Pub Date : 2025-11-01Epub Date: 2025-08-05DOI: 10.1016/j.metabol.2025.156358
Christine Mund, Anupam Sinha, Anika Aderhold, Ivona Mateska, Eman Hagag, Sofia Traikov, Bettina Gercken, Andres Soto, Jonathan Pollock, Lilli Arndt, Michele Wölk, Natalie Werner, Georgia Fodelianaki, Pallavi Subramanian, Kyoung-Jin Chung, Sylvia Grossklaus, Mathias Langner, Mohamed Elgendy, Tatyana Grinenko, Ben Wielockx, Andreas Dahl, Martin Gericke, Matthias Blüher, Ünal Coskun, David Voehringer, Maria Fedorova, Mirko Peitzsch, Peter J Murray, Triantafyllos Chavakis, Vasileia Ismini Alexaki
Background and aims: Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. The cell metabolic pathways regulating adipose tissue growth and homeostasis are little understood. Here we studied the role of polyamine metabolism in adipose tissue (patho)physiology.
Methods: We generated mice with global and adipocyte progenitor (AP)-specific Antizyme inhibitor 2 (AZIN2) deficiency and performed diet-induced obesity studies. APs were isolated from the subcutaneous and gonadal adipose tissue of mice and cultured.
Results: Polyamine metabolism components, including AZIN2, were highly expressed in APs and their expression in the adipose tissue was downregulated with obesity. IL4 induced Azin2 expression in APs. AZIN2 facilitated polyamine synthesis and acetylation, and regulated total acetyl-CoA levels in APs. AZIN2 deficiency upregulated histone acetylation in genes related to lipid metabolism. Azin2-/- APs committed more efficiently to adipogenesis in vivo and in vitro, and were more prone to senescence compared to wild-type counterparts. Upon diet-induced obesity, global and AP-specific AZIN2 deficiency in mice provoked AP depletion, adipocyte hypertrophy, obesity, inflammation, glucose intolerance and insulin resistance. In human adipose tissue, AZIN2 expression strongly correlated with expression of progenitor markers.
Conclusions: Altogether, we identified AZIN2 as a novel AP marker that regulates AP fate and preserves adipose tissue health.
{"title":"A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity.","authors":"Christine Mund, Anupam Sinha, Anika Aderhold, Ivona Mateska, Eman Hagag, Sofia Traikov, Bettina Gercken, Andres Soto, Jonathan Pollock, Lilli Arndt, Michele Wölk, Natalie Werner, Georgia Fodelianaki, Pallavi Subramanian, Kyoung-Jin Chung, Sylvia Grossklaus, Mathias Langner, Mohamed Elgendy, Tatyana Grinenko, Ben Wielockx, Andreas Dahl, Martin Gericke, Matthias Blüher, Ünal Coskun, David Voehringer, Maria Fedorova, Mirko Peitzsch, Peter J Murray, Triantafyllos Chavakis, Vasileia Ismini Alexaki","doi":"10.1016/j.metabol.2025.156358","DOIUrl":"10.1016/j.metabol.2025.156358","url":null,"abstract":"<p><strong>Background and aims: </strong>Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. The cell metabolic pathways regulating adipose tissue growth and homeostasis are little understood. Here we studied the role of polyamine metabolism in adipose tissue (patho)physiology.</p><p><strong>Methods: </strong>We generated mice with global and adipocyte progenitor (AP)-specific Antizyme inhibitor 2 (AZIN2) deficiency and performed diet-induced obesity studies. APs were isolated from the subcutaneous and gonadal adipose tissue of mice and cultured.</p><p><strong>Results: </strong>Polyamine metabolism components, including AZIN2, were highly expressed in APs and their expression in the adipose tissue was downregulated with obesity. IL4 induced Azin2 expression in APs. AZIN2 facilitated polyamine synthesis and acetylation, and regulated total acetyl-CoA levels in APs. AZIN2 deficiency upregulated histone acetylation in genes related to lipid metabolism. Azin2<sup>-/-</sup> APs committed more efficiently to adipogenesis in vivo and in vitro, and were more prone to senescence compared to wild-type counterparts. Upon diet-induced obesity, global and AP-specific AZIN2 deficiency in mice provoked AP depletion, adipocyte hypertrophy, obesity, inflammation, glucose intolerance and insulin resistance. In human adipose tissue, AZIN2 expression strongly correlated with expression of progenitor markers.</p><p><strong>Conclusions: </strong>Altogether, we identified AZIN2 as a novel AP marker that regulates AP fate and preserves adipose tissue health.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156358"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775789","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 : 2025-11-01Epub Date: 2025-08-07DOI: 10.1016/j.metabol.2025.156361
Mona Hendlinger, Lucia Mastrototaro, Marten Exterkate, Maria Apostolopoulou, Yanislava Karusheva, Geronimo Heilmann, Polina Lipaeva, Klaus Straßburger, Sofiya Gancheva, Sabine Kahl, Michael Roden
Lipotoxic ceramides (CERs) are implicated in the development of insulin resistance, type 2 diabetes (T2D) and related complications. Exercise training improves insulin sensitivity, potentially via reducing intracellular lipids or enhancing mitochondrial oxidation. Acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin (SM) to CERs, is crucial for muscle repair and development, yet its role in insulin-resistant states and response to exercise remain unclear. We assessed ASM protein and activity, neutral sphingomyelinase (NSM) and sphingolipid species in skeletal muscle of insulin-sensitive (IS, n = 12), insulin-resistant (IR, n = 11) and T2D men (n = 20), before and after a 12-week high-intensity interval training (HIIT). Comprehensive phenotyping comprised hyperinsulinemic-euglycemic clamps, spiroergometry, targeted lipidomics and assessment of markers of mitochondrial quality control. ASM protein was lower at baseline and increased after HIIT only in T2D (p < 0.05), while ASM activity rose across all groups (IS p < 0.01; IR and T2D p < 0.001). HIIT also increased NSM protein in all groups (p < 0.05). Despite lower baseline SM levels in T2D, HIIT led to elevated CERs species in T2D (C16:0, C20:0, C22:0, C24:1, C24:0) and in IR (C16:0, C20:0) (all p < 0.05). Regression analysis suggested that changes in ASM protein and activity relate to changes in mitochondrial fusion and fission as well as AMP-activated protein kinase (AMPK)-mediated mitophagy. In conclusion, HIIT induces expression of both ASM and NSM and alters CER profiles in insulin-resistant skeletal muscle, independently of changes in insulin sensitivity. ASM could therefore rather contribute to exercise-induced mitochondrial remodeling than driving lipotoxicity, warranting further investigation of ASM as a potential target for exercise mimetic therapies.
脂毒性神经酰胺（CERs）与胰岛素抵抗、2型糖尿病（T2D）及相关并发症的发生有关。运动训练可能通过降低细胞内脂质或增强线粒体氧化来改善胰岛素敏感性。酸性鞘磷脂酶（ASM）将鞘磷脂（SM）水解为CERs，对肌肉修复和发育至关重要，但其在胰岛素抵抗状态和运动反应中的作用尚不清楚。我们评估了胰岛素敏感（IS, n = 12）、胰岛素抵抗（IR, n = 11）和T2D男性（n = 20）在进行12周高强度间歇训练（HIIT）前后骨骼肌中ASM蛋白和活性、中性鞘磷脂酶（NSM）和鞘脂种。综合表型包括高胰岛素-正血糖钳，螺旋测量，靶向脂质组学和线粒体质量控制标记物评估。ASM蛋白在基线时较低，HIIT后仅在T2D时升高(p
{"title":"Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes.","authors":"Mona Hendlinger, Lucia Mastrototaro, Marten Exterkate, Maria Apostolopoulou, Yanislava Karusheva, Geronimo Heilmann, Polina Lipaeva, Klaus Straßburger, Sofiya Gancheva, Sabine Kahl, Michael Roden","doi":"10.1016/j.metabol.2025.156361","DOIUrl":"10.1016/j.metabol.2025.156361","url":null,"abstract":"<p><p>Lipotoxic ceramides (CERs) are implicated in the development of insulin resistance, type 2 diabetes (T2D) and related complications. Exercise training improves insulin sensitivity, potentially via reducing intracellular lipids or enhancing mitochondrial oxidation. Acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin (SM) to CERs, is crucial for muscle repair and development, yet its role in insulin-resistant states and response to exercise remain unclear. We assessed ASM protein and activity, neutral sphingomyelinase (NSM) and sphingolipid species in skeletal muscle of insulin-sensitive (IS, n = 12), insulin-resistant (IR, n = 11) and T2D men (n = 20), before and after a 12-week high-intensity interval training (HIIT). Comprehensive phenotyping comprised hyperinsulinemic-euglycemic clamps, spiroergometry, targeted lipidomics and assessment of markers of mitochondrial quality control. ASM protein was lower at baseline and increased after HIIT only in T2D (p < 0.05), while ASM activity rose across all groups (IS p < 0.01; IR and T2D p < 0.001). HIIT also increased NSM protein in all groups (p < 0.05). Despite lower baseline SM levels in T2D, HIIT led to elevated CERs species in T2D (C16:0, C20:0, C22:0, C24:1, C24:0) and in IR (C16:0, C20:0) (all p < 0.05). Regression analysis suggested that changes in ASM protein and activity relate to changes in mitochondrial fusion and fission as well as AMP-activated protein kinase (AMPK)-mediated mitophagy. In conclusion, HIIT induces expression of both ASM and NSM and alters CER profiles in insulin-resistant skeletal muscle, independently of changes in insulin sensitivity. ASM could therefore rather contribute to exercise-induced mitochondrial remodeling than driving lipotoxicity, warranting further investigation of ASM as a potential target for exercise mimetic therapies.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156361"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784781","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 : 2025-11-01Epub Date: 2025-08-06DOI: 10.1016/j.metabol.2025.156373
Anna Stubbendorff, Suzanne Janzi, Juulia Jukkola, Moa Morency, Shunming Zhang, Yan Borné, Emily Sonestedt
Human diets play a crucial role in both human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems introduced the EAT-Lancet planetary health diet, a universal reference diet designed to promote human health while minimizing environmental degradation. It is a predominantly plant-based dietary pattern, rich in whole grains, vegetables, fruits, legumes, and nuts, while low in red meat and added sugars. In this mini-review, we summarize findings from prospective cohorts examining the EAT-Lancet diet in relation to mortality and cardiometabolic outcomes. Higher adherence to this diet was generally associated with lower risk of all-cause mortality, cardiovascular disease, and type 2 diabetes. However, the magnitude of associations varied depending on cohort characteristics, scoring systems, and methodological factors. In addition, adherence to the EAT-Lancet diet was generally low in the studies reviewed. These results suggest potential public health benefits of adopting the EAT-Lancet diet but also highlight the need for harmonized definitions and further research on underlying mechanisms.
{"title":"Mini-review of the EAT-Lancet planetary health diet and its role in cardiometabolic disease prevention.","authors":"Anna Stubbendorff, Suzanne Janzi, Juulia Jukkola, Moa Morency, Shunming Zhang, Yan Borné, Emily Sonestedt","doi":"10.1016/j.metabol.2025.156373","DOIUrl":"10.1016/j.metabol.2025.156373","url":null,"abstract":"<p><p>Human diets play a crucial role in both human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems introduced the EAT-Lancet planetary health diet, a universal reference diet designed to promote human health while minimizing environmental degradation. It is a predominantly plant-based dietary pattern, rich in whole grains, vegetables, fruits, legumes, and nuts, while low in red meat and added sugars. In this mini-review, we summarize findings from prospective cohorts examining the EAT-Lancet diet in relation to mortality and cardiometabolic outcomes. Higher adherence to this diet was generally associated with lower risk of all-cause mortality, cardiovascular disease, and type 2 diabetes. However, the magnitude of associations varied depending on cohort characteristics, scoring systems, and methodological factors. In addition, adherence to the EAT-Lancet diet was generally low in the studies reviewed. These results suggest potential public health benefits of adopting the EAT-Lancet diet but also highlight the need for harmonized definitions and further research on underlying mechanisms.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156373"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804434","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 : 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":"2025-10-28","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 : 2025-10-26DOI: 10.1016/j.metabol.2025.156425
Patrizia Palumbo , Giada Di Betto , Renata Menozzi , Ger H. Koek , Elena Buzzetti
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).
{"title":"Pros and cons of different dietary patterns for the treatment of metabolic dysfunction-associated steatotic liver disease","authors":"Patrizia Palumbo , Giada Di Betto , Renata Menozzi , Ger H. Koek , 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":"2025-10-26","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}
Pub Date : 2025-10-24DOI: 10.1016/j.metabol.2025.156424
Guanghong Jia , Christos S. Mantzoros , Michael A. Hill
{"title":"Inter-organ crosstalk in health and cardiovascular-renal-hepatic-metabolic disease: A multidisciplinary perspective","authors":"Guanghong Jia , Christos S. Mantzoros , 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":"2025-10-24","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}
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":"2025-10-24","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 : 2025-10-24DOI: 10.1016/j.metabol.2025.156421
Xue You , Qian Peng , Wenju Qian , Zhiqin Xie , Yijun Lin , Yikuo Gai , Jingran Ye , Ying Feng
Background
β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on β-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in β-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic β-cells, we seek to elucidate the mechanisms linking SRSF1 to β-cell maintenance and function.
Methods
Mice with pancreatic β-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4-month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis.
Results
SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced β-cell proliferation accompanied by compensatory α-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of α-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased β-cell fraction, an increased α-cell fraction, and a small subset of α-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered β-cell fate in knockout β-cells from 10-month-old mice. Notably, these changes were absent in 4-month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote β-cell proliferation, with its effects on β-cells through the regulation of MYC expression.
Conclusions
SRSF1 is essential for β-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts β-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional β-cells and maintaining glucose balance.
{"title":"SRSF1 is essential for pancreatic β-cell proliferation and the maintenance of glucose homeostasis in mice","authors":"Xue You , Qian Peng , Wenju Qian , Zhiqin Xie , Yijun Lin , Yikuo Gai , Jingran Ye , Ying Feng","doi":"10.1016/j.metabol.2025.156421","DOIUrl":"10.1016/j.metabol.2025.156421","url":null,"abstract":"<div><h3>Background</h3><div>β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on β-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in β-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic β-cells, we seek to elucidate the mechanisms linking SRSF1 to β-cell maintenance and function.</div></div><div><h3>Methods</h3><div>Mice with pancreatic β-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4-month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis.</div></div><div><h3>Results</h3><div>SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced β-cell proliferation accompanied by compensatory α-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of α-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased β-cell fraction, an increased α-cell fraction, and a small subset of α-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered β-cell fate in knockout β-cells from 10-month-old mice. Notably, these changes were absent in 4-month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote β-cell proliferation, with its effects on β-cells through the regulation of MYC expression.</div></div><div><h3>Conclusions</h3><div>SRSF1 is essential for β-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts β-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional β-cells and maintaining glucose balance.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156421"},"PeriodicalIF":11.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370426","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 : 2025-10-17DOI: 10.1016/j.metabol.2025.156418
Limeng Pan , Yi He , Yuxi Xiang , Beibei Mao , Xiaoyu Meng , Yaming Guo , Zhihan Wang , Ranran Kan , Siyi Wang , Xuhang Shen , Tianrong Pan , Zhelong Liu , Junhui Xie , Yan Yang , Danpei Li , Xuefeng Yu
Background and aims
Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain unclear. This study aimed to elucidate the novel role of ANGPTL8 in DKD progression.
Methods
The renal expression of ANGPTL8 was measured in patients and murine models with DKD. Proximal tubule-specific Angptl8 knockout mice were generated to elucidate the role of ANGPTL8 in the pathogenesis of DKD. In vitro, ANGPTL8 was inhibited in human proximal tubular epithelial cells (PTECs) under high glucose plus palmitic acid (HGPA) stress. ANGPTL8 interacting proteins were screened using the human proteome microarray and validated by complementary interaction assays. Functional validation employed the Akt2 small interfering RNA and the specific Akt2 inhibitor in vitro and proximal tubule-specific Akt2 knockout mice in vivo.
Results
ANGPTL8 expression was significantly increased in renal proximal tubules during DKD. Proximal tubule-specific Angptl8 knockout ameliorated tubular injury and reduced tubular inflammation and fibrosis in DKD mice. In vitro, ANGPTL8 inhibition protected human PTECs against HGPA-induced inflammation and epithelial-mesenchymal transition (EMT). Mechanistically, intracellular ANGPTL8 directly binds to and activates Akt2, triggering downstream NF-κB pathway activation and GSK3β inhibition. Akt2 inhibition abolished ANGPTL8's pathogenic effects in vitro and in vivo.
Conclusions
Our findings demonstrate for the first time that elevated tubular ANGPTL8 promotes tubular inflammation and fibrosis during DKD by interacting with Akt2, highlighting the ANGPTL8-Akt2 axis as a promising target to prevent DKD progression.
{"title":"Angiopoietin-like protein 8 mediates inflammation and fibrosis of tubular cells in diabetic kidney disease progression by interacting with Akt2","authors":"Limeng Pan , Yi He , Yuxi Xiang , Beibei Mao , Xiaoyu Meng , Yaming Guo , Zhihan Wang , Ranran Kan , Siyi Wang , Xuhang Shen , Tianrong Pan , Zhelong Liu , Junhui Xie , Yan Yang , Danpei Li , Xuefeng Yu","doi":"10.1016/j.metabol.2025.156418","DOIUrl":"10.1016/j.metabol.2025.156418","url":null,"abstract":"<div><h3>Background and aims</h3><div>Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain unclear. This study aimed to elucidate the novel role of ANGPTL8 in DKD progression.</div></div><div><h3>Methods</h3><div>The renal expression of ANGPTL8 was measured in patients and murine models with DKD. Proximal tubule-specific <em>Angptl8</em> knockout mice were generated to elucidate the role of ANGPTL8 in the pathogenesis of DKD. <em>In vitro</em>, ANGPTL8 was inhibited in human proximal tubular epithelial cells (PTECs) under high glucose plus palmitic acid (HGPA) stress. ANGPTL8 interacting proteins were screened using the human proteome microarray and validated by complementary interaction assays. Functional validation employed the Akt2 small interfering RNA and the specific Akt2 inhibitor <em>in vitro</em> and proximal tubule-specific <em>Akt2</em> knockout mice <em>in vivo</em>.</div></div><div><h3>Results</h3><div>ANGPTL8 expression was significantly increased in renal proximal tubules during DKD. Proximal tubule-specific <em>Angptl8</em> knockout ameliorated tubular injury and reduced tubular inflammation and fibrosis in DKD mice. <em>In vitro</em>, ANGPTL8 inhibition protected human PTECs against HGPA-induced inflammation and epithelial-mesenchymal transition (EMT). Mechanistically, intracellular ANGPTL8 directly binds to and activates Akt2, triggering downstream NF-κB pathway activation and GSK3β inhibition. Akt2 inhibition abolished ANGPTL8's pathogenic effects <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate for the first time that elevated tubular ANGPTL8 promotes tubular inflammation and fibrosis during DKD by interacting with Akt2, highlighting the ANGPTL8-Akt2 axis as a promising target to prevent DKD progression.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156418"},"PeriodicalIF":11.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329578","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}
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.
{"title":"Pancreas meets brain: β-hydroxybutyrate as a novel “β-cellular” metabolism therapy","authors":"Caroline Lopa , Donatella Pietrangelo , Gaetano Santulli , Jessica Gambardella , Speranza Rubattu , Mihaela Stefan-Lifshitz , Crystal Nieves Garcia , Stanislovas S. Jankauskas , 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":"2025-10-16","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}
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