Diabetes & Metabolism Journal最新文献

{"title":"Exon Sequencing of HNF1β in Chinese Patients with Early-Onset Diabetes.","authors":"Siqian Gong, Hong Lian, Yating Li, Xiaoling Cai, Wei Liu, Yingying Luo, Meng Li, Si-Min Zhang, Rui Zhang, Lingli Zhou, Yu Zhu, Qian Ren, Xiuying Zhang, Jing Chen, Jing Wu, Xianghai Zhou, Xirui Wang, Xueyao Han, Linong Ji","doi":"10.4093/dmj.2024.0159","DOIUrl":"10.4093/dmj.2024.0159","url":null,"abstract":"<p><strong>Backgruound: </strong>Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients.</p><p><strong>Methods: </strong>Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines.</p><p><strong>Results: </strong>Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher.</p><p><strong>Conclusion: </strong>MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.</p>","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":" ","pages":"321-330"},"PeriodicalIF":6.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Meal Frequency on Insulin Resistance in Middle-Aged and Older Adults: A Prospective Cohort Study.","authors":"Ha-Eun Ryu, Jong Hee Lee, Byoungjin Park, Seok-Jae Heo, Yu-Jin Kwon","doi":"10.4093/dmj.2024.0407","DOIUrl":"10.4093/dmj.2024.0407","url":null,"abstract":"<p><strong>Backgruound: </strong>Insulin resistance (IR) is central to metabolic disorders and significantly influenced by diet. Studies on meal frequency (MF) and metabolic indicators have shown mixed results. This study explores the link between MF and IR in middle-aged and older adults.</p><p><strong>Methods: </strong>This prospective cohort study included 4,570 adults aged 40 to 69 years from the Korean Genome and Epidemiologic Study. MF were divided into two groups based on whether they consumed three or more, or fewer than three, meals daily. IR was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR); participants were classified as IR if their HOMA-IR value was ≥2.5. Multiple Cox proportional hazard regression analyses were conducted to examine the association between MF and the incidence of IR.</p><p><strong>Results: </strong>After adjusting for all variables, individuals in the MF ≥3 group showed a reduced incidence of IR compared to those in the MF <3 group (hazard ratio, 0.880; 95% confidence interval, 0.782 to 0.990). Additionally, subgroup analyses by sex, diabetes mellitus (DM), and body mass index (BMI) showed that this association persisted only in men, individuals without DM, and those with a BMI <25.</p><p><strong>Conclusion: </strong>Our findings indicate that a higher MF among middle-aged and older adults is associated with a reduced incidence of IR. However, this association was maintained only in men, individuals without DM, and those without obesity.</p>","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":" ","pages":"311-320"},"PeriodicalIF":6.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kidney Gastrin/CCKBR Attenuates Type 2 Diabetes Mellitus by Inhibiting SGLT2-Mediated Glucose Reabsorption through Erk/NF-κB Signaling Pathway.","authors":"Xue Zhang, Yuhan Zhang, Yang Shi, Dou Shi, Min Niu, Xue Liu, Xing Liu, Zhiwei Yang, Xianxian Wu","doi":"10.4093/dmj.2023.0397","DOIUrl":"10.4093/dmj.2023.0397","url":null,"abstract":"<p><strong>Backgruound: </strong>Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption.</p><p><strong>Methods: </strong>Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells.</p><p><strong>Results: </strong>CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. <italic>In vitro</italic> experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erk/nuclear factor-kappa B (NF-κB) pathway.</p><p><strong>Conclusion: </strong>Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.</p>","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":" ","pages":"194-209"},"PeriodicalIF":6.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Older Adults with Diabetes in Korea: Latest Clinical and Epidemiologic Trends.","authors":"Kyuho Kim, Bongseong Kim, Kyuna Lee, Yu-Bae Ahn, Seung-Hyun Ko, Sung Hee Choi, Kyungdo Han, Jae-Seung Yun","doi":"10.4093/dmj.2024.0836","DOIUrl":"10.4093/dmj.2024.0836","url":null,"abstract":"<p><strong>Backgruound: </strong>Diabetes in older adults is becoming a significant public burden to South Korea. However, a comprehensive understanding of epidemiologic trends and the detailed clinical characteristics of older adults with diabetes is lacking. Therefore, we evaluated epidemiologic trends and the metabolic and lifestyle characteristics of diabetes in Korean older adults.</p><p><strong>Methods: </strong>We analyzed data from the Korea National Health and Nutrition Examination Survey to assess diabetes prevalence according to diabetes duration and lifestyle behaviors. In addition, we drew upon the National Health Information Database of the National Health Insurance System to assess physical activity levels, antidiabetic medication use, polypharmacy, medication adherence, and major comorbidities.</p><p><strong>Results: </strong>The absolute number of newly diagnosed cases of diabetes among older adults doubled over the past decade. Management rates of metabolic indicators were higher in older adults with diabetes compared to those without diabetes. The proportion of older adults with diabetes meeting the minimum recommended physical activity increased over the years. Compared to 10 years before, the use of dipeptidyl peptidase-4 inhibitor or sodium-glucose cotransporter-2 inhibitor had increased, as had comorbidities such as dyslipidemia, dementia, cancer, heart failure, atrial fibrillation, and chronic kidney disease. Initial medication adherence was significantly lower in those with end-stage kidney disease or dementia, insulin use, high-risk alcohol use, and living alone. Continuing insulin use 1 year after diagnosis of diabetes was significantly higher in those who initiated insulin therapy at diagnosis, had retinopathy, were on triple antidiabetic medications, and had a history of cancer.</p><p><strong>Conclusion: </strong>Comprehensive management of metabolic indicators and physical activity is essential for older adults with diabetes. Improvements in prescribing guidelines, personalized management of age-related comorbidities, and individualized approaches that consider the heterogeneous nature of older adults with diabetes are desirable. Further research, such as high-quality cohort and intervention studies specific to older adults, is needed to establish evidence-based management for older adults with diabetes.</p>","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":"49 2","pages":"183-193"},"PeriodicalIF":6.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and Safety of Automated Insulin Delivery Systems in Patients with Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis.","authors":"Wenqi Fan, Chao Deng, Ruoyao Xu, Zhenqi Liu, Richard David Leslie, Zhiguang Zhou, Xia Li","doi":"10.4093/dmj.2024.0130","DOIUrl":"10.4093/dmj.2024.0130","url":null,"abstract":"<p><strong>Backgruound: </strong>Automated insulin delivery (AID) systems studies are upsurging, half of which were published in the last 5 years. We aimed to evaluate the efficacy and safety of AID systems in patients with type 1 diabetes mellitus (T1DM).</p><p><strong>Methods: </strong>We searched PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov until August 31, 2023. Randomized clinical trials that compared AID systems with other insulin-based treatments in patients with T1DM were considered eligible. Studies characteristics and glycemic metrics was extracted by three researchers independently.</p><p><strong>Results: </strong>Sixty-five trials (3,623 patients) were included. The percentage of time in range (TIR) was 11.74% (95% confidence interval [CI], 9.37 to 14.12; P<0.001) higher with AID systems compared with control treatments. Patients on AID systems had more pronounced improvement of time below range when diabetes duration was more than 20 years (-1.80% vs. -0.86%, P=0.031) and baseline glycosylated hemoglobin lower than 7.5% (-1.93% vs. -0.87%, P=0.033). Dual-hormone full closed-loop systems revealed a greater improvement in TIR compared with hybrid closed-loop systems (-19.64% vs. -10.87%). Notably, glycemia risk index (GRI) (-3.74; 95% CI, -6.34 to -1.14; P<0.01) was also improved with AID therapy.</p><p><strong>Conclusion: </strong>AID systems showed significant advantages compared to other insulin-based treatments in improving glucose control represented by TIR and GRI in patients with T1DM, with more favorable effect in euglycemia by dual-hormone full closedloop systems as well as less hypoglycemia for patients who are within target for glycemic control and have longer diabetes duration.</p>","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":" ","pages":"235-251"},"PeriodicalIF":6.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucagon-Like Peptide-1 Receptor Agonists: What's the Optimizing Policies for Obesity-Related Metabolic Diseases?","authors":"Tae Sun Park","doi":"10.4093/dmj.2025.0047","DOIUrl":"10.4093/dmj.2025.0047","url":null,"abstract":"","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":"49 2","pages":"169-171"},"PeriodicalIF":6.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rbbp6-Mediated Bmal1 Ubiquitination Inhibits YAP1 Signaling Pathway to Promote Ferroptosis in Diabetes-Induced Testicular Damage.","authors":"Yuan Tian, Zhiqiang Zhu, Jun Qiao, Bei Liu, Yuehai Xiao","doi":"10.4093/dmj.2024.0099","DOIUrl":"10.4093/dmj.2024.0099","url":null,"abstract":"<p><strong>Backgruound: </strong>Diabetes-induced testicular damage (DITD) is a common complication of diabetes. We investigated underlying mechanism of retinoblastoma-binding protein 6 (Rbbp6)-mediated brain and muscle ARNT-like 1 (Bmal1) ubiquitination in modulating ferroptosis in DITD.</p><p><strong>Methods: </strong>Spermatogenic cell apoptosis and viability were measured by flow cytometry and cell counting kit 8 (CCK-8), respectively. The impact of Rbbp6 and Bmal1 on ferroptosis was assessed by determining expression of ferroptosis markers glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and levels of malondialdehyde (MDA), glutathione (GSH), iron, and lipid peroxidation. Co-immunoprecipitation was performed to determine the interaction between Rbbp6 and Bmal1, as well as the ubiquitination level of Bmal1. The expression levels of Rbbp6, Bmal1, Yes-associated protein 1 (YAP1), ferroptosis markers, and testicular steroidogenic enzymes were tested by Western blot.</p><p><strong>Results: </strong>Bmal1 protein expression was significantly downregulated, while Rbbp6 was upregulated in DITD mouse model and high glucose (HG)-induced GC-1 spg cells. Overexpression of Bmal1 improved testicular injury in diabetic mice, reduced 4-hydroxynonenal (4-HNE), MDA, iron levels, and increased expression levels of GPX4, SLC7A11, GSH, as well as testicular steroidogenic enzymes. Rbbp6 decreased Bmal1 level through promoting its ubiquitination. Meanwhile, Rbbp6 knockdown inhibited the ferroptosis of HG-induced GC-1 spg cells, which were abolished by silencing Bmal1. In addition, knockdown of YAP1 or treatment with ferroptosis inducer erastin blocked the above effects caused by Bmal1 overexpression.</p><p><strong>Conclusion: </strong>Rbbp6-mediated Bmal1 ubiquitination suppressed YAP1 pathway, promoting ferroptosis in DITD. This study highlighted Rbbp6/Bmal1/YAP1 axis as a potential therapeutic target for mitigating DITD.</p>","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":" ","pages":"210-224"},"PeriodicalIF":6.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Obesity on the Association between Parity and Risk of Type 2 Diabetes Mellitus.","authors":"Yuki Gen, Kyuho Kim, Joonyub Lee, Junyoung Jung, Sang-Hyuk Jung, Hong-Hee Won, Dokyoon Kim, Yun-Sung Jo, Yu-Bae Ahn, Seung-Hyun Ko, Jae-Seung Yun","doi":"10.4093/dmj.2024.0536","DOIUrl":"https://doi.org/10.4093/dmj.2024.0536","url":null,"abstract":"<p><strong>Background: </strong>Most studies focus solely on the relationship between parity and type 2 diabetes mellitus (T2DM) risk, providing limited insights into other contributing or protective factors. This study aims to explore the complex relationship between parity and T2DM risk, considering additional factors such as obesity, race, and body composition.</p><p><strong>Methods: </strong>This prospective cohort study used data from 242,159 women aged 40 to 69 from the UK Biobank, none of whom had T2DM at baseline. Multivariable Cox proportional hazard models were applied to assess the association between parity and T2DM. Subgroup analyses were performed based on body mass index (BMI), waist circumference (WC), and race.</p><p><strong>Results: </strong>The hazard ratio for T2DM per additional child was 1.16 (95% confidence interval, 1.13 to 1.16). Subgroup analysis revealed that Asian women and those with obesity or abdominal obesity had a higher risk of T2DM associated with multiparity. No increased risk was observed in women with normal BMI or WC. Mediation analysis showed that WC and BMI significantly mediated the parity-T2DM relationship, accounting for 49% and 38% of the effect, respectively.</p><p><strong>Conclusion: </strong>There is a clear positive association between multiparity and T2DM risk, particularly in Asian women and those with obesity. Maintaining normal BMI and WC appears to mitigate this risk, highlighting the importance of weight management for women at higher parity levels. These findings offer crucial insights for public health interventions aimed at reducing T2DM risk among women.</p>","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contributions of Hepatic Insulin Resistance and Islet β-Cell Dysfunction to the Blood Glucose Spectrum in Newly Diagnosed Type 2 Diabetes Mellitus.","authors":"Mengge Yang, Ying Wei, Jia Liu, Ying Wang, Guang Wang","doi":"10.4093/dmj.2024.0537","DOIUrl":"https://doi.org/10.4093/dmj.2024.0537","url":null,"abstract":"<p><strong>Background: </strong>Our previous studies have investigated the role of hepatic insulin resistance (hepatic IR) and islet β-cell function in the pathogenesis of diabetes. This study aimed to explore the contributions of hepatic IR and islet β-cell dysfunction to the blood glucose spectrum in patients with newly diagnosed type 2 diabetes mellitus.</p><p><strong>Methods: </strong>Hepatic IR was assessed by the hepatic insulin resistance index (HIRI). Islet β-cell function was assessed by insulin secretion- sensitivity index-2 (ISSI2). The associations between blood glucose spectrum and hepatic IR and ISSI2 were analyzed.</p><p><strong>Results: </strong>A total of 707 patients with new-onset diabetes were included. The fasting blood glucose (FBG) and 30 minutes postload blood glucose elevated with rising HIRI (both P for trend <0.001). The FBG, 30 minutes, 2 hours, and 3 hours post-load blood glucose elevated with decreasing ISSI2 quartiles (all P for trend <0.001). There was a negative correlation between ISSI2 and HIRI after adjusting blood glucose levels (r=-0.199, P<0.001).</p><p><strong>Conclusion: </strong>Hepatic IR mainly contributed to FBG and early-phase postprandial plasma glucose, whereas β-cell dysfunction contributed to fasting and postprandial plasma glucose at each phase.</p>","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease.","authors":"Inseon Hwang, Jung Eun Nam, Wonsuk Choi, Won Gun Choi, Eunji Lee, Hyeongseok Kim, Young-Ah Moon, Jun Yong Park, Hail Kim","doi":"10.4093/dmj.2024.0215","DOIUrl":"https://doi.org/10.4093/dmj.2024.0215","url":null,"abstract":"<p><strong>Background: </strong>Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine neurotransmitter that has various functions in central and peripheral tissues. While 5-HT is known to regulate various biological processes in liver, direct role of 5-HT and its receptors, especially 5-HT receptor 2A (HTR2A) and HTR2B, in development and progression of alcoholic liver disease (ALD) in vivo is not well understood.</p><p><strong>Methods: </strong>Blood 5-HT level was measured from both human ALD patients and ethanol (EtOH) diet-fed mouse models. Gut-specific tryptophan hydroxylase 1 (Tph1) knockout mice, liver-specific Htr2a knockout mice, and liver-specific Htr2b knockout mice were fed with EtOH diet. Then we evaluated liver damage, hepatic steatosis, endoplasmic reticulum (ER) stress, and inflammation.</p><p><strong>Results: </strong>Blood 5-HT concentrations are increased in both humans and mice with ALD. Both gut-specific Tph1 knockout and liver- specific Htr2a knockout mice are resistant to steatosis by down-regulating lipogenic pathways in liver of chronic EtOH diet-fed mice. Moreover, genetic inhibition of both gut-derived serotonin (GDS) synthesis and hepatic HTR2A signaling prevents ER stress in liver of chronic EtOH diet-fed mice. Additionally, we found that ablation of HTR2A signaling protects against disease progression by attenuating liver injury and inflammation in chronic plus binge EtOH diet-fed mice. Also, inhibiting HTR2A signaling ameliorates alcohol-induced liver injury and ER stress in an acute EtOH diet-fed mice model.</p><p><strong>Conclusion: </strong>GDS directly regulates lipogenesis and ER stress via signaling through hepatic HTR2A in the context of ALD. Inhibiting HTR2A signaling protects against alcohol-induced steatosis, liver injury and disease progression in various ALD mouse models and may also provide a novel therapeutic strategy for ALD.</p>","PeriodicalId":11153,"journal":{"name":"Diabetes & Metabolism Journal","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}