Pub Date : 2026-01-01Epub Date: 2025-11-03DOI: 10.1016/j.metabol.2025.156430
Yiying Wang , Arvid Sandforth , Reiner Jumprtz-von Schwartzenberg , Marlene Ganslmeier , Yurong Cheng , Leontine Sandforth , Sarah Katzenstein , Jürgen Machann , Fritz Schick , Konstantinos Kantartzis , Hubert Preissl , Andreas Fritsche , Norbert Stefan , Michael Bergman , Andreas L. Birkenfeld
Background
High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glucose regulation (IGR) and is amendable to greater lifestyle intervention (LI) benefit.
Methods
In the Tübingen Lifestyle Intervention Program, 317 people with either NGR, IGR or isolated high 1 h-PG without IGR underwent LI for 9 months to achieve ≥5 % weight loss.
Results
Before LI initiation, insulin sensitivity and β-cell function declined progressively from NGR (n = 106) to high 1 h-PG (n = 96) and to IGR (n = 115). Visceral adipose tissue (VAT) volume and liver fat content increased from NGT to high 1 h-PG and to IGR. LI improved insulin sensitivity and ß-cell function in the high 1 h-PG group to levels observed in NGR together with a marked reduction in hepatic fat content. Compared to the IGR group, T2D risk was reduced by 80 % (37–96 %, p = 0.005) in the high 1 h-PG group during a 12-year follow-up period. The odds of remission to complete normoglycemia were doubled in the high 1 h-PG group compared to the IGR group (2.18 [1.13–4.28], p = 0.021).
Conclusion
High 1 h-PG indicates an intermediate metabolic state with pathophysiological changes more severe than in NGR but milder than in IGR. In people with high 1 h-PG, LI significantly improved insulin sensitivity and β-cell function and reduced ectopic lipid deposition and the risk of developing T2D compared to IGR. These findings highlight the value of 1 h-PG as a clinically useful biomarker, providing a critical window for early intervention to reverse core metabolic defects driving prediabetes and T2D.
{"title":"Lifestyle intervention is more effective in high 1-hour post-load glucose than in prediabetes for restoring β-cell function, reducing ectopic fat, and preventing type 2 diabetes","authors":"Yiying Wang , Arvid Sandforth , Reiner Jumprtz-von Schwartzenberg , Marlene Ganslmeier , Yurong Cheng , Leontine Sandforth , Sarah Katzenstein , Jürgen Machann , Fritz Schick , Konstantinos Kantartzis , Hubert Preissl , Andreas Fritsche , Norbert Stefan , Michael Bergman , Andreas L. Birkenfeld","doi":"10.1016/j.metabol.2025.156430","DOIUrl":"10.1016/j.metabol.2025.156430","url":null,"abstract":"<div><h3>Background</h3><div>High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glucose regulation (IGR) and is amendable to greater lifestyle intervention (LI) benefit.</div></div><div><h3>Methods</h3><div>In the Tübingen Lifestyle Intervention Program, 317 people with either NGR, IGR or isolated high 1 h-PG without IGR underwent LI for 9 months to achieve ≥5 % weight loss.</div></div><div><h3>Results</h3><div>Before LI initiation, insulin sensitivity and β-cell function declined progressively from NGR (<em>n</em> = 106) to high 1 h-PG (<em>n</em> = 96) and to IGR (<em>n</em> = 115). Visceral adipose tissue (VAT) volume and liver fat content increased from NGT to high 1 h-PG and to IGR. LI improved insulin sensitivity and ß-cell function in the high 1 h-PG group to levels observed in NGR together with a marked reduction in hepatic fat content. Compared to the IGR group, T2D risk was reduced by 80 % (37–96 %, <em>p</em> = 0.005) in the high 1 h-PG group during a 12-year follow-up period. The odds of remission to complete normoglycemia were doubled in the high 1 h-PG group compared to the IGR group (2.18 [1.13–4.28], <em>p</em> = 0.021).</div></div><div><h3>Conclusion</h3><div>High 1 h-PG indicates an intermediate metabolic state with pathophysiological changes more severe than in NGR but milder than in IGR. In people with high 1 h-PG, LI significantly improved insulin sensitivity and β-cell function and reduced ectopic lipid deposition and the risk of developing T2D compared to IGR. These findings highlight the value of 1 h-PG as a clinically useful biomarker, providing a critical window for early intervention to reverse core metabolic defects driving prediabetes and T2D.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156430"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452341","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}
Classical biomarkers of diabetic kidney disease (DKD), including serum creatinine and albuminuria, cannot detect the disease in early stages, leading to worsened complications. This study aimed to introduce a panel of early diagnostic biomarkers for DKD through meta-analysis of longitudinal metabolomics studies.
Methods
A systematic search was conducted across PubMed, Web of Science, and Scopus up to May 12, 2025. Only studies were included in which urine or blood samples were collected from individuals with diabetes and the participants were followed over time. The outcomes were defined as DKD incidence, albuminuria progression, rapid estimated glomerular filtration rate decline, end-stage renal disease, or all-cause mortality. Relative ratio (95 % confidence intervals (CI)) or correlation coefficients (95 % CI) of baseline metabolites with these outcomes were extracted from the included studies.
Results
The analysis included 39 studies covering 52 populations, with a total sample size of 31,012 individuals. The meta-analysis incorporated 170 blood and 12 urine metabolites, of which 65 and 11 showed significant associations with the outcomes, respectively. Enrichment analyses of the differential metabolites highlighted the reprogramming of amino acid, lipid, and energy metabolism.
Conclusion
This meta-analysis introduces metabolic biomarkers strongly associated with DKD incidence or progression. Furthermore, this study underscores the rewiring of metabolic pathways related to energy homeostasis as an adaptation to the prolonged insults of diabetic milieu. The limitations of this study are, the variation in multivariable adjustment methods used across the included studies and the lack of established decision thresholds for the proposed biomarkers.
糖尿病肾病（DKD）的经典生物标志物，包括血清肌酐和蛋白尿，不能在早期发现疾病，导致并发症恶化。本研究旨在通过纵向代谢组学研究的荟萃分析，介绍一组DKD的早期诊断生物标志物。方法系统检索截至2025年5月12日的PubMed、Web of Science和Scopus。只有从糖尿病患者身上收集尿液或血液样本，并对参与者进行长期随访的研究才被纳入其中。结果定义为DKD发生率、蛋白尿进展、肾小球滤过率快速下降、终末期肾病或全因死亡率。从纳入的研究中提取基线代谢物与这些结果的相对比率（95%置信区间（CI））或相关系数（95% CI）。结果该分析包括39项研究，涵盖52个人群，总样本量为31,012人。荟萃分析纳入了170种血液代谢物和12种尿液代谢物，其中65种和11种分别显示与结果显著相关。对差异代谢物的富集分析强调了氨基酸、脂质和能量代谢的重编程。该荟萃分析引入了与DKD发病率或进展密切相关的代谢生物标志物。此外，这项研究强调了与能量稳态相关的代谢途径的重新布线，作为对糖尿病环境长期损害的适应。本研究的局限性是，在纳入的研究中使用的多变量调整方法存在差异，并且缺乏所提议的生物标志物的既定决策阈值。
{"title":"Metabolomics analysis of diabetic kidney disease for discovering early diagnostic biomarkers: A systematic review and meta-analysis of prospective studies","authors":"Zahra Ramazani , Rezvan Adibi , Alieh Gholaminejad , Marjan Mansourian , Yousof Gheisari","doi":"10.1016/j.metabol.2025.156422","DOIUrl":"10.1016/j.metabol.2025.156422","url":null,"abstract":"<div><h3>Background</h3><div>Classical biomarkers of diabetic kidney disease (DKD), including serum creatinine and albuminuria, cannot detect the disease in early stages, leading to worsened complications. This study aimed to introduce a panel of early diagnostic biomarkers for DKD through meta-analysis of longitudinal metabolomics studies.</div></div><div><h3>Methods</h3><div>A systematic search was conducted across PubMed, Web of Science, and Scopus up to May 12, 2025. Only studies were included in which urine or blood samples were collected from individuals with diabetes and the participants were followed over time. The outcomes were defined as DKD incidence, albuminuria progression, rapid estimated glomerular filtration rate decline, end-stage renal disease, or all-cause mortality. Relative ratio (95 % confidence intervals (CI)) or correlation coefficients (95 % CI) of baseline metabolites with these outcomes were extracted from the included studies.</div></div><div><h3>Results</h3><div>The analysis included 39 studies covering 52 populations, with a total sample size of 31,012 individuals. The meta-analysis incorporated 170 blood and 12 urine metabolites, of which 65 and 11 showed significant associations with the outcomes, respectively. Enrichment analyses of the differential metabolites highlighted the reprogramming of amino acid, lipid, and energy metabolism.</div></div><div><h3>Conclusion</h3><div>This meta-analysis introduces metabolic biomarkers strongly associated with DKD incidence or progression. Furthermore, this study underscores the rewiring of metabolic pathways related to energy homeostasis as an adaptation to the prolonged insults of diabetic milieu. The limitations of this study are, the variation in multivariable adjustment methods used across the included studies and the lack of established decision thresholds for the proposed biomarkers.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156422"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516604","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}
Pub Date : 2026-01-01Epub Date: 2025-10-09DOI: 10.1016/j.metabol.2025.156417
Linyi Li , Yu Wang , Zhiyong Du , Huahui Yu , Yunyun Yang , Zihan Zhang , Yanru Duan , Lijie Han , Chaowei Hu , Yunhui Du , Haili Sun , Xuechun Sun , Jingci Xing , Xiaoqian Gao , Dong Chen , Yuhui Wang , Xinwei Hua , Jianping Li , Yanwen Qin
Background and aims
Targeting key enzymes in hepatic de novo lipogenesis (DNL) presents a promising strategy for treating hypercholesterolemia. However, the precise regulatory mechanisms governing hepatic DNL remain incompletely understood. Cytosolic citrate plays a crucial role in DNL, with aconitase 1 (ACO1), a key enzyme in citrate metabolism, potentially influencing lipid metabolism. The aim of this study was to clarify the role of hepatic ACO1 in regulating both hepatic and systemic lipid homeostasis.
Methods
ACO1 expression and activity were assessed in liver tissues from multiple hypercholesterolemic animal models. Using liver-specific genetic manipulation, we examined the effects of hepatic ACO1 knockout and overexpression on hypercholesterolemia and atherosclerosis. Targeted metabolomics and stable isotope-based flux analysis were used to profile hepatic substrate utilization patterns.
Results
Hepatic ACO1 expression was significantly reduced in both hypercholesterolemic patients and animal models. Hepatocyte-specific ACO1 deletion exacerbated dyslipidemia, while ACO1 overexpression improved hypercholesterolemia, hepatic steatosis, and atherosclerosis in mouse models. Mechanistically, ACO1 overexpression redirected cytosolic citrate metabolism toward α-ketoglutarate, thereby limiting acetyl-CoA availability for DNL and suppressing fatty acid and cholesterol synthesis. These lipid-lowering effects were dependent on ACO1 enzymatic activity, as catalytically inactive ACO1 mutants failed to replicate the observed benefits.
Conclusion
Our findings identify hepatic ACO1 as a critical regulator of lipid metabolism homeostasis. Promoting ACO1-mediated citrate redirection effectively mitigates hypercholesterolemia and atherosclerosis by suppressing hepatic DNL, highlighting ACO1 as a potential target for lipid-lowering therapies.
{"title":"Hepatic aconitase 1 redirects citrate flux to suppress lipogenesis and ameliorate hypercholesterolemia","authors":"Linyi Li , Yu Wang , Zhiyong Du , Huahui Yu , Yunyun Yang , Zihan Zhang , Yanru Duan , Lijie Han , Chaowei Hu , Yunhui Du , Haili Sun , Xuechun Sun , Jingci Xing , Xiaoqian Gao , Dong Chen , Yuhui Wang , Xinwei Hua , Jianping Li , Yanwen Qin","doi":"10.1016/j.metabol.2025.156417","DOIUrl":"10.1016/j.metabol.2025.156417","url":null,"abstract":"<div><h3>Background and aims</h3><div>Targeting key enzymes in hepatic de novo lipogenesis (DNL) presents a promising strategy for treating hypercholesterolemia. However, the precise regulatory mechanisms governing hepatic DNL remain incompletely understood. Cytosolic citrate plays a crucial role in DNL, with aconitase 1 (ACO1), a key enzyme in citrate metabolism, potentially influencing lipid metabolism. The aim of this study was to clarify the role of hepatic ACO1 in regulating both hepatic and systemic lipid homeostasis.</div></div><div><h3>Methods</h3><div>ACO1 expression and activity were assessed in liver tissues from multiple hypercholesterolemic animal models. Using liver-specific genetic manipulation, we examined the effects of hepatic ACO1 knockout and overexpression on hypercholesterolemia and atherosclerosis. Targeted metabolomics and stable isotope-based flux analysis were used to profile hepatic substrate utilization patterns.</div></div><div><h3>Results</h3><div>Hepatic ACO1 expression was significantly reduced in both hypercholesterolemic patients and animal models. Hepatocyte-specific ACO1 deletion exacerbated dyslipidemia, while ACO1 overexpression improved hypercholesterolemia, hepatic steatosis, and atherosclerosis in mouse models. Mechanistically, ACO1 overexpression redirected cytosolic citrate metabolism toward α-ketoglutarate, thereby limiting acetyl-CoA availability for DNL and suppressing fatty acid and cholesterol synthesis. These lipid-lowering effects were dependent on ACO1 enzymatic activity, as catalytically inactive ACO1 mutants failed to replicate the observed benefits.</div></div><div><h3>Conclusion</h3><div>Our findings identify hepatic ACO1 as a critical regulator of lipid metabolism homeostasis. Promoting ACO1-mediated citrate redirection effectively mitigates hypercholesterolemia and atherosclerosis by suppressing hepatic DNL, highlighting ACO1 as a potential target for lipid-lowering therapies.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156417"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258780","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}
Pub Date : 2026-01-01Epub Date: 2025-10-28DOI: 10.1016/j.metabol.2025.156423
Felipe Muñoz , Qian Gao , Matthias Mattanovich , Kajetan Trost , Ondřej Hodek , Andreas Lindqvist , Nils Wierup , Malin Fex , Thomas Moritz , Hindrik Mulder , Luis Rodrigo Cataldo
Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored.
Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1, and HADH, were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing AASS in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in Aass-KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted.
Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector.
Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.
{"title":"Lysine potentiates insulin secretion via AASS-dependent catabolism and regulation of GABA content and signaling","authors":"Felipe Muñoz , Qian Gao , Matthias Mattanovich , Kajetan Trost , Ondřej Hodek , Andreas Lindqvist , Nils Wierup , Malin Fex , Thomas Moritz , Hindrik Mulder , Luis Rodrigo Cataldo","doi":"10.1016/j.metabol.2025.156423","DOIUrl":"10.1016/j.metabol.2025.156423","url":null,"abstract":"<div><div>Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored.</div><div>Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including <em>AASS, ALDH7A1, DHTKD1</em>, and <em>HADH</em>, were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing <em>AASS</em> in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in <em>Aass</em>-KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted.</div><div>Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector.</div><div>Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156423"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409747","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}
Pub Date : 2026-01-01Epub Date: 2025-10-06DOI: 10.1016/j.metabol.2025.156413
Pieter R. Norden , Riley J. Wedan , Samuel E.J. Preston , Morgan Canfield , Naomi Graber , Jacob Z. Longenecker , Olivia A. Pentecost , Elizabeth McLaughlin , Madeleine L. Hart , Sara M. Nowinski
4′-Phosphopantetheinyl (4’PP) groups are essential co-factors added to target proteins by phosphopantetheinyl transferase (PPTase) enzymes. Although mitochondrial 4’PP-modified proteins have been described for decades, a mitochondrially-localized PPTase has never been found in mammals. We discovered that the cytoplasmic PPTase aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT) is required for mitochondrial respiration and oxidative metabolism. Loss of AASDHPPT results in failed 4’PP modification of the mitochondrial acyl carrier protein and blunted activity of the mitochondrial fatty acid synthesis (mtFAS) pathway. We found that in addition to its cytoplasmic localization, AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 20 amino acids of the protein. Our data show that this novel mitochondrial localization of AASDHPPT is required to support mtFAS activity and oxidative metabolism. We further identify five variants of uncertain significance in AASDHPPT that are likely pathogenic in humans due to loss of mtFAS activity.
{"title":"Mitochondrial phosphopantetheinylation is required for oxidative metabolism","authors":"Pieter R. Norden , Riley J. Wedan , Samuel E.J. Preston , Morgan Canfield , Naomi Graber , Jacob Z. Longenecker , Olivia A. Pentecost , Elizabeth McLaughlin , Madeleine L. Hart , Sara M. Nowinski","doi":"10.1016/j.metabol.2025.156413","DOIUrl":"10.1016/j.metabol.2025.156413","url":null,"abstract":"<div><div>4′-Phosphopantetheinyl (4’PP) groups are essential co-factors added to target proteins by <u>p</u>hospho<u>p</u>antetheinyl <u>t</u>ransferase (PPTase) enzymes. Although mitochondrial 4’PP-modified proteins have been described for decades, a mitochondrially-localized PPTase has never been found in mammals. We discovered that the cytoplasmic PPTase <u>a</u>mino<u>a</u>dipate <u>s</u>emialdehyde <u>d</u>ehydrogenase <u>p</u>hospho<u>p</u>antetheinyl <u>t</u>ransferase (AASDHPPT) is required for mitochondrial respiration and oxidative metabolism. Loss of AASDHPPT results in failed 4’PP modification of the mitochondrial acyl carrier protein and blunted activity of the mitochondrial fatty acid synthesis (mtFAS) pathway. We found that in addition to its cytoplasmic localization, AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 20 amino acids of the protein. Our data show that this novel mitochondrial localization of AASDHPPT is required to support mtFAS activity and oxidative metabolism. We further identify five variants of uncertain significance in <em>AASDHPPT</em> that are likely pathogenic in humans due to loss of mtFAS activity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156413"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251663","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}
Pub Date : 2026-01-01Epub Date: 2025-10-09DOI: 10.1016/j.metabol.2025.156411
Dehui Hou , Kehui Yang , Yang Liu, Han Du, Hongwei Yue, Fengyang Xu, Wentao Sang, Xiangkai Zhao, Yijun Sun, Feng Xu, Yuguo Chen
Background and aims
Vascular injury-induced restenosis is an important cause of poor long-term prognosis in patients with coronary artery disease (CAD). Although aldehyde dehydrogenase 2 (ALDH2) deficiency has been linked to poor outcomes in CAD patients, the precise mechanisms through which ALDH2 influences vascular injury-induced restenosis remain elusive. Herein, we attempted to explore the role of ALDH2 in modulating vascular smooth muscle cell (VSMC) proliferation and vascular injury-induced restenosis.
Methods and results
Immunofluorescence and immunoblotting revealed that ALDH2 expression was significantly decreased in VSMCs in human stenotic coronary segments and injured mouse femoral and carotid arteries. Global ALDH2 knockout and VSMC-specific ALDH2 knockout exacerbated injury-induced neointima formation, whereas VSMC-specific ALDH2 overexpression reduced neointima formation. Endothelial cell (EC)-specific ALDH2 knockout had little effect on injury-induced neointima formation. Mechanistic studies revealed that ALDH2 deficiency facilitated VSMC proliferation by upregulating the expression of the glutamine transporter SLC38A2, which is a novel ALDH2 target gene. Further bioinformatics analysis, luciferase assays, and ChIP–qPCR revealed that ALDH2 deficiency increased SLC38A2 expression via activating transcription factor 4 (ATF4) and that ATF4 knockdown largely reversed the ability of ALDH2 deficiency to promote VSMC proliferation. Moreover, ALDH2 deficiency promoted the accumulation of 4-HNE adducted proteins, thereby activating ATF4, which subsequently increased SLC28A2 transcriptional activity in VSMCs. Importantly, downregulation of SLC38A2 by adeno-associated virus serotype 2 (AAV2) shRNA or by the inhibitor MeAIB has promising therapeutic potential in limiting VSMC proliferation and neointima formation. Finally, we demonstrated that VSMC proliferation was aggravated and that neointima formation occurred in ALDH2E506k mutant mice.
Conclusion
Our study elucidates a novel mechanism through which ALDH2 deficiency aggravates neointimal formation by enhancing VSMC proliferation through an increase in glutamine uptake, suggesting a promising translational strategy for the prevention of vascular injury-induced restenosis.
{"title":"ALDH2 deficiency aggravates vascular injury-induced restenosis by enhancing vascular smooth muscle cell proliferation through SLC38A2-mediated upregulation of glutamine uptake","authors":"Dehui Hou , Kehui Yang , Yang Liu, Han Du, Hongwei Yue, Fengyang Xu, Wentao Sang, Xiangkai Zhao, Yijun Sun, Feng Xu, Yuguo Chen","doi":"10.1016/j.metabol.2025.156411","DOIUrl":"10.1016/j.metabol.2025.156411","url":null,"abstract":"<div><h3>Background and aims</h3><div>Vascular injury-induced restenosis is an important cause of poor long-term prognosis in patients with coronary artery disease (CAD). Although aldehyde dehydrogenase 2 (ALDH2) deficiency has been linked to poor outcomes in CAD patients, the precise mechanisms through which ALDH2 influences vascular injury-induced restenosis remain elusive. Herein, we attempted to explore the role of ALDH2 in modulating vascular smooth muscle cell (VSMC) proliferation and vascular injury-induced restenosis.</div></div><div><h3>Methods and results</h3><div>Immunofluorescence and immunoblotting revealed that ALDH2 expression was significantly decreased in VSMCs in human stenotic coronary segments and injured mouse femoral and carotid arteries. Global ALDH2 knockout and VSMC-specific ALDH2 knockout exacerbated injury-induced neointima formation, whereas VSMC-specific ALDH2 overexpression reduced neointima formation. Endothelial cell (EC)-specific ALDH2 knockout had little effect on injury-induced neointima formation. Mechanistic studies revealed that ALDH2 deficiency facilitated VSMC proliferation by upregulating the expression of the glutamine transporter SLC38A2, which is a novel ALDH2 target gene. Further bioinformatics analysis, luciferase assays, and ChIP–qPCR revealed that ALDH2 deficiency increased SLC38A2 expression <em>via</em> activating transcription factor 4 (ATF4) and that ATF4 knockdown largely reversed the ability of ALDH2 deficiency to promote VSMC proliferation. Moreover, ALDH2 deficiency promoted the accumulation of 4-HNE adducted proteins, thereby activating ATF4, which subsequently increased SLC28A2 transcriptional activity in VSMCs. Importantly, downregulation of SLC38A2 by adeno-associated virus serotype 2 (AAV2) shRNA or by the inhibitor MeAIB has promising therapeutic potential in limiting VSMC proliferation and neointima formation. Finally, we demonstrated that VSMC proliferation was aggravated and that neointima formation occurred in ALDH2<sup>E506k</sup> mutant mice.</div></div><div><h3>Conclusion</h3><div>Our study elucidates a novel mechanism through which ALDH2 deficiency aggravates neointimal formation by enhancing VSMC proliferation through an increase in glutamine uptake, suggesting a promising translational strategy for the prevention of vascular injury-induced restenosis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156411"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258767","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}
Pub Date : 2026-01-01Epub Date: 2025-10-14DOI: 10.1016/j.metabol.2025.156420
Jiang Du , Yujie Li , Xinxing Zhu , Jingwen Gao , Yuxuan Zhang , Chiheng Wang , Di Han , Liang Qiao , Beilin Kou , Rui Guo , Hongen Zhang , Juntang Lin
Metabolic dysfunction-associated fatty liver disease (MASLD) is characterized by the accumulation and degeneration of lipids in hepatocytes, presenting a complex pathogenesis that complicates drug development. In this study, we found that methyltransferase-like 1 (METTL1) is upregulated in the livers of both MASLD mice and clinical samples. Hepatocyte-specific depletion of METTL1 inhibits lipid synthesis and promotes lipid oxidation, alleviating metabolic disorders in high-fat diet (HFD)-induced MASLD mice. Conversely, overexpression of METTL1 enhances lipid synthesis while suppressing lipid oxidation. Mechanistically, METTL1 regulates the stability and protein expression levels of FoxO1 mRNA by methylating the Exon1 region of FoxO1, as demonstrated by m7G sequencing. Additionally, we found that overexpression of FoxO1 counteracts the protective effects of METTL1 deficiency on metabolic disorders in MASLD mice. Moreover, we identified a potent small-molecule inhibitor of METTL1, specifically Homatropine Methylbromide (HtMBm), which significantly ameliorated HFD-induced MASLD. Overall, our study suggests that METTL1 plays a crucial role in the progression of MASLD and highlights the therapeutic potential of targeting METTL1 to modulate fatty acid metabolism in this condition.
{"title":"METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease","authors":"Jiang Du , Yujie Li , Xinxing Zhu , Jingwen Gao , Yuxuan Zhang , Chiheng Wang , Di Han , Liang Qiao , Beilin Kou , Rui Guo , Hongen Zhang , Juntang Lin","doi":"10.1016/j.metabol.2025.156420","DOIUrl":"10.1016/j.metabol.2025.156420","url":null,"abstract":"<div><div>Metabolic dysfunction-associated fatty liver disease (MASLD) is characterized by the accumulation and degeneration of lipids in hepatocytes, presenting a complex pathogenesis that complicates drug development. In this study, we found that methyltransferase-like 1 (METTL1) is upregulated in the livers of both MASLD mice and clinical samples. Hepatocyte-specific depletion of METTL1 inhibits lipid synthesis and promotes lipid oxidation, alleviating metabolic disorders in high-fat diet (HFD)-induced MASLD mice. Conversely, overexpression of METTL1 enhances lipid synthesis while suppressing lipid oxidation. Mechanistically, METTL1 regulates the stability and protein expression levels of FoxO1 mRNA by methylating the Exon1 region of FoxO1, as demonstrated by m7G sequencing. Additionally, we found that overexpression of FoxO1 counteracts the protective effects of METTL1 deficiency on metabolic disorders in MASLD mice. Moreover, we identified a potent small-molecule inhibitor of METTL1, specifically Homatropine Methylbromide (HtMBm), which significantly ameliorated HFD-induced MASLD. Overall, our study suggests that METTL1 plays a crucial role in the progression of MASLD and highlights the therapeutic potential of targeting METTL1 to modulate fatty acid metabolism in this condition.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156420"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308571","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}
Pub Date : 2026-01-01Epub Date: 2025-10-13DOI: 10.1016/j.metabol.2025.156414
Emily F. Ashlaw , Clinton T. Elfers , Kylie S. Chichura , Isabella Chavez Miranda , Aelish McGivney , Oleg G. Chepurny , George G. Holz , Ginger Mullins , Laura J. den Hartigh , Yongjun Liu , Christian L. Roth , Robert P. Doyle
Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.
{"title":"A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity","authors":"Emily F. Ashlaw , Clinton T. Elfers , Kylie S. Chichura , Isabella Chavez Miranda , Aelish McGivney , Oleg G. Chepurny , George G. Holz , Ginger Mullins , Laura J. den Hartigh , Yongjun Liu , Christian L. Roth , Robert P. Doyle","doi":"10.1016/j.metabol.2025.156414","DOIUrl":"10.1016/j.metabol.2025.156414","url":null,"abstract":"<div><div>Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156414"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301916","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}
Pub Date : 2026-01-01Epub Date: 2025-09-21DOI: 10.1016/j.metabol.2025.156394
Jiaxing Wang , Qiangzhou Wang , Xinrui Li , Qingqing Cai , Yulin Bi , Chenyang Xu , Hao Bai , Lihong Gu , Guobin Chang , Shihao Chen
Recent findings have broadened our understanding of the tripartite motif (TRIM) protein family, positioning these proteins as pivotal regulators of cellular metabolism and cell fate. Primarily functioning as versatile E3 ubiquitin ligases, TRIM proteins orchestrate key metabolic pathways—including glucose, lipid, and amino acid metabolism—through both ubiquitination-dependent and -independent mechanisms such as oligomerization and epigenetic modification. For example, TRIM38, TRIM11, and TRIM24 have been reported to modulate glycolytic flux and insulin signaling by targeting key glucose transporters and glycolytic enzymes, with effects on cancer metabolism and insulin responses in model systems. Similarly, TRIM21 and TRIM56 have been implicated in fatty acid synthesis, oxidation, and cholesterol balance, with potential relevance to fatty-liver conditions and atherosclerosis. Moreover, TRIM-mediated regulation of amino acid metabolism-particularly through pathways involving glutamine and branched-chain amino acids-plays a central role in tumor metabolic reprogramming and survival. Beyond enzymatic regulation, TRIM proteins exert non-canonical functions through epigenetic modulation and interactions with signaling networks. This review synthesizes current insights into the multifaceted roles of TRIM proteins in metabolic control and cell death, suggesting that ferroptosis may link TRIM proteins to lipid and amino acid metabolism, and highlights the connection between TRIM proteins and metabolic stress as a key area for future research.
{"title":"Emerging roles of TRIM in metabolic regulation","authors":"Jiaxing Wang , Qiangzhou Wang , Xinrui Li , Qingqing Cai , Yulin Bi , Chenyang Xu , Hao Bai , Lihong Gu , Guobin Chang , Shihao Chen","doi":"10.1016/j.metabol.2025.156394","DOIUrl":"10.1016/j.metabol.2025.156394","url":null,"abstract":"<div><div>Recent findings have broadened our understanding of the tripartite motif (TRIM) protein family, positioning these proteins as pivotal regulators of cellular metabolism and cell fate. Primarily functioning as versatile E3 ubiquitin ligases, TRIM proteins orchestrate key metabolic pathways—including glucose, lipid, and amino acid metabolism—through both ubiquitination-dependent and -independent mechanisms such as oligomerization and epigenetic modification. For example, TRIM38, TRIM11, and TRIM24 have been reported to modulate glycolytic flux and insulin signaling by targeting key glucose transporters and glycolytic enzymes, with effects on cancer metabolism and insulin responses in model systems. Similarly, TRIM21 and TRIM56 have been implicated in fatty acid synthesis, oxidation, and cholesterol balance, with potential relevance to fatty-liver conditions and atherosclerosis. Moreover, TRIM-mediated regulation of amino acid metabolism-particularly through pathways involving glutamine and branched-chain amino acids-plays a central role in tumor metabolic reprogramming and survival. Beyond enzymatic regulation, TRIM proteins exert non-canonical functions through epigenetic modulation and interactions with signaling networks. This review synthesizes current insights into the multifaceted roles of TRIM proteins in metabolic control and cell death, suggesting that ferroptosis may link TRIM proteins to lipid and amino acid metabolism, and highlights the connection between TRIM proteins and metabolic stress as a key area for future research.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156394"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109903","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}
Pub Date : 2026-01-01Epub Date: 2025-10-10DOI: 10.1016/j.metabol.2025.156415
Nawarat Rattanajearakul , Kunio Kondoh , Ou Fu , Shiki Okamoto , Kenta Kobayashi , Ken-ichiro Nakajima , Yasuhiko Minokoshi
Background
Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection.
Methods
Male mice were subjected to glucoprivation through the intraperitoneal (i.p.) administration of 2-deoxy-d-glucose (2DG) and were examined for food selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) in a diet choice paradigm. This involved the chemogenetic or optogenetic modulation of the neural activity of AMP-activated protein kinase (AMPK)-regulated corticotropin-releasing hormone (CRH) neurons, melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus of the hypothalamus (PVH), and neuropeptide Y (NPY) neurons projecting to the PVH.
Results
Glucoprivation induced by 2DG administration in mice influenced two distinct neural pathways in the PVH that separately promote the intake of an HCD or an HFD. Injection of 2DG activated PVH-projecting NPY neurons in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), resulting in a rapid increase in HCD intake through stimulation of PVH AMPK–regulated CRH neurons and recovery from glucoprivation. In contrast, PVH-projecting NPY neurons in the NTS, VLM, and arcuate nucleus of the hypothalamus (ARC) promoted HFD intake by inhibiting MC4R neurons in the PVH, reflecting the strong innate preference for an HFD in mice. The ARC NPY neurons specifically promoted HFD selection.
Conclusion
Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.
{"title":"Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus","authors":"Nawarat Rattanajearakul , Kunio Kondoh , Ou Fu , Shiki Okamoto , Kenta Kobayashi , Ken-ichiro Nakajima , Yasuhiko Minokoshi","doi":"10.1016/j.metabol.2025.156415","DOIUrl":"10.1016/j.metabol.2025.156415","url":null,"abstract":"<div><h3>Background</h3><div>Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection.</div></div><div><h3>Methods</h3><div>Male mice were subjected to glucoprivation through the intraperitoneal (i.p.) administration of 2-deoxy-<span>d</span>-glucose (2DG) and were examined for food selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) in a diet choice paradigm. This involved the chemogenetic or optogenetic modulation of the neural activity of AMP-activated protein kinase (AMPK)-regulated corticotropin-releasing hormone (CRH) neurons, melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus of the hypothalamus (PVH), and neuropeptide Y (NPY) neurons projecting to the PVH.</div></div><div><h3>Results</h3><div>Glucoprivation induced by 2DG administration in mice influenced two distinct neural pathways in the PVH that separately promote the intake of an HCD or an HFD. Injection of 2DG activated PVH-projecting NPY neurons in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), resulting in a rapid increase in HCD intake through stimulation of PVH AMPK–regulated CRH neurons and recovery from glucoprivation. In contrast, PVH-projecting NPY neurons in the NTS, VLM, and arcuate nucleus of the hypothalamus (ARC) promoted HFD intake by inhibiting MC4R neurons in the PVH, reflecting the strong innate preference for an HFD in mice. The ARC NPY neurons specifically promoted HFD selection.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156415"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280693","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}
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