Metabolism: clinical and experimental最新文献

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Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1 β细胞功能和糖耐量受损的人胰岛内完整GLP-1水平较高。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI: 10.1016/j.metabol.2024.156087
Teresa Mezza , Nicolai J. Wewer Albrechtsen , Gianfranco Di Giuseppe , Pietro Manuel Ferraro , Laura Soldovieri , Gea Ciccarelli , Michela Brunetti , Giuseppe Quero , Sergio Alfieri , Enrico Celestino Nista , Antonio Gasbarrini , Vincenzo Tondolo , Andrea Mari , Alfredo Pontecorvi , Andrea Giaccari , Jens J. Holst
{"title":"Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1","authors":"Teresa Mezza ,&nbsp;Nicolai J. Wewer Albrechtsen ,&nbsp;Gianfranco Di Giuseppe ,&nbsp;Pietro Manuel Ferraro ,&nbsp;Laura Soldovieri ,&nbsp;Gea Ciccarelli ,&nbsp;Michela Brunetti ,&nbsp;Giuseppe Quero ,&nbsp;Sergio Alfieri ,&nbsp;Enrico Celestino Nista ,&nbsp;Antonio Gasbarrini ,&nbsp;Vincenzo Tondolo ,&nbsp;Andrea Mari ,&nbsp;Alfredo Pontecorvi ,&nbsp;Andrea Giaccari ,&nbsp;Jens J. Holst","doi":"10.1016/j.metabol.2024.156087","DOIUrl":"10.1016/j.metabol.2024.156087","url":null,"abstract":"<div><h3>Aims</h3><div>A number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance.</div></div><div><h3>Methods</h3><div>We enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m<sup>2</sup>) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, <em>n</em> = 19), impaired glucose tolerant (IGT, <em>n</em> = 20) or newly diagnosed diabetes (DM) (<em>n</em> = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters.</div></div><div><h3>Results</h3><div>Extractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo.</div></div><div><h3>Conclusions</h3><div>Our data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156087"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Accurate non-invasive detection of MASH with fibrosis F2-F3 using a lightweight machine learning model with minimal clinical and metabolomic variables 利用轻量级机器学习模型,以最少的临床和代谢组学变量,对纤维化 F2-F3 的 MASH 进行准确的无创检测。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI: 10.1016/j.metabol.2024.156082
Konstantinos Stefanakis , Geltrude Mingrone , Jacob George , Christos S. Mantzoros
{"title":"Accurate non-invasive detection of MASH with fibrosis F2-F3 using a lightweight machine learning model with minimal clinical and metabolomic variables","authors":"Konstantinos Stefanakis ,&nbsp;Geltrude Mingrone ,&nbsp;Jacob George ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156082","DOIUrl":"10.1016/j.metabol.2024.156082","url":null,"abstract":"<div><h3>Background</h3><div>There are no known non-invasive tests (NITs) designed for accurately detecting metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2-F3, excluding cirrhosis—the FDA-defined range for prescribing Resmetirom and other drugs in clinical trials. We aimed to validate and re-optimize known NITs, and most importantly to develop new machine learning (ML)-based NITs to accurately detect MASH F2-F3.</div></div><div><h3>Methods</h3><div>Clinical and metabolomic data were collected from 443 patients across three countries and two clinic types (metabolic surgery, gastroenterology/hepatology) covering the entire spectrum of biopsy-proven MASH, including cirrhosis and healthy controls. Three novel types of ML models were developed using a categorical gradient boosting machine pipeline under a classic 4:1 split and a secondary independent validation analysis. These were compared with twenty-three biomarker, imaging, and algorithm-based NITs with both known and re-optimized cutoffs for MASH F2-F3.</div></div><div><h3>Results</h3><div>The NAFLD (Non-Alcoholic Fatty Liver Disease) Fibrosis Score (NFS) at a − 1.455 cutoff attained an area under the receiver operating characteristic curve (AUC) of 0.59, the highest sensitivity (90.9 %), and a negative predictive value (NPV) of 87.2 %. FIB-4 risk stratification followed by elastography (8 kPa) had the best specificity (86.9 %) and positive predictive value (PPV) (63.3 %), with an AUC of 0.57. NFS followed by elastography improved the PPV to 65.3 % and AUC to 0.62. Re-optimized FibroScan-AST (FAST) at a 0.22 cutoff had the highest PPV (69.1 %). ML models using aminotransferases, metabolic syndrome components, BMI, and 3-ureidopropionate achieved an AUC of 0.89, which further increased to 0.91 following hyperparameter optimization and the addition of alpha-ketoglutarate. These new ML models outperformed all other NITs and displayed accuracy, sensitivity, specificity, PPV, and NPV up to 91.2 %, 85.3 %, 97.0 %, 92.4 %, and 90.7 % respectively. The models were reproduced and validated in a secondary sensitivity analysis, that used one of the cohorts as feature selection/training, and the rest as independent validation, likewise outperforming all other applicable NITs.</div></div><div><h3>Conclusions</h3><div>We report for the first time the diagnostic characteristics of non-invasive, metabolomics-based biomarker models to detect MASH with fibrosis F2-F3 required for Resmetirom treatment and inclusion in ongoing phase-III trials. These models may be used alone or in combination with other NITs to accurately determine treatment eligibility.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156082"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prevalence, characteristics and outcomes of patients with metabolic and alcohol related/associated liver disease (MetALD): a systematic review and meta-analysis 代谢性和酒精相关/相关肝病患者的患病率、特征和结局:一项系统综述和荟萃分析
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI: 10.1016/j.metabol.2024.156101
Maria Tampaki , Emmanouil Tsochatzis , Vasileios Lekakis , Evangelos Cholongitas
{"title":"Prevalence, characteristics and outcomes of patients with metabolic and alcohol related/associated liver disease (MetALD): a systematic review and meta-analysis","authors":"Maria Tampaki ,&nbsp;Emmanouil Tsochatzis ,&nbsp;Vasileios Lekakis ,&nbsp;Evangelos Cholongitas","doi":"10.1016/j.metabol.2024.156101","DOIUrl":"10.1016/j.metabol.2024.156101","url":null,"abstract":"<div><h3>Background</h3><div>In light of the new nomenclature of steatotic liver disease (SLD), we aimed to enhance the existing knowledge on the epidemiology and clinical outcomes of metabolic and alcohol related/associated liver disease (MetALD).</div></div><div><h3>Methods</h3><div>A systematic review and meta-analysis were performed in Medline/PubMed, Embase, Scopus and Cochrane databases to evaluate the prevalence and outcomes of MetALD within the SLD population and to compare the characteristics between MetALD patients and those with metabolic dysfunction associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD). Nineteen studies from nine countries that evaluated 4,543,341 adult participants with SLD were included.</div></div><div><h3>Results</h3><div>The pooled overall prevalence of MetALD among the SLD population was 10 % (95%CI:7–13 %) without significant difference between Asian and non-Asian populations. However, MetALD was more frequent in men than women (86 % vs 14 %, <em>p</em> &lt; 0.01), while Asian MetALD patients, were more frequent men (92 % vs 66 %, p &lt; 0.01) compared to non-Asians. Additionally, in terms of metabolic characteristics there were no significant differences between MetALD, MASLD and ALD patients. Regarding outcomes, patients with MetALD, compared to non-SLD, were at increased risk of all-cause [HR 1.44 (95%CI:1.24–1.66)], cardiovascular disease (CVD) [HR 1.17 (95%CI:1.12–1.21)] and cancer-related mortality [HR 2.07 (95%CI:1.32–3.25)]. Finally, patients with MetALD, had increased incidence of CVD and liver decompensating events, compared to non-SLD participants [HR 1.49 (95%CI:1.03–2.15); HR 10.55 (95%CI:3.46–32.16) respectively].</div></div><div><h3>Conclusions</h3><div>Based on the existing literature, patients with MetALD consist a significant part of the SLD population, with high all-cause, CVD and cancer-related mortality and increased risk for CVD and hepatic decompensation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156101"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibiting IP6K1 confers atheroprotection by elevating circulating apolipoprotein A-I 抑制IP6K1通过提高循环载脂蛋白A-I来保护动脉粥样硬化。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI: 10.1016/j.metabol.2024.156098
Xiaoqi Liu , Zixuan Zhang , Tim Aguirre , Megan L. Shipton , Lin Fu , Jimin Du , David Furkert , Ji Qi , Alfred C. Chin , Andrew M. Riley , Tong Liu , Xu Zhang , Barry V.L. Potter , Dorothea Fiedler , Yi Zhu , Chenglai Fu
{"title":"Inhibiting IP6K1 confers atheroprotection by elevating circulating apolipoprotein A-I","authors":"Xiaoqi Liu ,&nbsp;Zixuan Zhang ,&nbsp;Tim Aguirre ,&nbsp;Megan L. Shipton ,&nbsp;Lin Fu ,&nbsp;Jimin Du ,&nbsp;David Furkert ,&nbsp;Ji Qi ,&nbsp;Alfred C. Chin ,&nbsp;Andrew M. Riley ,&nbsp;Tong Liu ,&nbsp;Xu Zhang ,&nbsp;Barry V.L. Potter ,&nbsp;Dorothea Fiedler ,&nbsp;Yi Zhu ,&nbsp;Chenglai Fu","doi":"10.1016/j.metabol.2024.156098","DOIUrl":"10.1016/j.metabol.2024.156098","url":null,"abstract":"<div><h3>Background and aims</h3><div>Atherosclerotic cardiovascular diseases are the leading cause of death. Apolipoprotein A-I (apoA-I) mediates cholesterol efflux to lower the risks of atherosclerosis. Elevating circulating apoA-I is an effective strategy for atheroprotection. However, the regulatory mechanisms of apoA-I have been elusive.</div></div><div><h3>Methods</h3><div>Protein-protein interactions were examined by co-immunoprecipitations. Chemical biology tools were used to determine the binding of 5PP-InsP<sub>5</sub> to its target proteins and its roles in mediating protein-protein interactions. The mouse atherosclerotic model was generated by injecting AAV-PCSK9 and feeding a Western diet. Atherosclerotic plaques were determined by Oil Red O and H&amp;E staining.</div></div><div><h3>Results</h3><div>We show that blocking IP6K1 activity increases apoA-I production in hepatocytes. IP6K1 binds to apoA-I and <em>via</em> its product 5PP-InsP<sub>5</sub> to induce apoA-I degradation, which requires ubiquitination factor E4A (UBE4A). Depleting 5PP-InsP<sub>5</sub> by deleting IP6K1 or blocking IP6K1 activity disrupts the interaction between UBE4A and apoA-I, preventing apoA-I degradation, leading to increased production of apoA-I. Hepatocyte-specific deletion of IP6K1 elevates circulating apoA-I levels, which augments cholesterol efflux and lowers the burden of atherosclerosis. Mice with both <em>apoA-I</em> KO and hepatocyte-specific <em>IP6K1</em> KO were generated to validate that IP6K1 deletion-induced atheroprotection requires apoA-I.</div></div><div><h3>Conclusions</h3><div>Our findings reveal a mechanism by which blocking IP6K1 boosts apoA-I production. Blocking IP6K1 represents a potential treatment strategy to elevate circulating apoA-I for atheroprotection.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156098"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Recent advances and therapeutic applications of PPARγ-targeted ligands based on the inhibition mechanism of Ser273 phosphorylation 基于Ser273磷酸化抑制机制的ppar γ靶向配体研究进展及治疗应用
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI: 10.1016/j.metabol.2024.156097
Fangyuan Chen , Lei Ma , Qingmei Liu, Zhi Zhou, Wei Yi
{"title":"Recent advances and therapeutic applications of PPARγ-targeted ligands based on the inhibition mechanism of Ser273 phosphorylation","authors":"Fangyuan Chen ,&nbsp;Lei Ma ,&nbsp;Qingmei Liu,&nbsp;Zhi Zhou,&nbsp;Wei Yi","doi":"10.1016/j.metabol.2024.156097","DOIUrl":"10.1016/j.metabol.2024.156097","url":null,"abstract":"<div><div>PPARγ functions as a master ligand-dependent transcription factor that regulates the expressions of a variety of key genes related to metabolic homeostasis and inflammatory immunity. It has been recognized as a popular and druggable target in modern drug discovery. Similar to other nuclear receptors, PPARγ is a phosphoprotein, and its biological functions are regulated by phosphorylation, especially at Ser273 site which is mediated by CDK5 or ERK. In the past decade, the excessive level of PPARγ-Ser273 phosphorylation has been confirmed to be a crucial factor in promoting the occurrence and development of some major diseases. Ligands capable of inhibiting PPARγ-Ser273 phosphorylation have shown great potentials for treatment. Despite these achievements, to our knowledge, no related review focusing on this topic has been conducted so far. Therefore, we herein summarize the basic knowledge of PPARγ and CDK5/ERK-mediated PPARγ-Ser273 phosphorylation as well as its physiopathological role in representative diseases. We also review the developments and therapeutic applications of PPARγ-targeted ligands based on this mechanism. Finally, we suggest several directions for future investigations. We expect that this review can evoke more inspiration of scientific communities, ultimately facilitating the promotion of the PPARγ-Ser273 phosphorylation-involved mechanism as a promising breakthrough point for addressing the clinical treatment of human diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156097"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
GDF-15 improves the predictive capacity of steatotic liver disease non-invasive tests for incident morbidity and mortality risk for cardio-renal-metabolic diseases and malignancies GDF-15 提高了脂肪肝无创检测对心肾代谢疾病和恶性肿瘤发病率和死亡率的预测能力。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI: 10.1016/j.metabol.2024.156047
Michail Kokkorakis , Pytrik Folkertsma , José Castela Forte , Bruce H.R. Wolffenbuttel , Sipko van Dam , Christos S. Mantzoros
{"title":"GDF-15 improves the predictive capacity of steatotic liver disease non-invasive tests for incident morbidity and mortality risk for cardio-renal-metabolic diseases and malignancies","authors":"Michail Kokkorakis ,&nbsp;Pytrik Folkertsma ,&nbsp;José Castela Forte ,&nbsp;Bruce H.R. Wolffenbuttel ,&nbsp;Sipko van Dam ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156047","DOIUrl":"10.1016/j.metabol.2024.156047","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Noninvasive tools (NITs) are currently used to stratify the risk of having or developing hepatic steatosis or fibrosis. Their performance and a proteomic-enabled improvement in forecasting long-term cardio-renal-metabolic morbidity, malignancies, as well as cause-specific and all-cause mortality, are lacking. Therefore, the performance of established NITs needs to be investigated in identifying cardio-renal-metabolic morbidity, malignancies, cause-specific and overall mortality and improve their performance with novel, proteomic-enabled NITs, including growth differentiation factor 15 (GDF-15), allowing multipurpose utilization.</div></div><div><h3>Methods</h3><div>502,359 UK Biobank participants free of the study outcomes at baseline with a 14-year median follow-up were grouped into three categories: a) general population, b) potentially metabolic dysfunction-associated steatotic liver disease (MASLD) population, c) individuals with type 2 diabetes mellitus. The investigated NITs include Aspartate aminotransferase to Platelet Ratio Index (APRI), Fibrosis 4 Index (FIB-4), Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Lipid Accumulation Product (LAP), and metabolic dysfunction–associated fibrosis (MAF-5) score.</div></div><div><h3>Results</h3><div>Adding GDF-15 to the existing NITs led to significantly increased prognostic performance compared to the traditional NITs in almost all instances, reaching substantially high C-indices, ranging between 0.601 and 0.808, with an overall &gt;0.2 improvement in C-index. Overall, with the GDF-15 enhanced NITs, up to more than seven times fewer individuals need to be screened to identify more incident cases of adverse outcomes compared to the traditional NITs. The cumulative incidence of all outcomes, based on the continuous value percentiles of NITs, is increasing exponentially in the upper quintile of the GDF-15 enhanced NITs.</div></div><div><h3>Conclusions</h3><div>The herein-developed GDF-15 enhanced indices demonstrate higher screening effectiveness and significantly improved prognostic abilities, which are reduced to practice through an easy-to-use web-based calculator tool (<span><span>https://clinicalpredictor.shinyapps.io/multimorbidity-mortality-risk/</span><svg><path></path></svg></span>).</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156047"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The role of IL-1 family cytokines in diabetic cardiomyopathy IL-1 家族细胞因子在糖尿病心肌病中的作用。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI: 10.1016/j.metabol.2024.156083
Qi Wu , Yan Zeng , Kang Geng , Man Guo , Fang-yuan Teng , Pi-jun Yan , Yi Lei , Yang Long , Zong-zhe Jiang , Betty Yuen-Kwan Law , Yong Xu
{"title":"The role of IL-1 family cytokines in diabetic cardiomyopathy","authors":"Qi Wu ,&nbsp;Yan Zeng ,&nbsp;Kang Geng ,&nbsp;Man Guo ,&nbsp;Fang-yuan Teng ,&nbsp;Pi-jun Yan ,&nbsp;Yi Lei ,&nbsp;Yang Long ,&nbsp;Zong-zhe Jiang ,&nbsp;Betty Yuen-Kwan Law ,&nbsp;Yong Xu","doi":"10.1016/j.metabol.2024.156083","DOIUrl":"10.1016/j.metabol.2024.156083","url":null,"abstract":"<div><div>Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with diabetes and is characterised by contractile dysfunction and left ventricular hypertrophy. The complex pathological and physiological mechanisms underlying DCM have contributed to a limited number of available treatment options. A substantial body of evidence has established that DCM is a low-grade inflammatory cardiovascular disorder, with the interleukin-1 (IL-1) family of cytokines playing crucial roles in initiating inflammatory responses and shaping innate and adaptive immunity. In this review, we aim to provide an overview of the underlying mechanisms of the IL-1 family and their relevance in DCM of various aetiologies. Furthermore, we highlighted potential therapeutic targets within the IL-1 family for the management of DCM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156083"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PCSK9 in metabolism and diseases 新陈代谢和疾病中的 PCSK9。
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI: 10.1016/j.metabol.2024.156064
Amir Ajoolabady , Domenico Pratico , Mohsen Mazidi , Ian G. Davies , Gregory Y.H. Lip , Nabil Seidah , Peter Libby , Guido Kroemer , Jun Ren
{"title":"PCSK9 in metabolism and diseases","authors":"Amir Ajoolabady ,&nbsp;Domenico Pratico ,&nbsp;Mohsen Mazidi ,&nbsp;Ian G. Davies ,&nbsp;Gregory Y.H. Lip ,&nbsp;Nabil Seidah ,&nbsp;Peter Libby ,&nbsp;Guido Kroemer ,&nbsp;Jun Ren","doi":"10.1016/j.metabol.2024.156064","DOIUrl":"10.1016/j.metabol.2024.156064","url":null,"abstract":"<div><div>PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones – including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156064"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association between the Life's essential 8 health behaviors score and all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease 代谢功能障碍相关脂肪变性肝病患者生活基本健康行为评分与全因死亡率的关系
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-02-01 DOI: 10.1016/j.metabol.2024.156096
Yan Han , Jing Tang , Na Wu , Zhao Li , Hong Ren , Peng Hu , Zhiwei Chen
{"title":"Association between the Life's essential 8 health behaviors score and all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease","authors":"Yan Han ,&nbsp;Jing Tang ,&nbsp;Na Wu ,&nbsp;Zhao Li ,&nbsp;Hong Ren ,&nbsp;Peng Hu ,&nbsp;Zhiwei Chen","doi":"10.1016/j.metabol.2024.156096","DOIUrl":"10.1016/j.metabol.2024.156096","url":null,"abstract":"<div><h3>Background</h3><div>The association between Life's Essential 8 (LE8) score and all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unknown.</div></div><div><h3>Methods</h3><div>This population-based prospective cohort study analyzed data of participants aged 20–79 years in the National Health and Nutrition Examination Survey from 2005 to 2018, with linked mortality information until 2019. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association between different cardiovascular health (CVH) scores and all-cause mortality in participants with MASLD.</div></div><div><h3>Results</h3><div>Among 11,988 participants, 4109 (34.3 %) were diagnosed with MASLD. During the median 7.8 years of follow-up, 912 deaths were recorded. Unexpectedly, the total LE8 CVH score was not associated with all-cause mortality in patients with MASLD (all <em>P</em> &gt; .05). However, individuals with MASLD with moderate and poor LE8 health behaviors scores exhibited an increased risk of all-cause mortality (moderate: HR, 1.51; 95 % CI, 1.05–2.17; poor: HR, 2.32; 95 % CI, 1.64–3.30), particularly among patients with advanced fibrosis (moderate: HR, 1.77; 95 % CI, 1.07–2.92; poor: HR, 2.43; 95 % CI, 1.23–4.78). Population-attributable fraction estimates suggest that 35.0 % of all-cause mortality attributed to poor or moderate health behaviors scores could be avoided if ideal CVH metrics were achieved in all patients with MASLD.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate a significant association between the LE8 health behaviors score and all-cause mortality in patients with MASLD, highlighting the usefulness of this score in optimizing risk management strategies for MASLD in future clinical practice.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156096"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effects of coding variants in the glucokinase regulatory protein gene on hepatic glucose and triglyceride metabolism suggest a gene regulatory function of glucokinase
IF 10.8 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-01-31 DOI: 10.1016/j.metabol.2025.156150
Sara Langer , David Jagdhuhn , Rica Waterstradt , Jessica Gromoll , Michael Müller , Matthew G. Rees , Anna L. Gloyn , Simone Baltrusch
{"title":"Effects of coding variants in the glucokinase regulatory protein gene on hepatic glucose and triglyceride metabolism suggest a gene regulatory function of glucokinase","authors":"Sara Langer ,&nbsp;David Jagdhuhn ,&nbsp;Rica Waterstradt ,&nbsp;Jessica Gromoll ,&nbsp;Michael Müller ,&nbsp;Matthew G. Rees ,&nbsp;Anna L. Gloyn ,&nbsp;Simone Baltrusch","doi":"10.1016/j.metabol.2025.156150","DOIUrl":"10.1016/j.metabol.2025.156150","url":null,"abstract":"<div><h3>Background</h3><div>Regulation of glucose metabolism after a meal is the major task of hepatic glucokinase (GCK). Inhibition and nuclear retention of glucokinase during fasting is achieved by glucokinase regulatory protein (GKRP). Compounds disrupting the GCK-GKRP interaction alter glucose but not triglyceride levels, whilst GKRP coding alleles lower glucose but elevate triglycerides. The aim of this study was to identify yet unknown functions of GKRP by examining human variants both rare (p.Q234P, p.H438Y) and common (p.P446L).</div></div><div><h3>Methods</h3><div>Fluorescently labelled human GKRP variant and GCK proteins were expressed in hepatoma cells or primary mouse hepatocytes to investigate the subcellular localization of both proteins, cellular glucose uptake, and triglyceride levels. Mutational effects on GKRP protein structure were analyzed with PyMOL. Nuclear-to-cytoplasmic distribution of the GCK-GKRP complex was modeled in MATLAB.</div></div><div><h3>Results</h3><div>Nuclear localization of the GKRP variants was decreased compared to wild-type. Only H438Y-GKRP still evoked WT-like GCK nuclear accumulation. Nuclear localization of Q234P-GKRP was most impaired and depended on the presence of GCK, which, supported by structural analyses, could stabilize its conformation. Nonetheless, inhibition of glucose uptake was least impaired with Q234P-GKRP. Triglyceride contents related to the glucose uptake of hepatoma cells were disproportionately high for cells expressing wild-type or H438Y-GKRP, the two variants that induced higher nuclear sequestration of GCK.</div></div><div><h3>Conclusions</h3><div>Our results, supported by a modeling approach, suggest that GKRP-mediated nuclear localization of GCK has a function in liver metabolism beyond GCK inhibition and sequestration. This needs further elucidation given that GKRP disruptors have been proposed for antihyperglycemic therapy.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156150"},"PeriodicalIF":10.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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