef

Diabetes, Obesity and Metabolism Big Data Articles (National Health Insurance Service Database)
The Effects of Glucose Lowering Agents on the Secondary Prevention of Coronary Artery Disease in Patients with Type 2 Diabetes: Inha Jung, Hyemi Kwon, Se Eun Park, Kyung-Do Han, Yong-Gyu Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2021;36(5):977-987. Published online October 14, 2021; DOI: https://doi.org/10.3803/EnM.2021.1046

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Background
Patients with diabetes have a higher risk of requiring repeated percutaneous coronary intervention (PCI) than non-diabetic patients. We aimed to evaluate and compare the effects of anti-diabetic drugs on the secondary prevention of myocardial infarction among type 2 diabetes mellitus patients.
Methods
We analyzed the general health check-up dataset and claims data of the Korean National Health Insurance Service of 199,714 participants (age ≥30 years) who underwent PCIs between 2010 and 2013. Those who underwent additional PCI within 1 year of their first PCI (n=3,325) and those who died within 1 year (n=1,312) were excluded. Patients were classified according to their prescription records for glucose-lowering agents. The primary endpoint was the incidence rate of coronary revascularization.
Results
A total of 35,348 patients were included in the study. Metformin significantly decreased the risk of requiring repeat PCI in all patients (adjusted hazard ratio [aHR], 0.77). In obese patients with body mass index (BMI) ≥25 kg/m², patients treated with thiazolidinedione (TZD) exhibited a decreased risk of requiring repeat revascularization than those who were not treated with TZD (aHR, 0.77; 95% confidence interval, 0.63 to 0.95). Patients treated with metformin showed a decreased risk of requiring revascularization regardless of their BMI. Insulin, meglitinide, and alpha-glucosidase inhibitor were associated with increased risk of repeated PCI.
Conclusion
The risk of requiring repeat revascularization was lower in diabetic patients treated with metformin and in obese patients treated with TZD. These results suggest that physicians should choose appropriate glucose-lowering agents for the secondary prevention of coronary artery disease.

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Application of systemic inflammation indices and lipid metabolism-related factors in coronary artery disease
Zhuoyan Zhao, Huan Lian, Yixiang Liu, Lixian Sun, Ying Zhang
Coronary Artery Disease.2023; 34(5): 306. CrossRef
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Zhicheng Xu, Haidong Zhang, Chenghui Wu, Yuxiang Zheng, Jingzhou Jiang
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Establishment of a Predictive Model for Poor Prognosis of Incomplete Revascularization in Patients with Coronary Heart Disease and Multivessel Disease
Huan Lian, Zhuoyan Zhao, Kelin Ma, Zhenjiang Ding, Lixian Sun, Ying Zhang
Clinical and Applied Thrombosis/Hemostasis.2022; 28: 107602962211392. CrossRef

Diabetes, Obesity and Metabolism
Increased Risk of Nonalcoholic Fatty Liver Disease in Individuals with High Weight Variability: Inha Jung, Dae-Jeong Koo, Mi Yeon Lee, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2021;36(4):845-854. Published online August 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.1098

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Background
Weight loss through lifestyle modification is recommended for patients with nonalcoholic fatty liver disease (NAFLD). Recent studies have suggested that repeated loss and gain of weight is associated with worse health outcomes. This study aimed to examine the association between weight variability and the risk of NAFLD in patients without diabetes.
Methods
We examined the health-checkup data of 30,708 participants who had undergone serial examinations between 2010 and 2014. Weight variability was assessed using coefficient of variation and the average successive variability of weight (ASVW), which was defined as the sum of absolute weight changes between successive years over the 5-year period divided by 4. The participants were classified according to the baseline body mass index and weight difference over 4 years.
Results
On dividing the participants into four groups according to ASVW quartile groups, those in the highest quartile showed a significantly increased risk of NAFLD compared to those in the lowest quartile (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.63 to 2.19). Among participants without obesity at baseline, individuals with high ASVW showed increased risk of NAFLD (OR, 1.80; 95% CI, 1.61 to 2.01). Participants with increased weight over 4 years and high ASVW demonstrated higher risk of NAFLD compared to those with stable weight and low ASVW (OR, 4.87; 95% CI, 4.29 to 5.53).
Conclusion
Regardless of participant baseline obesity status, high weight variability was associated with an increased risk of developing NAFLD. Our results suggest that further effort is required to minimize weight fluctuations after achieving a desirable body weight.

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Changes in Macronutrients during Dieting Lead to Weight Cycling and Metabolic Complications in Mouse Model
Anouk Charlot, Anthony Bringolf, Léa Debrut, Joris Mallard, Anne-Laure Charles, Emilie Crouchet, Delphine Duteil, Bernard Geny, Joffrey Zoll
Nutrients.2024; 16(5): 646. CrossRef
Body weight variability and the risk of liver‐related outcomes in type 2 diabetes and steatotic liver disease: a cohort study
Nathalie C. Leite, Claudia R. L. Cardoso, Cristiane A. Villela‐Nogueira, Gil F. Salles
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Weight variability, physical functioning and incident disability in older adults
Katie J. McMenamin, Tamara B. Harris, Joshua F. Baker
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Dulaglutide Ameliorates Palmitic Acid-Induced Hepatic Steatosis by Activating FAM3A Signaling Pathway
Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee
Endocrinology and Metabolism.2022; 37(1): 74. CrossRef
Triglyceride and glucose index is a simple and easy‐to‐calculate marker associated with nonalcoholic fatty liver disease
Kyung‐Soo Kim, Sangmo Hong, Hong‐Yup Ahn, Cheol‐Young Park
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Metabolic (dysfunction)-associated fatty liver disease in individuals of normal weight
Mohammed Eslam, Hashem B. El-Serag, Sven Francque, Shiv K. Sarin, Lai Wei, Elisabetta Bugianesi, Jacob George
Nature Reviews Gastroenterology & Hepatology.2022; 19(10): 638. CrossRef
Impact of COVID-19 Lockdown on Non-Alcoholic Fatty Liver Disease and Insulin Resistance in Adults: A before and after Pandemic Lockdown Longitudinal Study
Ángel Arturo López-González, Bárbara Altisench Jané, Luis Masmiquel Comas, Sebastiana Arroyo Bote, Hilda María González San Miguel, José Ignacio Ramírez Manent
Nutrients.2022; 14(14): 2795. CrossRef
Higher Weight Variability Could Bring You a Fatty Liver
Yeoree Yang, Jae-Hyoung Cho
Endocrinology and Metabolism.2021; 36(4): 766. CrossRef
Autonomic Imbalance Increases the Risk for Non-alcoholic Fatty Liver Disease
Inha Jung, Da Young Lee, Mi Yeon Lee, Hyemi Kwon, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Won-Young Lee, Sung-Woo Park, Se Eun Park
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Special Article

Miscellaneous
COVID-19 Vaccination for Endocrine Patients: A Position Statement from the Korean Endocrine Society: Cheol Ryong Ku, Kyong Yeun Jung, Chang Ho Ahn, Jun Sung Moon, Ju Hee Lee, Eun Heui Kim, Hyemi Kwon, Hee Kyung Kim, Sunghwan Suh, Sangmo Hong, Jeonghoon Ha, Eun Roh, Jin Hwa Kim, Mi-kyung Kim, the Committee of Clinical Practice Guideline of the Korean Endocrine Society; Endocrinol Metab. 2021;36(4):757-765. Published online August 17, 2021; DOI: https://doi.org/10.3803/EnM.2021.404

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Since the first outbreak of coronavirus disease 2019 (COVID-19), ongoing efforts have been made to discover an efficacious vaccine against COVID-19 to combat the pandemic. In most countries, both mRNA and DNA vaccines have been administered, and their side effects have also been reported. The clinical course of COVID-19 and the effects of vaccination against COVID-19 are both influenced by patients’ health status and involve a systemic physiological response. In view of the systemic function of endocrine hormones, endocrine disorders themselves and the therapeutics used to treat them can influence the outcomes of vaccination for COVID-19. However, there are very limited data to support the development of clinical guidelines for patients with specific medical backgrounds based on large clinical trials. In the current severe circumstances of the COVID-19 pandemic, position statements made by clinical specialists are essential to provide appropriate recommendations based on both medical evidence and clinical experiences. As endocrinologists, we would like to present the medical background of COVID-19 vaccination, as well as precautions to prevent the side effects of COVID-19 vaccination in patients with specific endocrine disorders, including adrenal insufficiency, diabetes mellitus, osteoporosis, autoimmune thyroid disease, hypogonadism, and pituitary disorders.

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Rimesh Pal, Ameya Joshi, Sanjay K. Bhadada, Mainak Banerjee, Suresh Vaikkakara, Satinath Mukhopadhyay
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Safety of Inactivated and mRNA COVID-19 Vaccination Among Patients Treated for Hypothyroidism: A Population-Based Cohort Study
Xi Xiong, Carlos King Ho Wong, Ivan Chi Ho Au, Francisco Tsz Tsun Lai, Xue Li, Eric Yuk Fai Wan, Celine Sze Ling Chui, Esther Wai Yin Chan, Franco Wing Tak Cheng, Kristy Tsz Kwan Lau, Chi Ho Lee, Yu Cho Woo, David Tak Wai Lui, Ian Chi Kei Wong
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Original Articles

Endocrine Research
Clusterin Protects Lipotoxicity-Induced Apoptosis via Upregulation of Autophagy in Insulin-Secreting Cells: Seok-Woo Hong, Jinmi Lee, Min Jeong Kim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2020;35(4):943-953. Published online December 2, 2020; DOI: https://doi.org/10.3803/EnM.2020.768

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Background
There is a great need to discover factors that could protect pancreatic β-cells from apoptosis and thus prevent diabetes mellitus. Clusterin (CLU), a chaperone protein, plays an important role in cell protection in numerous cells and is involved in various cellular mechanisms, including autophagy. In the present study, we investigated the protective role of CLU through autophagy regulation in pancreatic β-cells.
Methods
To identify the protective role of CLU, mouse insulinoma 6 (MIN6) cells were incubated with CLU and/or free fatty acid (FFA) palmitate, and cellular apoptosis and autophagy were examined.
Results
Treatment with CLU remarkably upregulated microtubule-associated protein 1-light chain 3 (LC3)-II conversion in a doseand time-dependent manner with a significant increase in the autophagy-related 3 (Atg3) gene expression level, which is a mediator of LC3-II conversion. Moreover, co-immunoprecipitation and fluorescence microscopy experiments showed that the molecular interaction of LC3 with Atg3 and p62 was markedly increased by CLU. Stimulation of LC3-II conversion by CLU persisted in lipotoxic conditions, and FFA-induced apoptosis and dysfunction were simultaneously improved by CLU treatment. Finally, inhibition of LC3-II conversion by Atg3 gene knockdown markedly attenuated the cytoprotective effect of CLU.
Conclusion
Taken together, these findings suggest that CLU protects pancreatic β-cells against lipotoxicity-induced apoptosis via autophagy stimulation mediated by facilitating LC3-II conversion. Thus, CLU has therapeutic effects on FFA-induced pancreatic β-cell dysfunction.

Citations

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Exercise as a non-pharmacological intervention to protect pancreatic beta cells in individuals with type 1 and type 2 diabetes
Alexandra Coomans de Brachène, Corentin Scoubeau, Anyïshai E. Musuaya, Jose Maria Costa-Junior, Angela Castela, Julie Carpentier, Vitalie Faoro, Malgorzata Klass, Miriam Cnop, Decio L. Eizirik
Diabetologia.2023; 66(3): 450. CrossRef
Apolipoprotein J Attenuates Vascular Restenosis by Promoting Autophagy and Inhibiting the Proliferation and Migration of Vascular Smooth Muscle Cells
Ning Yang, Bo Dong, Yanqiu Song, Yang Li, Lu Kou, Qin Qin
Journal of Cardiovascular Translational Research.2022; 15(5): 1086. CrossRef
Targets for rescue from fatty acid-induced lipotoxicity in pancreatic beta cells
Seok-Woo Hong, Won-Young Lee
Cardiovascular Prevention and Pharmacotherapy.2022; 4(2): 57. CrossRef
Co-regulators of autophagy and the cell cycle in HFD − As treated mice
Marzieh Zeinvand-Lorestani, Mohammad Javad Khodayar, Ali Teimoori, Najmaldin Saki, Akram Ahangarpour, Ali Ranjbar, Hamed Zeinvand-Lorestani
Journal of Trace Elements and Minerals.2022; 2: 100018. CrossRef
Targeting pancreatic β cells for diabetes treatment
Chirag Jain, Ansarullah, Sara Bilekova, Heiko Lickert
Nature Metabolism.2022; 4(9): 1097. CrossRef
Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies
Safia Costes, Gyslaine Bertrand, Magalie A. Ravier
International Journal of Molecular Sciences.2021; 22(10): 5303. CrossRef

Clinical Study
The Prevalence and Risk of Type 2 Diabetes in Adults with Disabilities in Korea: Inha Jung, Hyemi Kwon, Se Eun Park, Kyung-Do Han, Yong-Gyu Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2020;35(3):552-561. Published online July 22, 2020; DOI: https://doi.org/10.3803/EnM.2020.653

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Background
People with disabilities are at risk of secondary conditions such as diabetes. The aim of this study was to evaluate the prevalence and risk of type 2 diabetes in South Korea, especially among people with all types of disabilities.
Methods
We conducted a cross-sectional study using data from the Korean National Health Insurance Service, with two disabilityfree controls matched for each participant with disabilities by age and sex. Information regarding the type, severity and grade of disabilities was obtained based on the National Disability Registry. Diagnosis of type 2 diabetes was defined according to the following criteria: presence of International Classification of Diseases, Tenth Revision, Clinical Modification codes E11, E12, E13, or E14 and claims for at least one oral anti-diabetic agent or insulin at baseline, or fasting glucose level ≥126 mg/dL.
Results
We included 1,297,806 participants with disabilities and 2,943,719 control. Out of 4,241,525 participants, 841,990 (19.9%) were diagnosed with diabetes. The prevalence of diabetes was higher in the disability group compared with individuals without disabilities (23.1% vs. 18.4%). The odds of having diabetes was higher in the disability group compared with the control group (adjusted odds ratio, 1.34; 95% confidence interval, 1.33 to 1.34). The results showed higher prevalence of diabetes in the mildly disabled group (23.2%) than in the severely disabled group (22.7%).
Conclusion
The prevalence and risk of diabetes were higher in people with disabilities compared with the general population. Physicians and public health authorities should focus on people with disabilities for proper diabetes management.

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I. Hwang, S.Y. Kim, Y.Y. Kim, J.H. Park
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Psychotic Disorders and the Risk of Type 2 Diabetes Mellitus, Atherosclerotic Cardiovascular Diseases, and All-Cause Mortality: A Population-Based Matched Cohort Study
You-Bin Lee, Hyewon Kim, Jungkuk Lee, Dongwoo Kang, Gyuri Kim, Sang-Man Jin, Jae Hyeon Kim, Hong Jin Jeon, Kyu Yeon Hur
Diabetes & Metabolism Journal.2024; 48(1): 122. CrossRef
Pathways linking health literacy to self-care in diabetic patients with physical disabilities: A moderated mediation model
Hye Jin Nam, Ju Young Yoon, Wen-Jun Tu
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Journal of Korean Medical Science.2023;[Epub] CrossRef
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Scientific Reports.2022;[Epub] CrossRef
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Jinwook Bahk, Hee-Yeon Kang, Young-Ho Khang
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Seon Mee Park, Hyun Jung Kim, Tae Uk Kang, Heather Swan, Hyeong Sik Ahn
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Clinical Study
Serum Adiponectin and Progranulin Level in Patients with Benign Thyroid Nodule or Papillary Thyroid Cancer: Hyemi Kwon, Se Eun Park, Ji-Sup Yun, Cheol-Young Park; Endocrinol Metab. 2020;35(2):396-406. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.396

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Background
Obesity is associated with thyroid cancer risk. Adiponectin has insulin-sensitizing and anti-inflammatory effects, while progranulin is associated with inflammation and tumorigenesis. We investigated serum adiponectin and progranulin levels in patients with benign thyroid nodule (benign group) and papillary thyroid cancer (PTC; PTC group). The associations between these levels and the clinicopathological features of PTC were evaluated.
Methods
We included 157 patients who underwent thyroid surgery (17% of benign and 83% of PTC group). Clinicopathological features including size, lymph node metastasis, extrathyroidal extension (ETE), multifocality, American Thyroid Association risk stratification were evaluated.
Results
The age was 42.0 years, and 69% were female. Serum adiponectin and progranulin levels were 6.3 μg/mL and 101.5 ng/mL in the benign group and 5.4 μg/mL and 106.1 ng/mL in the PTC group, respectively (P=0.6 and P=0.4, respectively). Serum adiponectin levels showed no significant differences according to clinicopathological features of PTC. The proportions of patients with primary tumor size >1 cm were 3%, 5%, 8%, and 8% according to serum progranulin level quartiles, respectively (P=0.03). The proportions of patients with microscopic/gross ETE were 8%/0%, 9%/1%, 11%/1%, and 11%/2% according to serum progranulin level quartiles, respectively. Median serum progranulin level was significantly higher in patients with PTC >1 cm than in patients with papillary thyroid microcarcinoma (P=0.04, 115.3 ng/mL and 104.7 ng/mL, respectively).
Conclusion
Serum adiponectin and progranulin levels showed no significant difference between benign and PTC groups. Increased serum progranulin levels were significantly associated with PTC >1 cm and microscopic and gross ETE.

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Lucas Fornari Laurindo, Andreline Franchi Sosin, Caroline Barbalho Lamas, Ricardo de Alvares Goulart, Jesselina Francisco dos Santos Haber, Claudia Rucco Penteado Detregiachi, Sandra Maria Barbalho
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Changlin Li, Jiao Zhang, Gianlorenzo Dionigi, Nan Liang, Haixia Guan, Hui Sun
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Elisa Ventura, Giacomo Ducci, Reyes Benot Dominguez, Valentina Ruggiero, Antonino Belfiore, Elena Sacco, Marco Vanoni, Renato V. Iozzo, Antonio Giordano, Andrea Morrione
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Lauren C. Burrage, Donald S.A. McLeod, Susan J. Jordan
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Progranulin promoted the proliferation, metastasis, and suppressed apoptosis via JAK2-STAT3/4 signaling pathway in papillary thyroid carcinoma
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Obesity and Overweight Are Associated with Minimal Extrathyroidal Extension, Multifocality and Bilaterality of Papillary Thyroid Cancer
Krzysztof Kaliszewski, Dorota Diakowska, Marta Rzeszutko, Jerzy Rudnicki
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Clinical Study
Visceral-to-Subcutaneous Abdominal Fat Ratio Is Associated with Nonalcoholic Fatty Liver Disease and Liver Fibrosis: Chan-Hee Jung, Eun-Jung Rhee, Hyemi Kwon, Yoosoo Chang, Seungho Ryu, Won-Young Lee; Endocrinol Metab. 2020;35(1):165-176. Published online March 19, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.1.165

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Background

We evaluated the association of visceral-to-subcutaneous fat ratio (VSR) with nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis degree based on noninvasive serum fibrosis markers in the general population with NAFLD.

Methods

This is a cross-sectional study, in 7,465 Korean adults who underwent health screening examinations. NAFLD was defined as fatty liver detected on ultrasonography, and visceral and subcutaneous abdominal fat was measured using computed tomography. We predicted fibrosis based on the fibrosis-4 (FIB-4) score and aspartate aminotransferase-to-platelet ratio index (APRI) and categorized the risk for advanced fibrosis as low, indeterminate, or high.

Results

The multivariable-adjusted prevalence ratios for indeterminate to high risk of advanced fibrosis based on FIB-4, determined by comparing the second, third, and fourth quartiles with the first quartile of VSR, were 3.38 (95% confidence interval [CI], 0.64 to 17.97), 9.41 (95% CI, 1.97 to 45.01), and 19.34 (95% CI, 4.06 to 92.18), respectively. The multivariable-adjusted prevalence ratios for intermediate to high degree of fibrosis according to APRI also increased across VSR quartiles (5.04 [95% CI, 2.65 to 9.59], 7.51 [95% CI, 3.91 to 14.42], and 19.55 [95% CI, 9.97 to 38.34], respectively). High VSR was more strongly associated with the prevalence of NAFLD in nonobese subjects than in obese subjects, and the associations between VSR and intermediate to high probability of advanced fibrosis in NAFLD were stronger in obese subjects than in nonobese subjects.

Conclusion

High VSR values predicted increased NAFLD risk and advanced fibrosis risk with NAFLD, and the predictive value of VSR for indeterminate to high risk of advanced fibrosis was higher in obese subjects than in nonobese subjects.

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Letter

Thyroid
Letter: Thyroid-Stimulating Hormone Reference Ranges in the First Trimester of Pregnancy in an Iodine-Sufficient Country (Endocrinol Metab 2018;33:466-72, Carmen Castillo et al.): Hyemi Kwon; Endocrinol Metab. 2019;34(1):93-94. Published online March 21, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.1.93

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