Metabolism: clinical and experimental最新文献

{"title":"Imeglimin ameliorates MASLD by targeting PEN2 to activate AMPK pathway","authors":"Jinghe Li ,&nbsp;Ruizhong Zhang ,&nbsp;Xin Zeng ,&nbsp;Weilong Xu ,&nbsp;Ling Gao ,&nbsp;Shuyun He ,&nbsp;Bingbing Wu ,&nbsp;Yanjie Ma ,&nbsp;Yunzhong Nie ,&nbsp;Jun Shirakawa ,&nbsp;Huimin Xia ,&nbsp;Wei Li","doi":"10.1016/j.metabol.2025.156458","DOIUrl":"10.1016/j.metabol.2025.156458","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat diet (HFD)-induced metabolic impairment. Although imeglimin, an antidiabetic agent known to improve insulin resistance, has demonstrated therapeutic potential in metabolic diseases, its effects and underlying molecular mechanism in MASLD remain unclear.</div></div><div><h3>Approach and results</h3><div>In this study, we employed a long-term (48-week) high-fat diet-induced murine model of MASLD to recapitulate human disease progression, then treated those mice with imeglimin for 6 months to investigate its therapeutic effects. Imeglimin treatment improved insulin resistance, restored liver function, attenuated hepatic inflammation, and promoted hepatocyte viability. PEN2, a component of the γ-secretase complex, is identified as the key target of imeglimin. The therapeutic effects of imeglimin are abrogated in liver-specific <em>Pen2</em>-deficient mice or upon pharmacologic inhibition of AMP-activated protein kinase (AMPK), indicating that activation of PEN2-AMPK signaling is required for its beneficial effects. Furthermore, we found that imeglimin also protected human pluripotent stem cell (hPSC)-derived hepatocyte-like cells from free fatty acid (FFA)-induced lipid accumulation.</div></div><div><h3>Conclusion</h3><div>Collectively, our findings indicate that imeglimin ameliorates hepatic lipotoxicity by targeting PEN2 to activate AMPK axis, suggesting its potential as a new drug for MASLD treatment in the near future.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156458"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615595","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}

{"title":"Calcitonin and procalcitonin: Revisiting the overlooked role of C cells","authors":"Eleonore Fröhlich ,&nbsp;Richard Wahl","doi":"10.1016/j.metabol.2025.156434","DOIUrl":"10.1016/j.metabol.2025.156434","url":null,"abstract":"<div><div>Calcitonin (CT) is a hormone produced by C cells in the thyroid gland. Its primary function is to regulate bone turnover. However, it is believed to be of little importance to human physiology because its absence following thyroidectomy has no dramatic effects. It was used in the treatment of osteoporosis but has now largely been replaced by bisphosphonates and monoclonal antibodies. However, some studies suggest that CT may have additional functions, such as those related to bone structure, osteoprotection, and pain management. This review summarizes CT synthesis and function and discusses its role and that of its precursor, procalcitonin, as biomarkers. Procalcitonin detection has advantages over some established markers in sepsis management and due to its greater stability, it is also an alternative to CT for managing medullary thyroid carcinoma. Recent research has raised the possibility that procalcitonin could serve as a direct molecular target for treating sepsis. Potential roles of various regulatory peptides released by C cells that may contribute to paracrine fine-tuning of thyroid hormone secretion by follicular thyrocytes are considered. Health-care providers should inform patients that despite optimal thyroxine replacement therapy, subtle symptoms may still occur due to the absence of C cells.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156434"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493273","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}

{"title":"SLC22A6-dependent lactylation of H3K9 aggravates endothelial dysfunction and atherosclerosis","authors":"Yuting Ma ,&nbsp;Sunye Feng ,&nbsp;Yujie Jiang ,&nbsp;Jingting Jiang ,&nbsp;Ronghui Liu ,&nbsp;Yuxin Ma ,&nbsp;Xinglei Yin ,&nbsp;Huimin Bian ,&nbsp;Ruigong Zhu","doi":"10.1016/j.metabol.2025.156426","DOIUrl":"10.1016/j.metabol.2025.156426","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis, a leading cause of cardiovascular morbidity and mortality, is driven by endothelial dysfunction. While metabolic reprogramming toward glycolysis in endothelial cells exacerbates disease progression, the role of lactate-derived lactylation in atherogenesis remains poorly understood.</div></div><div><h3>Methods</h3><div>We performed RNA-seq on aortic tissues from atherosclerotic mice to identify differentially expressed genes, along with Seahorse XF metabolic flux analysis. Endothelium-specific solute carrier family 22 member 6 (Slc22a6) knockout and AAV-delivered acyl-CoA synthetase short-chain family member 1 (Acss1) knockdown mice were established on an ApoE^KO background. Integrated multi-omics (RNA-seq, CUT&amp;Tag, metabolomics) elucidated downstream regulatory networks, and in vivo pharmacological inhibition validated key pathways.</div></div><div><h3>Results</h3><div>Our study reveals a marked elevation of histone H3 Lysine 9 Lactylation (H3K9la) relative to acetylation in atherosclerotic aortic tissue, potentially via SLC22A6-mediated glycolytic enhancement and lactate uptake. Additionally, endothelial-specific knockout of Slc22a6 attenuates H3K9la-driven endothelial dysfunction and atherosclerosis. Integrated RNA-seq and CUT&amp;Tag analyses identify that upregulated ACSS1 and E1A binding protein p300 (EP300) drive H3K9la, which transcriptionally activates stearoyl-CoA desaturase 1 (SCD1), thereby exacerbating endothelial dysfunction. Pharmacological inhibition of H3K9la or SCD1 alleviates endothelial dysfunction and atherosclerosis in vitro and in vivo. We further establish the clinical relevance of lactate, SLC22A6, and ACSS1 in atherosclerosis.</div></div><div><h3>Conclusions</h3><div>Our findings unveil a metabolism-epigenetics-transcription regulatory axis in endothelial pathophysiology, thus providing novel therapeutic strategies for atherosclerosis by targeting the SLC22A6-dependent ACSS1-H3K9la-SCD1 pathway.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156426"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459312","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}

{"title":"Air pollution exacerbates cardiovascular-kidney-metabolic syndrome and sarcopenia comorbidity via shared genetic-epigenetic mechanisms: A multi-omics and Mendelian Randomization study","authors":"Shuxu Wei ,&nbsp;Zhouwu Shu ,&nbsp;Xinyi Li ,&nbsp;Suiqin Zhong ,&nbsp;Ling Xiao ,&nbsp;Ronghuai Shen ,&nbsp;Xiaojia Lu ,&nbsp;Lingbin He ,&nbsp;Youti Zhang ,&nbsp;Yan Quan ,&nbsp;Xianxi Huang","doi":"10.1016/j.metabol.2025.156452","DOIUrl":"10.1016/j.metabol.2025.156452","url":null,"abstract":"<div><h3>Background</h3><div>Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood.</div></div><div><h3>Methods</h3><div>We integrated genome-wide association study (GWAS) data for CKM components (cardiovascular disease [CVD], chronic kidney disease [CKD], metabolic syndrome), CKM-related cardiovascular events, and sarcopenia diagnostic criteria from European-ancestry cohorts, and conducted meta-analyses harmonizing each phenotype across at least three studies. We employed Mendelian Randomization (MR) to assess potential causal links and genetic correlation analyses (global and local) to quantify shared heritability. Multi-omics analyses included two sequential phases: Phase 1 identified and validated novel shared CKM-sarcopenia genes through integrated methylation (n = 1980) and expression (n = 31,684) analyses, followed by cross-validation using two complementary transcriptome-wide association studies (TWAS). Phase 2 prioritized druggable targets through proteomic analysis across five independent cohorts (deCODE, n = 35,559; UK Biobank Pharma Proteomics Project (UKB-PPP), n = 54,219; Fenland, n = 10,708; FinnGen Olink, n = 619; FinnGen Somascan, n = 828) and integrated colocalization.</div></div><div><h3>Results</h3><div>MR suggested genetically predicted associations between sarcopenia and CKM; genetically slower walking pace was associated with higher CVD risk (OR = 0.85, <em>P</em> = 9.56 × 10⁻⁶) and metabolic syndrome risk (OR = 0.43, <em>P</em> = 3.90 × 10⁻¹⁷), while conversely, genetically predicted lower appendicular lean mass exhibited inverse associations with heart failure with heart failure and atrial fibrillation. Multi-omics identified key shared genes (ANAPC4, UNC50, TPO), with ANAPC4 methylation sites linked to CVD (cg13918811, <em>P</em>_adj = 0.0212) and reduced muscle mass (cg04009456, <em>P</em>_adj = 0.0049). Blood-based analyses identified 13 air pollution-associated comorbid genes, primarily responsive to PM_2.5/NO₂, with 11 confirmed by cross-tissue validation. Proteomics (F-statistics &gt; 10) revealed potential targets linking CKM/sarcopenia (HP, FCGR3B, GALNT2) and CKM-events/sarcopenia (SERPINA1, FER).</div></div><div><h3>Conclusion</h3><div>Ambient air pollution likely promotes CKM–sarcopenia comorbidity chiefly via inflammatory signaling and epigenetic modifications. Our multi-omics integration reveals convergent pathways, candidate driver genes, and differential methylation sites that link these conditions. We propose these targets for environmental mitigation and molecular intervention, which require validation in diverse populations.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156452"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573852","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}

{"title":"Sphk2 suppresses ferroptosis in ischemic hearts by promoting HSP90AA1-mediated TFEB nuclear translocation, lysosome biogenesis and lysosome-autophagy pathway-dependent lipid-ROS clearance","authors":"Ting Gong ,&nbsp;Danru Wang ,&nbsp;Yawei Jin ,&nbsp;Liming Chen ,&nbsp;Nan Qiu ,&nbsp;Wenyan Qiu ,&nbsp;Na Zheng ,&nbsp;Yang Lv ,&nbsp;Suling Ding ,&nbsp;Jie Yuan ,&nbsp;Jian Wu ,&nbsp;Ling Lin ,&nbsp;Chunjie Yang ,&nbsp;Miyesaier Abudureyimu ,&nbsp;Xiang Wang ,&nbsp;Gulinazi Yesitayi ,&nbsp;Lei Xu ,&nbsp;Peng Zhang ,&nbsp;Wei Hu ,&nbsp;Gang Zhao ,&nbsp;Shijun Wang","doi":"10.1016/j.metabol.2025.156428","DOIUrl":"10.1016/j.metabol.2025.156428","url":null,"abstract":"<div><h3>Background</h3><div>Lipid peroxidation and iron overload-mediated cardiac ferroptosis play a critical role in myocardial ischemic injury and remodeling. Sphingosine kinase 2 (Sphk2) is implicated in lipid metabolism and cell survival, yet its role in myocardial infarction (MI) remains elusive. Given the critical function of ferroptosis in ischemic injury, we investigated whether Sphk2 protects the heart by regulating this novel cell death pathway.</div></div><div><h3>Methods</h3><div>Sphk2 expression was assessed in human failing hearts and a murine MI model. Sphk2^−/− mice and AAV9-mediated cardiac-specific Sphk2 overexpression were used to assess cardiac function by echocardiography, remodeling by Masson's trichrome staining and molecular events.</div></div><div><h3>Results</h3><div>Sphk2 was significantly downregulated in human and murine failing hearts. Sphk2^−/− mice exhibited exacerbated cardiac dysfunction, fibrosis and ferroptosis post-MI. Inhibition of CD36 signaling attenuated lipid uptake and ischemia-induced ferroptosis in Sphk2^−/− mice, whereas pharmacological activation of TFEB restored autophagosome-lysosome function and further suppressed ferroptosis. Mechanistically, Sphk2 deficiency impaired the interaction with and stability of HSP90, leading to suppressed TFEB nuclear translocation, lysosomal biogenesis, and autophagic clearance of lipid peroxides. This exacerbated ferroptosis and ischemic injury via lipid-ROS accumulation and oxidative stress. Crucially, cardiac-specific overexpression of Sphk2 in knockout mice restored HSP90-TFEB signaling, ameliorated ferroptosis, and fully rescued cardiac function and remodeling after MI.</div></div><div><h3>Conclusion</h3><div>Our study unveils a novel role of Sphk2 in stabilizing HSP90 to activate TFEB-dependent lysosomal function, thereby mitigating lipid peroxidation and ferroptosis following ischemic injury. Our findings establish a direct causal link between Sphk2 deficiency and ischemic heart failure, which highlights the therapeutic potential of Sphk2 restoration in treating ischemic heart disease.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156428"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471504","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}

{"title":"Inter-organ crosstalk in health and cardiovascular-renal-hepatic-metabolic disease: A multidisciplinary perspective","authors":"Guanghong Jia ,&nbsp;Christos S. Mantzoros ,&nbsp;Michael A. Hill","doi":"10.1016/j.metabol.2025.156424","DOIUrl":"10.1016/j.metabol.2025.156424","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156424"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145417358","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}

{"title":"Pancreas meets brain: β-hydroxybutyrate as a novel “β-cellular” metabolism therapy","authors":"Caroline Lopa ,&nbsp;Donatella Pietrangelo ,&nbsp;Gaetano Santulli ,&nbsp;Jessica Gambardella ,&nbsp;Speranza Rubattu ,&nbsp;Mihaela Stefan-Lifshitz ,&nbsp;Crystal Nieves Garcia ,&nbsp;Stanislovas S. Jankauskas ,&nbsp;Angela Lombardi","doi":"10.1016/j.metabol.2025.156419","DOIUrl":"10.1016/j.metabol.2025.156419","url":null,"abstract":"<div><div>β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156419"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318588","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}

{"title":"Pros and cons of different dietary patterns for the treatment of metabolic dysfunction-associated steatotic liver disease","authors":"Patrizia Palumbo ,&nbsp;Giada Di Betto ,&nbsp;Renata Menozzi ,&nbsp;Ger H. Koek ,&nbsp;Elena Buzzetti","doi":"10.1016/j.metabol.2025.156425","DOIUrl":"10.1016/j.metabol.2025.156425","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming the most prevalent hepatic disorder, affecting up to 33 % of the global population. An altered lifestyle, characterized by extended physical inactivity and increased consumption of highly caloric food, often low in nutritional value, is recognised as one of the main contributing factors for MASLD. Cornerstone for MASLD treatment is a healthy lifestyle, starting from diet. However, the most appropriate dietary pattern for the treatment of MASLD remains a subject of debate. The aims of this narrative review are therefore to explore the mechanisms through which nutrition influences MASLD pathogenesis and to evaluate different dietary patterns for MASLD treatment, highlighting their advantages and limitations. Multiple dietary patterns—including the Mediterranean Diet (MD), the Dietary Approaches to Stop Hypertension (DASH), the Low-Carb Diet (LCD), the Ketogenic Diet (specifically the Very Low-Calorie Ketogenic Diet, VLCKD), the Low-Fat Diet (LFD), Vegetarian Diets (VDs), and Intermittent Fasting (IF)—are reviewed, with a focus on their efficacy on MASLD and the ameliorating of the associated cardiometabolic risks factors (CMRF).</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156425"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145391489","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}

{"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 ,&nbsp;Arvid Sandforth ,&nbsp;Reiner Jumprtz-von Schwartzenberg ,&nbsp;Marlene Ganslmeier ,&nbsp;Yurong Cheng ,&nbsp;Leontine Sandforth ,&nbsp;Sarah Katzenstein ,&nbsp;Jürgen Machann ,&nbsp;Fritz Schick ,&nbsp;Konstantinos Kantartzis ,&nbsp;Hubert Preissl ,&nbsp;Andreas Fritsche ,&nbsp;Norbert Stefan ,&nbsp;Michael Bergman ,&nbsp;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}

{"title":"Metabolomics analysis of diabetic kidney disease for discovering early diagnostic biomarkers: A systematic review and meta-analysis of prospective studies","authors":"Zahra Ramazani ,&nbsp;Rezvan Adibi ,&nbsp;Alieh Gholaminejad ,&nbsp;Marjan Mansourian ,&nbsp;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}