American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Glucagon increases plasma levels of cyclic AMP responses in mice and humans, and this may be independent of MASLD.","authors":"Josephine Reiche, Alexander Jakobsen, Sasha A S Kjeldsen, Christine Rasmussen, Lise Lotte Gluud, Michael Martin Richter, Marie Winther-Sørensen, Nicolai J Wewer Albrechtsen","doi":"10.1152/ajpendo.00296.2025","DOIUrl":"10.1152/ajpendo.00296.2025","url":null,"abstract":"<p><p>Glucagon resistance impairs amino acid metabolism in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanism remains unclear. Given that glucagon mediates its effects through cyclic adenosine monophosphate (cAMP), impaired cAMP responses have been proposed as the molecular center of glucagon resistance. In this study, we investigated if the glucagon-induced cAMP response is impaired by metabolic dysfunction, thereby contributing to glucagon resistance. Plasma cAMP responses to an intravenous bolus injection of glucagon were analyzed in 64 individuals with or without MASLD and type 1 diabetes. In parallel, hepatic cAMP secretion during glucagon stimulation was determined using in situ liver perfusion in lean and diet-induced obese (DIO) mice with hepatic steatosis. Participants with obesity and MASLD showed higher baseline plasma cAMP, but neither glucagon, insulin, steatosis, nor BMI could explain this. Across all groups, glucagon-induced cAMP responses were similar. Similarly, DIO mice displayed preserved hepatic cAMP release in response to glucagon compared with lean controls. These findings suggest that the glucagon-induced cAMP response is maintained in MASLD independently of insulin. Thus, hepatic glucagon resistance in MASLD may be due to non-cAMP-dependent signaling.<b>NEW & NOTEWORTHY</b> Here, we investigate the molecular cause for hepatic glucagon resistance in MASLD. We demonstrate that cAMP responses to glucagon are preserved in both humans and mice with liver steatosis, suggesting that the defect lies downstream of cAMP production. These findings redefine the understanding of glucagon resistance and point toward alternative mechanisms beyond second messenger activation.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E581-E590"},"PeriodicalIF":3.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endogenous expression of cellular communication network factor 5 on normal β-cells growth and insulin resistance caused by diet-induced obesity.","authors":"Viktoria Xega, Martina Hong Yang, Noah Lopez, Marzieh Eskandari Shahraki, Xiaohong Liu, Maia Kokoeva, Karen M Lyons, Jun-Li Liu","doi":"10.1152/ajpendo.00384.2024","DOIUrl":"10.1152/ajpendo.00384.2024","url":null,"abstract":"<p><p>Cellular communication network factor 5 (CCN5; WISP2) is a matricellular protein. Our previous studies suggest that CCN5 promotes the proliferation and survival of pancreatic β-cells, thereby conferring metabolic advantages. A recent report indicated that a systemic deficiency in CCN5 expression leads to increased adiposity, glycemia, and insulin resistance. These conditions worsen when subjected to a high-fat diet (HFD). To further understand the metabolic roles of endogenous CCN5, we reassessed CCN5 knockout mice that were fed either a chow diet or a 60% HFD. In contrast to the previous report, our findings reveal that CCN5 knockout mice of both sexes maintain normal lean/fat mass, body weight, glycemia, insulin levels, and insulin sensitivity when fed a chow diet. However, the expression of the CCN5 gene seems to be essential for maintaining normal β-cell growth. Even under the stress of extended HFD feeding, CCN5 knockout mice exhibited similar weight gain and did not show an elevation in glycemia. Male knockout mice displayed improved glucose tolerance, insulin sensitivity, and a slight decrease in glycemia compared with wild-type counterparts. Interestingly, the lack of CCN5 did not affect obesity-induced β-cell compensation. These findings further reinforce the role of CCN5 as a comprehensive metabolic regulator, although the effects could be sex specific. In male mice affected by diet-induced obesity, the endogenous expression of CCN5 seems to have a negative impact on insulin and glucose tolerance. Under different physiological conditions, the systemic effects of CCN5 and its specific influence on β-cells may interact to shape the metabolic outcomes.<b>NEW & NOTEWORTHY</b> This study challenges prior findings by demonstrating that CCN5 knockout mice maintain normal body weight and glucose tolerance on a chow diet but exhibit impaired β-cell expansion. Strikingly, under a high-fat diet, male knockout mice display enhanced glucose tolerance without compromising β-cell compensation. These results suggest that CCN5's influence on metabolism is context-dependent, shaped by both diet and sex, and may critically modulate metabolic outcomes through its regulatory effects on β-cells.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E591-E602"},"PeriodicalIF":3.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-6 Blockade Does Not Impair Exercise-Induced Glucose Uptake and Insulin Sensitivity in Rheumatoid Arthritis.","authors":"Andresa Rossilho Casale, Italo Ribeiro Lemes, Fabiana I Smaira, Camilla Astley, Gersiel Nascimento de Oliveira Júnior, Ana Lúcia Sá-Pinto, Ana Cristina de Medeiros Ribeiro, Alexandre Leme Godoy-Santos, Marcos Lima, Camila de Godoi Carneiro, Carlos Alberto Buchpiguel, Wagner Silva Dantas, Christopher L Axelrod, Pravalika Javvadi, Sujoy Ghosh, John P Kirwan, Hamilton Roschel, Bruno Gualano","doi":"10.1152/ajpendo.00348.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00348.2025","url":null,"abstract":"<p><p>Patients with rheumatoid arthritis (RA) are at increased risk of insulin resistance and cardiovascular disease, and exercise is a key non-pharmacological therapy. We examined whether IL-6 inhibition, a common biologic treatment for RA, impairs the acute metabolic benefits of exercise, given IL-6's proposed role as a mediator of exercise-induced glucose metabolism. This was a single-center, non-randomized study involving 20 postmenopausal women with RA (10 on IL-6i, 10 on TNF-αi). Participants underwent a hyperinsulinemic-euglycemic clamp (HEC) and Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography and Magnetic Resonance Imaging ([¹⁸F] FDG PET/MRI) to assess whole-body and skeletal muscle glucose uptake. Muscle biopsies were performed before and 240 minutes after a 30-minute moderate-to-vigorous intensity aerobic exercise session to analyze molecular responses, including RNA sequencing and protein expression. Participants had a mean age of 57.8 ± 5.1 years and a mean BMI of 28.2 ± 4.9 kg/m². Disease duration averaged 18.0 ± 7.5 years, and both groups had comparable clinical characteristics. Acute exercise did not elicit significant between-group differences in insulin sensitivity (M-value: 4.51 ± 1.34 vs. 4.28 ± 0.87; p-value >0.05) or skeletal muscle glucose uptake, indicating that IL-6 inhibition does not impair the metabolic responses to acute exercise. Comparing post to pre-exercise, IL-6i participants exhibited increased GLUT4 expression (<i>p</i>-value = 0.01) and distinct cytokine profiles, including elevated IL-8 (<i>p</i>-value = 0.04) and IL-10 (<i>p</i>-value = 0.02) levels. RNA-seq analysis showed comparable pathway enrichment between groups, with upregulation of TNF-α and IL-6-JAK-STAT3 signaling. IL-6 inhibition does not blunt the acute metabolic benefits of exercise in RA, supporting its safety as a non-pharmacological intervention. <b>Trial registration:</b> Clinicaltrials.gov (NCT04927546).</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut-Derived Lipopolysaccharides and Metabolic Endotoxemia: A Critical Review.","authors":"Bandy Chen, Laurent Gautron","doi":"10.1152/ajpendo.00355.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00355.2025","url":null,"abstract":"<p><p>The metabolic endotoxemia hypothesis proposes that low levels of gut-derived lipopolysaccharides (LPS) act in a hormone-like manner to influence metabolism, contributing to obesity and dysregulation of glucose homeostasis. However, due to methodological limitations, it remains unclear whether a significant amount of bioactive gut-derived LPS reaches the bloodstream and, if so, whether it has a meaningful impact on metabolic processes. Additionally, there are several theoretical challenges regarding the coherence of the metabolic endotoxemia hypothesis, raising questions about its validity. Here, in the light of recent literature, we critically review arguments for and against the metabolic endotoxemia hypothesis.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cAMP-phosphodiesterase PDE4B2 controls peroxisome proliferator-activated receptor γ (PPARγ) expression and the initiation of adipogenesis in 3T3-L1 cells.","authors":"Edward Fiedler, Abigail Boyd, Daniel Irelan, Lyudmilla I Rachek, Lina Abou Saleh, Wito Richter","doi":"10.1152/ajpendo.00215.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00215.2025","url":null,"abstract":"<p><p>The cAMP-phosphodiesterase 4 (PDE4) family comprises four genes that together are expressed as ~25 protein variants. Non-selective PAN-PDE4 inhibition exerts various metabolic benefits, including reduced body weight and adiposity in humans and animals, but the role of individual PDE4s in mediating these effects remains ill-defined. We noticed that the hormonal induction of adipogenesis in 3T3-L1 pre-adipocytes increased the mRNA and protein expression of a single PDE4 variant, PDE4B2. Conversely, its siRNA-mediated knockdown markedly suppressed adipogenic differentiation and lipid accumulation, suggesting a critical role for PDE4B2 in adipogenesis. The onset of adipogenesis is well understood and involves the consecutive upregulation of pro-adipogenic transcription factors CCAAT-enhancer-binding proteins (C/EBPs) C/EBPδ, C/EBPβ, and C/EBPα, which ultimately induce peroxisome proliferator-activated receptor gamma (PPARγ) as the master regulator of adipogenesis. PDE4B knockdown potently suppressed the upregulation of C/EBPα and PPARγ expression, thereby curbing the early steps in adipogenic differentiation. Mirroring its anti-adipogenic effects in 3T3-L1 cells, PDE4B ablation in mice produces a lean phenotype characterized by reduced adipose tissue weight and reduced expression of C/EBPα and PPARγ. Although PPARγ agonists promote weight gain, they are also effective insulin sensitizers and are used therapeutically to treat type 2 diabetes. Conversely, despite reducing PPARγ expression and adiposity, PDE4B knockout mice exhibit slightly improved glucose homeostasis. Taken together, we show that a PDE4B-dependent regulation of C/EBPα and PPARγ expression is conserved between cell- and animal models. To what extent this mechanism contributes to the overall metabolic phenotypes of targeting PDE4B or PPARγ <i>in vivo</i> remains to be elucidated.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulation of Angiotensin II Type 2 Receptor Recruit Skeletal and Cardiac Muscle Microvasculature in Humans.","authors":"Wai Kit Alvin Tan, Linda A Jahn, Lee Hartline, Kevin W Aylor, Zhenqi Liu","doi":"10.1152/ajpendo.00267.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00267.2025","url":null,"abstract":"<p><p><b>Purpose:</b> Acute angiotensin II (Ang II) type 1 receptor (AT₁R) blockade recruits skeletal and cardiac muscle microvasculature in healthy humans without altering insulin-mediated whole-body glucose disposal. We aimed to elucidate the vascular and metabolic effects of Ang II type 2 receptor (AT₂R) stimulation in healthy humans. <b>Methods:</b> Following AT₁R blockade with candesartan, healthy adults received an intravenous infusion of either Ang II or saline for 180 minutes with or without a euglycemic hyperinsulinemic clamp superimposed during the final 120 minutes. Skeletal and cardiac muscle microvascular perfusion, brachial artery diameter and flow velocity, augmentation index, pulse wave velocity (PWV) and insulin-mediated whole-body glucose disposal were assessed. <b>Results:</b> In the presence of AT₁R blockade, Ang II infusion did not alter hemodynamic parameters or insulin-mediated whole-body glucose disposal. Both insulin and Ang II increased skeletal and cardiac muscle microvascular perfusion; however, superimposing insulin on Ang II infusion did not further augment microvascular perfusion in either tissue. Infusion of Ang II, insulin, or their combination significantly increased total brachial artery blood flow. Ang II infusion increased PWV, an effect attenuated by insulin. <b>Main conclusions:</b> Selective stimulation of AT₂R significantly enhanced skeletal and cardiac muscle microvascular perfusion and total tissue blood flow without altering insulin's vascular and metabolic actions in healthy humans. These findings may help explain the cardiovascular and metabolic benefits observed in individuals treated with AT₁R blockers.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Characterisation and cAMP-Mediated Rescue of a Novel Truncating AVPR2 Mutation Causing Nephrogenic Diabetes Insipidus.","authors":"Diogo Manoel, Idris Mohammed, Khalid Hussain, Luis Saraiva","doi":"10.1152/ajpendo.00325.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00325.2025","url":null,"abstract":"<p><p>Vasopressin plays a central endocrine role in water homeostasis by activating the AVPR2 receptor in renal collecting duct cells. Mutations in AVPR2 are a leading cause of X-linked nephrogenic diabetes insipidus (NDI), a disorder marked by renal insensitivity to vasopressin, leading to polyuria, polydipsia, and hypernatremia. We identified a novel truncating AVPR2 mutation (c.570dup; D191*) in a pediatric patient with NDI and investigated its molecular and functional consequences using a renal epithelial cell model (mIMCD-3). The D191* mutant exhibited marked reduction in total and surface receptor expression due to intracellular retention and rapid proteasomal degradation. Functional assays revealed that dDAVP stimulation failed to elicit cAMP production or activate downstream signalling targets, including CREB and ERK1/2, in cells expressing the mutant receptor. Aquaporin-2 (AQP2) membrane translocation, essential for water reabsorption, was also impaired. Notably, treatment with Forskolin or 8-bromo-cAMP restored cAMP levels, reactivated downstream signalling, and rescued AQP2 localisation to the apical membrane, independent of AVPR2 activation. These findings uncover the pathophysiological mechanism by which D191* impairs vasopressin signalling and suggest that bypassing the receptor via direct cAMP pathway activation offers a promising therapeutic strategy for NDI. This study highlights the endocrine relevance of precision molecular diagnostics and supports functional rescue approaches for receptor-based disorders.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Markers of mitochondrial function and oxidative metabolism in skeletal muscle do not display intrinsic circadian regulation in female mice.","authors":"Liam S Fitzgerald, Connor Scott Reynoso Spurrier, Nathan Lau, Miles Melamed, Lindsey A Burnett, Gretchen A Meyer, Chang Gui, Andrea L Hevener, James A Sanford, Simon Schenk","doi":"10.1152/ajpendo.00027.2025","DOIUrl":"10.1152/ajpendo.00027.2025","url":null,"abstract":"<p><p>Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured post-absorptive transcript abundance of markers of mitochondrial autophagy, dynamics, and metabolism (extensor digitorum longus [EDL], soleus, gastrocnemius), protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of SDH (tibialis anterior and plantaris), and maximal mitochondrial respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times: 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genes <i>Bmal1</i> and <i>Dbp</i> exhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 hours.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ribosome collisions and ZAKα activation: explores the therapeutic potential of metabolic diseases.","authors":"Wenqiang Zhang, Kexin Zhang, Chengxia Kan, Sufang Sheng, Ningning Hou, Fang Han, Jingwen Zhang, Xiaodong Sun","doi":"10.1152/ajpendo.00334.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00334.2025","url":null,"abstract":"<p><p>Metabolic diseases such as diabetes, hypertension, and fatty liver, driven by obesity, are increasing due to overnutrition and physical inactivity. In these conditions, the ribosomal stress response (RSR) represents a previously underexplored mechanism. Dysregulated production of reactive oxygen species from sources including NADPH oxidase and the mitochondrial electron transport chain leads to oxidative stress, which can induce ribosome collisions. This, in turn, activates ZAKα and the RSR pathway, driving metabolic dysfunction through stress-activated kinases such as c-Jun N-terminal kinase and p38. Elucidating the interplay between reactive oxygen species, ribosomal stress, and metabolic disease could open new therapeutic avenues. Dietary interventions, including polyunsaturated fatty acids and natural antioxidants, have the potential to reduce oxidative stress and improve metabolic health. The aim of this review is to highlight the link between ROS and ribosomal stress, with a focus on targeting ribosome collisions as a therapeutic strategy in metabolic disorders. Future studies should also establish reliable biomarkers of aberrant oxidative stress to guide clinical interventions for metabolic disease.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetic heart shows preferential secretion of inner mitochondrial membrane proteins in the presence of mitochondrial oxidative stress.","authors":"Paula M Miotto, Jacqueline Bayliss, Gio Fidelito, James R Bell, Lea M D Delbridge, Matthew J Watt, Magdalene K Montgomery","doi":"10.1152/ajpendo.00073.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00073.2025","url":null,"abstract":"<p><p>Heart disease, including diabetic cardiomyopathy, is a leading cause of mortality in patients with type 2 diabetes (T2D). Defects in heart function are accompanied by marked changes in cardiac metabolism, including dysregulation of lipid and glucose metabolism, mitochondrial dysfunction, and oxidative stress. In addition to these metabolic defects, the heart is an important endocrine organ. However, while T2D has been shown to impact the secretome of liver, skeletal muscle and adipose tissue (among others), little is known about the secretome of the heart, and the influence of T2D on cardiac protein secretion. Using precision-cut heart slices from mice with insulin resistance (20-weeks of high-fat feeding) and T2D (db/db mice) compared to their respective controls, we performed mass spectrometry proteomics analysis of cardiac protein secretion as well as proteins contained within extracellular vesicles (EV). We reveal striking remodelling of cardiac protein secretion in T2D but not diet-induced insulin resistance. Specifically, we show a marked increase in the secretion of inner mitochondrial membrane (IMM) proteins in T2D, which was accompanied by a disproportional accumulation of outer mitochondrial membrane proteins within the heart. This was associated with increased mitochondrial oxidative stress, selective oxidative damage to IMM proteins, and reduced markers of LC3-mediated mitophagy in the db/db heart, highlighting secretion of mitochondrial components as a potential alternative pathway for mitochondrial quality control. Altogether, this study provides an in-depth proteomics analysis showing remodelling of cardiac protein secretion in T2D and provides insights into a possible link between mitochondrial oxidative stress and the release of mitochondrial components.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}