Endocrinology and Metabolism

Original Article

Sodium-Glucose Cotransporter-2 Inhibitor Enhances Hepatic Gluconeogenesis and Reduces Lipid Accumulation via AMPK-SIRT1 Activation and Autophagy Induction: Si Woo Lee, Hyunki Park, Minyoung Lee, Hyangkyu Lee, Eun Seok Kang; Received October 25, 2024 Accepted February 12, 2025 Published online May 12, 2025; DOI: https://doi.org/10.3803/EnM.2024.2223 [Epub ahead of print]

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Abstract PDF: Background
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors, such as dapagliflozin, are primarily used to lower glucose in type 2 diabetes. Recent studies suggest broader metabolic effects, particularly in the liver. This study explores the molecular mechanisms by which dapagliflozin influences hepatic glucose and lipid metabolism, hypothesizing that it activates the 5’-adenosine monophosphate-activated protein kinase (AMPK)-sirtuin 1 (Sirt1) pathway to promote gluconeogenesis and reduce lipid accumulation via autophagy.
Methods
HepG2 hepatocellular carcinoma cells were treated with dapagliflozin, and Western blotting, quantitative reverse transcription polymerase chain reaction, and fluorescence microscopy were used to assess gluconeogenic enzyme expression and autophagy. In vivo, mice with liver-specific autophagy related 7 (Atg7) deletion and those on a high-fat diet were used to evaluate glucose regulation, lipid metabolism, and autophagy.
Results
Dapagliflozin significantly increased expression of gluconeogenic enzymes like phosphoenolpyruvate carboxykinase (PEPCK) in HepG2 cells and enhanced autophagic flux, evidenced by increased light chain 3B (LC3B)-II levels and autophagosome formation. AMPK-Sirt1 activation was confirmed as the underlying mechanism. Additionally, dapagliflozin reduced fatty acid synthesis by suppressing enzymes such as acetyl-CoA carboxylase and fatty acid synthase, while promoting fatty acid degradation via carnitine palmitoyltransferase 1α (CPT1α) upregulation. In high-fat diet mice, dapagliflozin increased hepatic gluconeogenesis and reduced lipid accumulation, though serum cholesterol and triglyceride levels were unaffected.
Conclusion
Dapagliflozin enhances hepatic gluconeogenesis and reduces steatosis by activating the AMPK-Sirt1 pathway and promoting autophagy. These findings suggest that SGLT2 inhibitors could offer therapeutic benefits for managing hepatic lipid disorders, beyond glycemic control.

Brief Reports

Characteristics of Metabolic Dysfunction-Associated Steatotic Liver Disease and Its Risk for Hepatic Fibrosis in 476,124 Korean Adults: A Cross-Sectional Study: Da Yeon Lee, Ji-Hee Ko, Han-Na Jang, Sun Joon Moon, Hye-Mi Kwon, Se Eun Park, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Eun-Jung Rhee; Received December 16, 2024 Accepted February 3, 2025 Published online March 27, 2025; DOI: https://doi.org/10.3803/EnM.2024.2281 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: As the new terminology of metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with increased alcohol intake (MetALD) has emerged, the clinical significance of MASLD is increasing. This cross-sectional study analyzed 476,124 health checkup participants (2002–2022) to compare hepatic fibrosis risks across MASLD, MetALD, non-alcoholic fatty liver disease (NAFLD), and metabolic dysfunction-associated fatty liver disease (MAFLD). Steatotic liver was identified via ultrasonography, and fibrosis risk was assessed using aspartate aminotransferase to platelet ratio index and NAFLD fibrosis score. The prevalence of NAFLD, MAFLD, MASLD, and MetALD was 30.1%, 32.3%, 29.8%, and 3.0%, respectively, with a 27.9% overlap among three conditions. Participants with steatotic liver were predominantly male, with higher glucose, lipids, liver enzymes, and homeostasis model assessment of insulin resistance levels. Three disease definitions largely overlapped, with MASLD and NAFLD being very similar, while participants with MAFLD and MetALD showed increased fibrosis risk (clinical trial registration number: 2024-11-050).

Diabetes, obesity and metabolism
Performance of Simple Fibrosis Score in Non-Alcoholic Fatty Liver Disease with and without Type 2 Diabetes: Seung Min Chung, Min Kyu Kang, Jun Sung Moon, Jung Gil Park; Endocrinol Metab. 2023;38(2):277-281. Published online March 13, 2023; DOI: https://doi.org/10.3803/EnM.2022.1635

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This cross-sectional study enrolled 267 patients with metabolic risk factors and established non-alcoholic fatty liver disease in the prospective cohort. The performance of fibrosis-4 (FIB-4) score (≥1.3) to diagnose advanced fibrosis using transient elastography (liver stiffness measurement [LSM] ≥8 kPa) was analyzed. Comparing patients with type 2 diabetes (T2D, n=87) and without (n=180), not FIB-4, but LSM was significantly higher in T2D (P=0.026). The prevalence of advanced fibrosis was 17.2% in T2D and 12.8% in non-T2D. FIB-4 exhibited higher proportion of false negatives in T2D patients (10.9%) than those without (5.2%). The diagnostic performance of FIB-4 was suboptimal in T2D (area under curve [AUC], 0.653; 95% confidence interval [CI], 0.462 to 0.844) compared to that in non-T2D (AUC, 0.826; 95% CI, 0.724 to 0.927). In conclusion, patients with T2D might be beneficial to conduct transient elastography without screening to avoid missing advanced fibrosis.

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The effect of semaglutide combined with metformin on liver inflammation and pancreatic beta-cell function in patients with type 2 diabetes and non-alcoholic fatty liver disease
Rong Ren, Yanxia Pei, Lufei Kong, Yixin Shi
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Metabolic-Associated Steatotic Liver Disease (MASLD) and Type 2 Diabetes: Mechanisms, Diagnostic Approaches, and Therapeutic Interventions
Anastasia Ntikoudi, Anastasia Papachristou, Afroditi Tsalkitzi, Nikoletta Margari, Eleni Evangelou, Eugenia Vlachou
Diabetology.2025; 6(4): 23. CrossRef
Multiple Definitions of Fatty Liver Disease: Which One Most Accurately Predicts Diabetes?
Eun-Jung Rhee
Endocrinology and Metabolism.2024; 39(2): 397. CrossRef
Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective
Inha Jung, Dae-Jeong Koo, Won-Young Lee
Diabetes & Metabolism Journal.2024; 48(3): 327. CrossRef
Epidemiology, screening, and co-management of type 2 diabetes mellitus and metabolic dysfunction–associated steatotic liver disease
Xiaolong Qi, Jie Li, Cyrielle Caussy, Gao-Jun Teng, Rohit Loomba
Hepatology.2024;[Epub] CrossRef
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Anubhav Mondal, Aninda Debnath, Ghurumourthy Dhandapani, Abhishek Sharma, Shveta Lukhmana, Geeta Yadav
Cureus.2023;[Epub] CrossRef

Original Article

Diabetes, Obesity and Metabolism
The Impact of Insulin Resistance on Hepatic Fibrosis among United States Adults with Non-Alcoholic Fatty Liver Disease: NHANES 2017 to 2018: Ji Cheol Bae, Lauren A. Beste, Kristina M. Utzschneider; Endocrinol Metab. 2022;37(3):455-465. Published online June 21, 2022; DOI: https://doi.org/10.3803/EnM.2022.1434

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Background
We aimed to investigate the association of hepatic steatosis with liver fibrosis and to assess the interactive effects of hepatic steatosis and insulin resistance on liver fibrosis in a nationally representative sample of United States adults.
Methods
We conducted a cross-sectional analysis using data from National Health and Nutrition Examination Survey 2017 to 2018, which for the first time included transient elastography to assess liver stiffness and hepatic steatosis. We evaluated the association between hepatic steatosis (using controlled attenuation parameter [CAP]) and clinically significant liver fibrosis (defined as liver stiffness ≥7.5 kPa) using logistic regression with an interaction term for hepatic steatosis and insulin resistance (defined as homeostatic model assessment of insulin resistance ≥3.0).
Results
Among adults undergoing transient elastography (n=2,023), 45.9% had moderate or greater hepatic steatosis and 11.3% had clinically significant liver fibrosis. After adjustment for demographic and metabolic factors, the odds of significant liver fibrosis increased as CAP score rose (odds ratio, 1.35 per standard deviation increment; 95% confidence interval, 1.11 to 1.64). We detected a significant interaction effect between CAP score and insulin resistance on the probability of significant liver fibrosis (P=0.016 for interaction). The probability of significant liver fibrosis increased in the presence of insulin resistance with increasing CAP score, while those without insulin resistance had low probability of significant liver fibrosis, even with high CAP scores.
Conclusion
Individuals with hepatic steatosis had higher odds of fibrosis when insulin resistance was present. Our findings emphasize the importance of the metabolic aspects of the disease on fibrosis risk and suggest a need to better identify patients with metabolic associated fatty liver disease.

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Association between the triglyceride-glucose index and liver fibrosis in adults with metabolism-related fatty liver disease in the United States: a cross-sectional study of NHANES 2017–2020
Yuou Ying, Yuan Ji, Ruyi Ju, Jinhan Chen, Mingxian Chen
BMC Gastroenterology.2025;[Epub] CrossRef
The Value of TyG‐Related Indices in Evaluating MASLD and Significant Liver Fibrosis in MASLD
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Pathogenic Mechanisms of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Associated Hepatocellular Carcinoma
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Metabolic Dysfunction-Associated Steatotic Liver Disease: The Role of Hepatic Steatosis in Insulin Resistance and Metabolic Health
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Association of insulin resistance indicators with hepatic steatosis and fibrosis in patients with metabolic syndrome
Tzu-chia Kuo, Yang-bor Lu, Chieh-lun Yang, Bin Wang, Lin-xin Chen, Ching-ping Su
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No More NAFLD: The Term Is Now MASLD
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Endocrinology and Metabolism.2024; 39(1): 92. CrossRef
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
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Yuval Ishay, Joel Neutel, Yotam Kolben, Ram Gelman, Orly Sneh Arbib, Oliver Lopez, Helena Katchman, Rizwana Mohseni, Miriam Kidron, Yaron Ilan
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Mehwish Qamar, Abeer Fatima, Ambreen Tauseef, Muhammad I Yousufzai, Ibrahim Liaqat, Qanbar Naqvi
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Metabolic dysfunction-associated steatotic liver disease heterogeneity: Need of subtyping
Shahid Habib
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Greater Severity of Steatosis Is Associated with a Higher Risk of Incident Diabetes: A Retrospective Longitudinal Study
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Hepatic T-cell senescence and exhaustion are implicated in the progression of fatty liver disease in patients with type 2 diabetes and mouse model with nonalcoholic steatohepatitis
Byeong Chang Sim, Yea Eun Kang, Sun Kyoung You, Seong Eun Lee, Ha Thi Nga, Ho Yeop Lee, Thi Linh Nguyen, Ji Sun Moon, Jingwen Tian, Hyo Ju Jang, Jeong Eun Lee, Hyon-Seung Yi
Cell Death & Disease.2023;[Epub] CrossRef
Familial clustering of nonalcoholic fatty liver disease in first‐degree relatives of adults with lean nonalcoholic fatty liver disease
Sorachat Niltwat, Chanin Limwongse, Natthinee Charatcharoenwitthaya, Duangkamon Bunditvorapoom, Wimolrak Bandidniyamanon, Phunchai Charatcharoenwitthaya
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Review Article

Diabetes, Obesity and Metabolism
State-of-the-Art Overview of the Pharmacological Treatment of Non-Alcoholic Steatohepatitis: Yongin Cho, Yong-ho Lee; Endocrinol Metab. 2022;37(1):38-52. Published online February 28, 2022; DOI: https://doi.org/10.3803/EnM.2022.102

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and non-alcoholic steatohepatitis (NASH), a subtype of NAFLD, can progress to cirrhosis, hepatocellular carcinoma, and death. Nevertheless, the current treatment for NAFLD/NASH is limited to lifestyle modifications, and no drugs are currently officially approved as treatments for NASH. Many global pharmaceutical companies are pursuing the development of medications for the treatment of NASH, and results from phase 2 and 3 clinical trials have been published in recent years. Here, we review data from these recent clinical trials and reports on the efficacy of newly developed antidiabetic drugs in NASH treatment.

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Impact of physical activities in metabolic dysfunction associated steatotic liver disease, sarcopenia, and cardiovascular disease
Eugene Han, Sin Yung Woo, Justin Y. Jeon, Eun Seok Kang, Bong-Soo Cha, Byung-Wan Lee, Yong-ho Lee
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Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study
Kyung-Soo Kim, Sangmo Hong, Kyungdo Han, Cheol-Young Park
BMJ.2024; : e076388. CrossRef
Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective
Inha Jung, Dae-Jeong Koo, Won-Young Lee
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Mitochondrial Quality Control: Its Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
Soyeon Shin, Jaeyoung Kim, Ju Yeon Lee, Jun Kim, Chang-Myung Oh
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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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Glucagon-like peptide-1 receptor agonists improve metabolic dysfunction-associated steatotic liver disease outcomes
Brandon Havranek, Rebecca Loh, Beatriz Torre, Rachel Redfield, Dina Halegoua-DeMarzio
Scientific Reports.2025;[Epub] CrossRef
Therapeutic effects and mechanisms of Xinmaitong formula for type 2 diabetes mellitus via GLP-1R signaling
Weidong Pu, Yang Pan, Kang Yang, Jian Gao, Fen Tian, Jingrui Song, Yubing Huang, Yanmei Li
Frontiers in Pharmacology.2025;[Epub] CrossRef
GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD
Haoran Jiang, Linquan Zang
Current Pharmaceutical Design.2024; 30(2): 100. CrossRef
Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism
Tong Bu, Ziyan Sun, Yi Pan, Xia Deng, Guoyue Yuan
Diabetes & Metabolism Journal.2024; 48(3): 354. CrossRef
Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective
Inha Jung, Dae-Jeong Koo, Won-Young Lee
Diabetes & Metabolism Journal.2024; 48(3): 327. CrossRef
Tirzepatide against obesity and insulin-resistance: pathophysiological aspects and clinical evidence
Salvatore Corrao, Chiara Pollicino, Dalila Maggio, Alessandra Torres, Christiano Argano
Frontiers in Endocrinology.2024;[Epub] CrossRef
Effects of the switch from dulaglutide to tirzepatide on glycemic control, body weight, and fatty liver: a retrospective study
Toshitaka Sawamura, Ren Mizoguchi, Ai Ohmori, Mitsuhiro Kometani, Takashi Yoneda, Shigehiro Karashima
Journal of Diabetes & Metabolic Disorders.2024; 23(2): 2105. CrossRef
FABP1 induces lipogenesis by regulating the processing of SREBP1 in hepatocytes of large yellow croaker (Larimichthys crocea)
Fan Chen, Tingting Hao, Qiang Chen, Yuning Sun, Yanan Shen, Zengqi Zhao, Jianlong Du, Yueru Li, Kangsen Mai, Qinghui Ai
The FASEB Journal.2024;[Epub] 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
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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
Frontiers in Physiology.2022;[Epub] CrossRef
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
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Diabetes, Obesity and Metabolism
The Effects of PPAR Agonists on Atherosclerosis and Nonalcoholic Fatty Liver Disease in ApoE^−/−FXR^−/− Mice: Yenna Lee, Bo-Rahm Kim, Geun-Hyung Kang, Gwan Jae Lee, Young Joo Park, Haeryoung Kim, Hak Chul Jang, Sung Hee Choi; Endocrinol Metab. 2021;36(6):1243-1253. Published online December 28, 2021; DOI: https://doi.org/10.3803/EnM.2021.1100

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Background
Farnesoid X receptor (FXR), a bile acid–activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency.
Methods
En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)^−/− and ApoE^−/−FXR^−/− mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice.
Results
Compared with ApoE^−/− mice, ApoE^−/−FXR^−/− mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE^−/−FXR^−/− mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver).
Conclusion
Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.

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Review Article

Diabetes, Obesity and Metabolism
Serotonergic Regulation of Hepatic Energy Metabolism: Jiwon Park, Wooju Jeong, Chahyeon Yun, Hail Kim, Chang-Myung Oh; Endocrinol Metab. 2021;36(6):1151-1160. Published online December 16, 2021; DOI: https://doi.org/10.3803/EnM.2021.1331

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The liver is a vital organ that regulates systemic energy metabolism and many physiological functions. Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease and end-stage liver failure. NAFLD is primarily caused by metabolic disruption of lipid and glucose homeostasis. Serotonin (5-hydroxytryptamine [5-HT]) is a biogenic amine with several functions in both the central and peripheral systems. 5-HT functions as a neurotransmitter in the brain and a hormone in peripheral tissues to regulate systemic energy homeostasis. Several recent studies have proposed various roles of 5-HT in hepatic metabolism and inflammation using tissue-specific knockout mice and 5-HT-receptor agonists/antagonists. This review compiles the most recent research on the relationship between 5-HT and hepatic metabolism, and the role of 5-HT signaling as a potential therapeutic target in NAFLD.

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Maternal nutrient metabolism in the liver during pregnancy
Hongxu Fang, Qingyang Li, Haichao Wang, Ying Ren, Leying Zhang, Ling Yang
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Neural Stem Cell-based Regenerative Therapy: A New Approach to Diabetes Treatment
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The Influence of BMP6 on Serotonin and Glucose Metabolism
Marina Milešević, Ivona Matić Jelić, Viktorija Rumenović, Natalia Ivanjko, Slobodan Vukičević, Tatjana Bordukalo-Nikšić
International Journal of Molecular Sciences.2024; 25(14): 7842. CrossRef
Exploring Endogenous Tryptamines: Overlooked Agents Against Fibrosis in Chronic Disease? A Narrative Review
Hunter W. Korsmo
Livers.2024; 4(4): 615. CrossRef
Metabolic and Molecular Response to High-Fat Diet Differs between Rats with Constitutionally High and Low Serotonin Tone
Petra Baković, Maja Kesić, Darko Kolarić, Jasminka Štefulj, Lipa Čičin-Šain
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Kapil Kumar Goel, Somesh Thapliyal, Rajeev Kharb, Gaurav Joshi, Arvind Negi, Bhupinder Kumar
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Involvement of the liver-gut peripheral neural axis in nonalcoholic fatty liver disease pathologies via hepatic HTR2A
Takashi Owaki, Kenya Kamimura, Masayoshi Ko, Itsuo Nagayama, Takuro Nagoya, Osamu Shibata, Chiyumi Oda, Shinichi Morita, Atsushi Kimura, Takeki Sato, Toru Setsu, Akira Sakamaki, Hiroteru Kamimura, Takeshi Yokoo, Shuji Terai
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Original Articles

Diabetes, Obesity and Metabolism
The Leg Fat to Total Fat Ratio Is Associated with Lower Risks of Non-Alcoholic Fatty Liver Disease and Less Severe Hepatic Fibrosis: Results from Nationwide Surveys (KNHANES 2008–2011): Hyun Min Kim, Yong-ho Lee; Endocrinol Metab. 2021;36(6):1232-1242. Published online November 23, 2021; DOI: https://doi.org/10.3803/EnM.2021.1087

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Background
The prevalence of non-alcoholic fatty liver disease (NAFLD) has rapidly increased worldwide. The aim of this study was to investigate whether there is an independent relationship between regional fat distribution, especially leg fat mass, and the presence of NAFLD using nationally representative data in Korea.
Methods
This cross-sectional study analyzed data from 14,502 participants in the Korea National Health and Nutrition Examination Survey 2008 to 2011. Total fat mass, leg fat mass, and appendicular skeletal muscle mass were measured by dual-energy X-ray absorptiometry. Validated NAFLD prediction models and scoring systems for hepatic fibrosis were used.
Results
The leg fat to total fat (LF/TF) ratio showed a negative relationship with many factors, including body mass index, waist circumference, blood pressure, fasting blood glucose, and liver enzyme levels. When the LF/TF ratio and indices of hepatic steatosis were stratified by quartiles, the LF/TF ratio showed a negative correlation with the scoring systems that were used. The LF/TF ratio showed better accuracy in predicting NAFLD than total fat mass or leg fat mass alone. After adjusting for various traditional and lifestyle factors, a low LF/TF ratio remained a risk factor for NAFLD. Among NAFLD subjects, the LF/TF ratio showed a negative relationship with hepatic fibrosis.
Conclusion
A lower LF/TF ratio was markedly associated with a higher risk of hepatic steatosis and advanced hepatic fibrosis using various predictive models in a Korean population. Therefore, the LF/TF ratio could be a useful anthropometric parameter to predict NAFLD or advanced hepatic fibrosis.

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Waistline to thigh circumference ratio as a predictor of MAFLD: a health care worker study with 2-year follow-up
Xiaoyan Hao, Honghai He, Liyuan Tao, Wei Zhao, Peng Wang
BMC Gastroenterology.2024;[Epub] CrossRef
Regional fat distribution and hepatic fibrosis and steatosis severity in patients with nonalcoholic fatty liver disease and type 2 diabetes
Asieh Mansour, Saeed Pourhassan, Hadis Gerami, Mohammad Reza Mohajeri‐Tehrani, Marziye Salahshour, Ali Abbasi, Elham Madreseh, Sayed Mahmoud Sajjadi‐Jazi
Obesity Science & Practice.2024;[Epub] CrossRef
Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective
Inha Jung, Dae-Jeong Koo, Won-Young Lee
Diabetes & Metabolism Journal.2024; 48(3): 327. CrossRef
Adipose tissue insulin resistance index was inversely associated with gluteofemoral fat and skeletal muscle mass in Japanese women
Satomi Minato-Inokawa, Mari Honda, Ayaka Tsuboi-Kaji, Mika Takeuchi, Kaori Kitaoka, Miki Kurata, Bin Wu, Tsutomu Kazumi, Keisuke Fukuo
Scientific Reports.2024;[Epub] CrossRef
A greater ratio of thigh subcutaneous fat to abdominal fat is associated with protection against non-alcoholic fatty liver disease
Yebei Liang, Peizhu Chen, Siyu Chen, Dan Liu, Fusong Jiang, Zhijun Zhu, Keqing Dong, Li Wei, Xuhong Hou
JHEP Reports.2023; 5(7): 100730. CrossRef
Association between Alcohol Consumption and Metabolic Dysfunction-Associated Steatotic Liver Disease Based on Alcohol Flushing Response in Men: The Korea National Health and Nutrition Examination Survey 2019–2021
Dae Eon Kang, Si Nae Oh
Nutrients.2023; 15(18): 3901. 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
Obesity.2024; 32(6): 1210. CrossRef
Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective
Inha Jung, Dae-Jeong Koo, Won-Young Lee
Diabetes & Metabolism Journal.2024; 48(3): 327. CrossRef
A machine-learned model for predicting weight loss success using weight change features early in treatment
Farzad Shahabi, Samuel L. Battalio, Angela Fidler Pfammatter, Donald Hedeker, Bonnie Spring, Nabil Alshurafa
npj Digital Medicine.2024;[Epub] CrossRef
Long-Term Yo-Yo Dieting Exaggerates Liver Steatosis and Lesions but Preserves Muscle Performance in Male Zebrafish
Tzu-Chieh Hsu, Chun-Hsien Chiang, I-Hsuan Liu, Chih-Yun Wang, Ching-Yi Chen
International Journal of Molecular Sciences.2024; 25(23): 13225. CrossRef
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
Obesity.2022; 30(6): 1279. CrossRef
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
Frontiers in Endocrinology.2021;[Epub] CrossRef

Diabetes, Obesity and Metabolism
Non-Laboratory-Based Simple Screening Model for Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Developed Using Multi-Center Cohorts: Jiwon Kim, Minyoung Lee, Soo Yeon Kim, Ji-Hye Kim, Ji Sun Nam, Sung Wan Chun, Se Eun Park, Kwang Joon Kim, Yong-ho Lee, Joo Young Nam, Eun Seok Kang; Endocrinol Metab. 2021;36(4):823-834. Published online August 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.1074

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Background
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. Type 2 diabetes mellitus (T2DM) is a risk factor that accelerates NAFLD progression, leading to fibrosis and cirrhosis. Thus, here we aimed to develop a simple model to predict the presence of NAFLD based on clinical parameters of patients with T2DM.
Methods
A total of 698 patients with T2DM who visited five medical centers were included. NAFLD was evaluated using transient elastography. Univariate logistic regression analyses were performed to identify potential contributors to NAFLD, followed by multivariable logistic regression analyses to create the final prediction model for NAFLD.
Results
Two NAFLD prediction models were developed, with and without serum biomarker use. The non-laboratory model comprised six variables: age, sex, waist circumference, body mass index (BMI), dyslipidemia, and smoking status. For a cutoff value of ≥60, the prediction accuracy was 0.780 (95% confidence interval [CI], 0.743 to 0.817). The second comprehensive model showed an improved discrimination ability of up to 0.815 (95% CI, 0.782 to 0.847) and comprised seven variables: age, sex, waist circumference, BMI, glycated hemoglobin, triglyceride, and alanine aminotransferase to aspartate aminotransferase ratio. Our non-laboratory model showed non-inferiority in the prediction of NAFLD versus previously established models, including serum parameters.
Conclusion
The new models are simple and user-friendly screening methods that can identify individuals with T2DM who are at high-risk for NAFLD. Additional studies are warranted to validate these new models as useful predictive tools for NAFLD in clinical practice.

Citations

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Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective
Inha Jung, Dae-Jeong Koo, Won-Young Lee
Diabetes & Metabolism Journal.2024; 48(3): 327. CrossRef
Non-Alcoholic Fatty Liver Disease or Type 2 Diabetes Mellitus—The Chicken or the Egg Dilemma
Marcin Kosmalski, Agnieszka Śliwińska, Józef Drzewoski
Biomedicines.2023; 11(4): 1097. CrossRef

Diabetes, Obesity and Metabolism
High Fibrosis-4 Index Is Related with Worse Clinical Outcome in Patients with Coronavirus Disease 2019 and Diabetes Mellitus: A Multicenter Observational Study: Sung-Woo Kim, Jae-Han Jeon, Jun Sung Moon, Mi Kyung Kim; Endocrinol Metab. 2021;36(4):800-809. Published online August 20, 2021; DOI: https://doi.org/10.3803/EnM.2021.1040

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Background
Based on recent evidence on the importance of the presence of diabetes mellitus (DM) and fibrosis-4 (FIB-4) index in coronavirus disease 2019 (COVID-19) mortality, we analyzed whether these factors could additively predict such mortality.
Methods
This multicenter observational study included 1,019 adult inpatients admitted to university hospitals in Daegu. The demographic and laboratory findings, mortality, prevalence of severe disease, and duration of quarantine were compared between patients with and without DM and/or a high FIB-4 index. The mortality risk and corresponding hazard ratio (HR) were analyzed using the Kaplan-Meier method and Cox proportional hazard models.
Results
The patients with DM (n=217) exhibited significantly higher FIB-4 index and mortality compared to those without DM. Although DM (HR, 2.66; 95% confidence interval [CI], 1.63 to 4.33) and a high FIB-4 index (HR, 4.20; 95% CI, 2.21 to 7.99) were separately identified as risk factors for COVID-19 mortality, the patients with both DM and high FIB-4 index had a significantly higher mortality (HR, 9.54; 95% CI, 4.11 to 22.15). Higher FIB-4 indices were associated with higher mortality regardless of DM. A high FIB-4 index with DM was more significantly associated with a severe clinical course with mortality (odds ratio, 11.24; 95% CI, 5.90 to 21.41) than a low FIB-4 index without DM, followed by a high FIB-4 index alone and DM alone. The duration of quarantine and hospital stay also tended to be longer in those with both DM and high FIB-4 index.
Conclusion
Both DM and high FIB-4 index are independent and additive risk factors for COVID-19 mortality.

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The clinical features and outcomes of diabetes patients infected with COVID-19: a systematic review and meta-analysis comprising 192,693 patients
Kai Liu, Shu Liu, Ting-ting Xu, Hong Qiao
Frontiers in Medicine.2025;[Epub] CrossRef
Impact of liver fibrosis on COVID-19 in-hospital mortality in Southern Italy
Raffaele Galiero, Giuseppe Loffredo, Vittorio Simeon, Alfredo Caturano, Erica Vetrano, Giulia Medicamento, Maria Alfano, Domenico Beccia, Chiara Brin, Sara Colantuoni, Jessica Di Salvo, Raffaella Epifani, Riccardo Nevola, Raffaele Marfella, Celestino Sard
PLOS ONE.2024; 19(5): e0296495. CrossRef
COVID-19 and hepatic injury: Diversity and risk assessment
Fares E M Ali, Mostafa K Abd El-Aziz, Mahmoud M Ali, Osama M Ghogar, Adel G Bakr
World Journal of Gastroenterology.2023; 29(3): 425. CrossRef
Differential Effects of COVID-19 Hospitalization on the Trajectory of Liver Disease Progression
Dilara Hatipoğlu, Connor Mulligan, Jeffrey Wang, Juan Peticco, Reid Grinspoon, Sanjay Gadi, Camilla Mills, Jay Luther, Raymond T. Chung
Gastro Hep Advances.2023; 2(4): 480. CrossRef
Association of non-alcoholic fatty liver and metabolic-associated fatty liver with COVID-19 outcomes: A systematic review and meta-analysis
Gowthami Sai Kogilathota Jagirdhar, Rakhtan K Qasba, Harsha Pattnaik, Kaanthi Rama, Akshat Banga, Shiva Teja Reddy, Anna Carolina Flumignan Bucharles, Rahul Kashyap, Praveen Reddy Elmati, Vikas Bansal, Yatinder Bains, Theodore DaCosta, Salim Surani
World Journal of Gastroenterology.2023; 29(21): 3362. CrossRef
COVID-19 and Fatty Liver Disorders
Maria Guarino, Valentina Cossiga, Francesco Cutolo, Maria Attanasio, Raffaele Lieto, Filomena Morisco
Journal of Clinical Medicine.2023; 12(13): 4316. CrossRef
Prevalence and Prognostic Significance of Liver Fibrosis in Patients With Aneurysmal Subarachnoid Hemorrhage
Tiangui Li, Peng Wang, Xiao Gong, Weelic Chong, Yang Hai, Chao You, Juan Kang, Fang Fang, Yu Zhang
Frontiers in Neurology.2022;[Epub] CrossRef

Clinical Study
Development of a Non-Invasive Liver Fibrosis Score Based on Transient Elastography for Risk Stratification in Patients with Type 2 Diabetes: Chi-Ho Lee, Wai-Kay Seto, Kelly Ieong, David T.W. Lui, Carol H.Y. Fong, Helen Y. Wan, Wing-Sun Chow, Yu-Cho Woo, Man-Fung Yuen, Karen S.L. Lam; Endocrinol Metab. 2021;36(1):134-145. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2020.887

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Background
In non-alcoholic fatty liver disease (NAFLD), transient elastography (TE) is an accurate non-invasive method to identify patients at risk of advanced fibrosis (AF). We developed a diabetes-specific, non-invasive liver fibrosis score based on TE to facilitate AF risk stratification, especially for use in diabetes clinics where TE is not readily available.
Methods
Seven hundred sixty-six adults with type 2 diabetes and NAFLD were recruited and randomly divided into a training set (n=534) for the development of diabetes fibrosis score (DFS), and a testing set (n=232) for internal validation. DFS identified patients with AF on TE, defined as liver stiffness (LS) ≥9.6 kPa, based on a clinical model comprising significant determinants of LS with the lowest Akaike information criteria. The performance of DFS was compared with conventional liver fibrosis scores (NFS, FIB-4, and APRI), using area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive and negative predictive values (NPV).
Results
DFS comprised body mass index, platelet, aspartate aminotransferase, high-density lipoprotein cholesterol, and albuminuria, five routine measurements in standard diabetes care. Derived low and high DFS cut-offs were 0.1 and 0.3, with 90% sensitivity and 90% specificity, respectively. Both cut-offs provided better NPVs of >90% than conventional fibrosis scores. The AUROC of DFS for AF on TE was also higher (P<0.01) than the conventional fibrosis scores, being 0.85 and 0.81 in the training and testing sets, respectively.
Conclusion
Compared to conventional fibrosis scores, DFS, with a high NPV, more accurately identified diabetes patients at-risk of AF, who need further evaluation by hepatologists.

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Chi‐Ho Lee, David Tak‐Wai Lui, Lung‐Yi Mak, Carol Ho‐Yi Fong, Kylie Sze‐Wing Chan, Jimmy Ho‐Cheung Mak, Chloe Yu‐Yan Cheung, Wing‐Sun Chow, Yu‐Cho Woo, Man‐Fung Yuen, Wai‐Kay Seto, Karen Siu‐Ling Lam
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Elisa Pose, Salvatore Piano, Maja Thiele, Núria Fabrellas, Emmanuel A. Tsochatzis, Pere Ginès
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Kushala W M Abeysekera, Luca Valenti, Zobair Younossi, John F Dillon, Alina M Allen, Mazen Noureddin, Mary E Rinella, Frank Tacke, Sven Francque, Pere Ginès, Maja Thiele, Philip N Newsome, Indra Neil Guha, Mohammed Eslam, Jörn M Schattenberg, Saleh A Alqa
The Lancet Gastroenterology & Hepatology.2024; 9(1): 83. CrossRef
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Sequential algorithm to stratify liver fibrosis risk in overweight/obese metabolic dysfunction-associated fatty liver disease
Chi-Ho Lee, David Tak-Wai Lui, Raymond Hang-Wun Li, Michele Mae-Ann Yuen, Carol Ho-Yi Fong, Ambrose Pak-Wah Leung, Justin Chiu-Man Chu, Loey Lung-Yi Mak, Tai-Hing Lam, Jean Woo, Yu-Cho Woo, Aimin Xu, Hung-Fat Tse, Kathryn Choon-Beng Tan, Bernard Man-Yung
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Georgiana-Diana Cazac, Cristina-Mihaela Lăcătușu, Cătălina Mihai, Elena-Daniela Grigorescu, Alina Onofriescu, Bogdan-Mircea Mihai
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Review Article

Obesity and Metabolism
Noninvasive Evaluation of Nonalcoholic Fatty Liver Disease: Dae Ho Lee; Endocrinol Metab. 2020;35(2):243-259. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.243

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Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver diseases and can progress to advanced fibrosis and end-stage liver disease. Thus, intensive research has been performed to develop noninvasive methods for the diagnosis of nonalcoholic steatohepatitis (NASH) and fibrosis. Currently, no single noninvasive tool covers all of the stages of pathologies and conditions of NAFLD, and the cost and feasibility of known techniques are also important issues. Blood biomarkers for NAFLD may be useful to select subjects who need ultrasonography (US) screening for NAFLD, and noninvasive tools for assessing fibrosis may be helpful to exclude the probability of significant fibrosis and to predict advanced fibrosis, thus guiding the decision of whether to perform liver biopsy in patients with NAFLD. Among various methods, magnetic resonance-based methods have been shown to perform better than other methods in assessing steatosis as well as in detecting hepatic fibrosis. Many genetic markers are associated with the development and progression of NAFLD. Further well-designed studies are needed to determine which biomarker panels, imaging studies, genetic marker panels, or combinations thereof perform well for diagnosing NAFLD, differentiating NASH and fibrosis, and following-up NAFLD, respectively.

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Mahdi Barazesh, Sajad Jalili, Morteza Akhzari, Fouzieyeh Faraji, Ebrahim Khorramdin
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Original Article

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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Abstract PDF Supplementary Material PubReader ePub

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.

Citations

Citations to this article as recorded by

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