Adipokines serve crucial functions in diabetic kidney disease (DKD) pathogenesis. Growth differentiation factor 5 (GDF5) is highly expressed in adipose tissue, but its specific role in DKD is unknown. In this study, we observed elevated GDF5 expression in both patients with DKD and db/db mice, suggesting a potential association between GDF5 and DKD progression. Elevated plasma GDF5 levels are associated with an increased risk of incident chronic kidney disease in patients with type 2 diabetes. In animal studies, adipose-specific overexpression of GDF5 increased circulating GDF5 and exacerbated renal injury in db/db mice, characterized by increased tubulointerstitial injury and inflammation infiltration. Conversely, adipose-specific knockdown reduced circulating GDF5 and alleviated renal injury. In vitro studies demonstrated that GDF5 induces partial epithelial–mesenchymal transition in renal tubular epithelial cells via activation of the SMAD1/5/8 signaling pathway, as evidenced by reduced E-cadherin expression and increased Snail1 levels. Notably, the supernatant from GDF5-treated injured HK-2 cells was found to enhance the secretion of proinflammatory cytokines by macrophages. These findings suggest that adipose-derived GDF5 acts as a novel mediator contributing to tubulointerstitial injury in DKD. Article Highlights Elevated growth differentiation factor 5 (GDF5) expression is correlated with disease progression in both patients with diabetic kidney disease and db/db mice. Adipose-specific GDF5 overexpression exacerbates, whereas its knockdown alleviates, renal tubulointerstitial injury in vivo. GDF5 directly induces partial epithelial–mesenchymal transition in tubular cells by activating the SMAD1/5/8 signaling pathway. Tubular cells exposed to GDF5 release factors that promote proinflammatory cytokine secretion in macrophages.
{"title":"GDF5 Exacerbates Tubulointerstitial Injury by Inducing Partial Epithelial–Mesenchymal Transition of Tubular Epithelial Cells in Diabetic Kidney Disease","authors":"Shiyun Tong, Chuan Peng, Yunjie Xiong, Jiangyun Lei, Rufei Gao, Ting Luo, Shuangxin Qi, Manman Du, Yunyan Liu, Linqiang Ma, Zhihong Wang, Wei Huang, Yong Xu, Shumin Yang, Jinbo Hu, Qifu Li, Xiangjun Chen","doi":"10.2337/db25-0599","DOIUrl":"https://doi.org/10.2337/db25-0599","url":null,"abstract":"Adipokines serve crucial functions in diabetic kidney disease (DKD) pathogenesis. Growth differentiation factor 5 (GDF5) is highly expressed in adipose tissue, but its specific role in DKD is unknown. In this study, we observed elevated GDF5 expression in both patients with DKD and db/db mice, suggesting a potential association between GDF5 and DKD progression. Elevated plasma GDF5 levels are associated with an increased risk of incident chronic kidney disease in patients with type 2 diabetes. In animal studies, adipose-specific overexpression of GDF5 increased circulating GDF5 and exacerbated renal injury in db/db mice, characterized by increased tubulointerstitial injury and inflammation infiltration. Conversely, adipose-specific knockdown reduced circulating GDF5 and alleviated renal injury. In vitro studies demonstrated that GDF5 induces partial epithelial–mesenchymal transition in renal tubular epithelial cells via activation of the SMAD1/5/8 signaling pathway, as evidenced by reduced E-cadherin expression and increased Snail1 levels. Notably, the supernatant from GDF5-treated injured HK-2 cells was found to enhance the secretion of proinflammatory cytokines by macrophages. These findings suggest that adipose-derived GDF5 acts as a novel mediator contributing to tubulointerstitial injury in DKD. Article Highlights Elevated growth differentiation factor 5 (GDF5) expression is correlated with disease progression in both patients with diabetic kidney disease and db/db mice. Adipose-specific GDF5 overexpression exacerbates, whereas its knockdown alleviates, renal tubulointerstitial injury in vivo. GDF5 directly induces partial epithelial–mesenchymal transition in tubular cells by activating the SMAD1/5/8 signaling pathway. Tubular cells exposed to GDF5 release factors that promote proinflammatory cytokine secretion in macrophages.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"110 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210490","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}
Valeria Fabriciova, Romana Bohuslavova, Laura Lebron-Mora, Vera Slaninova, Pavel Abaffy, Zuzana Berkova, Frantisek Saudek, Klaus H. Kaestner, Gabriela Pavlinkova
Pancreatic islet cells differentiate from a common progenitor pool through tightly regulated transcriptional and epigenetic programs. ISL1, a LIM homeodomain transcription factor, is essential for islet development, but its molecular functions remain poorly defined. Here, we demonstrate that ISL1 is critical for maintaining endocrine cell identity and enabling terminal differentiation, particularly of α- and β-cells. Using conditional Isl1 deletion in endocrine precursors, combined with single-cell RNA sequencing and chromatin profiling (H3K27ac and H3K27me3), we reveal disruption of the transcriptional and epigenetic landscape in Isl1-deficient islets. Loss of Isl1 results in the failure to establish α-cell identity, loss of δ- and γ-cell lineages, and the persistence of immature β-cells with impaired functional profiles in Isl1CKO mice. Longitudinal single-cell analysis shows that Isl1CKO endocrine cells exhibit sustained progenitor-like states and defective β-cell maturation. These defects are accompanied by activation of stress and diabetes-associated transcriptional programs, along with sex-specific responses that may influence disease onset and progression. Mechanistically, ISL1 represses intermediate progenitor programs and facilitates chromatin remodeling necessary for endocrine lineage commitment and terminal maturation. Our findings highlight a previously underappreciated role for ISL1 in preserving endocrine cell fate and function and offer insight into how its dysregulation may contribute to diabetes. Article Highlights ISL1 is a known maturity-onset diabetes of the young candidate and type 2 diabetes susceptibility gene, yet its molecular role in pancreatic endocrine maturation has remained unresolved. Deletion of Isl1 in endocrine progenitors results in islets composed of dysfunctional α-cells lacking glucagon production and immature β-cells with impaired basal insulin secretion, ultimately accelerating diabetes progression. ISL1 functions as a transcriptional repressor guiding chromatin remodeling and transcriptional transitions toward hormone-producing endocrine cells. The metabolic phenotype resulting from Isl1 deletion is associated with sustained progenitor-like states and activation of diabetes- and stress-associated pathways, with distinct sex-specific responses observed between male and female mice.
{"title":"ISL1 Restricts Progenitor Programs and Promotes β-Cell Maturation, Revealing Sex Differences in Diabetes Progression","authors":"Valeria Fabriciova, Romana Bohuslavova, Laura Lebron-Mora, Vera Slaninova, Pavel Abaffy, Zuzana Berkova, Frantisek Saudek, Klaus H. Kaestner, Gabriela Pavlinkova","doi":"10.2337/db25-0673","DOIUrl":"https://doi.org/10.2337/db25-0673","url":null,"abstract":"Pancreatic islet cells differentiate from a common progenitor pool through tightly regulated transcriptional and epigenetic programs. ISL1, a LIM homeodomain transcription factor, is essential for islet development, but its molecular functions remain poorly defined. Here, we demonstrate that ISL1 is critical for maintaining endocrine cell identity and enabling terminal differentiation, particularly of α- and β-cells. Using conditional Isl1 deletion in endocrine precursors, combined with single-cell RNA sequencing and chromatin profiling (H3K27ac and H3K27me3), we reveal disruption of the transcriptional and epigenetic landscape in Isl1-deficient islets. Loss of Isl1 results in the failure to establish α-cell identity, loss of δ- and γ-cell lineages, and the persistence of immature β-cells with impaired functional profiles in Isl1CKO mice. Longitudinal single-cell analysis shows that Isl1CKO endocrine cells exhibit sustained progenitor-like states and defective β-cell maturation. These defects are accompanied by activation of stress and diabetes-associated transcriptional programs, along with sex-specific responses that may influence disease onset and progression. Mechanistically, ISL1 represses intermediate progenitor programs and facilitates chromatin remodeling necessary for endocrine lineage commitment and terminal maturation. Our findings highlight a previously underappreciated role for ISL1 in preserving endocrine cell fate and function and offer insight into how its dysregulation may contribute to diabetes. Article Highlights ISL1 is a known maturity-onset diabetes of the young candidate and type 2 diabetes susceptibility gene, yet its molecular role in pancreatic endocrine maturation has remained unresolved. Deletion of Isl1 in endocrine progenitors results in islets composed of dysfunctional α-cells lacking glucagon production and immature β-cells with impaired basal insulin secretion, ultimately accelerating diabetes progression. ISL1 functions as a transcriptional repressor guiding chromatin remodeling and transcriptional transitions toward hormone-producing endocrine cells. The metabolic phenotype resulting from Isl1 deletion is associated with sustained progenitor-like states and activation of diabetes- and stress-associated pathways, with distinct sex-specific responses observed between male and female mice.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205060","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}
Caroline Miranda, Cristiano Santos, Johan Tolö, Rui Gao, Thomas G. Hill, Lakshmi Kothegala, Andrei I. Tarasov, Quan Zhang, Patrik Rorsman, Haiqiang Dou
In the article cited above, affiliation School of Biomedical Sciences, Ulster University, Coleraine, U.K., was inadvertently omitted at submission for author Andrei I. Tarosov. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db25-0302) has been updated with the correct affiliation information.
在上面引用的文章中，隶属于Ulster大学生物医学科学学院，Coleraine，英国，在提交作者Andrei I. Tarosov时无意中省略了。作者为这个错误道歉。文章的在线版本（https://doi.org/10.2337/db25-0302）已经更新了正确的从属信息。
{"title":"Erratum. δ-Cells Control a Subset of β-Cells in Mouse Pancreatic Islets. Diabetes 2025;74:2372–2374","authors":"Caroline Miranda, Cristiano Santos, Johan Tolö, Rui Gao, Thomas G. Hill, Lakshmi Kothegala, Andrei I. Tarasov, Quan Zhang, Patrik Rorsman, Haiqiang Dou","doi":"10.2337/db26-er04b","DOIUrl":"https://doi.org/10.2337/db26-er04b","url":null,"abstract":"In the article cited above, affiliation School of Biomedical Sciences, Ulster University, Coleraine, U.K., was inadvertently omitted at submission for author Andrei I. Tarosov. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db25-0302) has been updated with the correct affiliation information.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"115 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101415","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}
Sebastià Alcover, Sergi López, Lisaidy Ramos-Regalado, Natàlia Muñoz-García, Alex Gallinat, Rosa Suades, Lina Badimon, Gemma Vilahur
In the article cited above, affiliation Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain, was inadvertently omitted at submission for author SebastiáAlcover. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db24-0510) has been updated with the correct affiliation information.
在上述引用的文章中，在提交给作者SebastiáAlcover时，无意中遗漏了西班牙巴塞罗那大学（Universitat de Barcelona）的生物学系。作者为这个错误道歉。文章的在线版本（https://doi.org/10.2337/db24-0510）已经更新了正确的从属信息。
{"title":"Erratum. Cardioprotection During Myocardial Infarction in Diabetic Cardiomyopathy. Diabetes 2025;74:1021–1032","authors":"Sebastià Alcover, Sergi López, Lisaidy Ramos-Regalado, Natàlia Muñoz-García, Alex Gallinat, Rosa Suades, Lina Badimon, Gemma Vilahur","doi":"10.2337/db26-er04a","DOIUrl":"https://doi.org/10.2337/db26-er04a","url":null,"abstract":"In the article cited above, affiliation Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain, was inadvertently omitted at submission for author SebastiáAlcover. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db24-0510) has been updated with the correct affiliation information.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"77 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101429","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}
Yue Sun, Jinfu Zhang, Yuanyuan Su, Tiancheng Wu, Jiaqi Chen, Nan Yang, Xiao Han, Haiyan Lin, Ye Yin
Chronic overnutrition promotes excessive hepatic triglyceride accumulation, subsequently leading to insulin resistance and systemic metabolic dysfunction. Inorganic pyrophosphatase 1 (PPA1), an enzyme that hydrolyzes inorganic pyrophosphate, plays a key role in driving synthetic biochemical reactions. Here, we identified PPA1 as a novel regulator of systemic energy expenditure that functions by controlling hepatic production of fibroblast growth factor 21 (FGF21). FGF21 is a hormone predominantly secreted by the liver that protects against obesity by enhancing whole-body energy expenditure. Although nutritional states and various transcription factors are known to regulate hepatic FGF21 expression, the underlying mechanisms remain elusive. In this study, we demonstrate that hepatic-specific deletion of PPA1 effectively attenuates high-fat diet–induced obesity, reduces hepatic lipid deposition, and improves systemic insulin sensitivity in vivo. PPA1 ablation in the liver significantly elevates circulating FGF21 levels and increases whole-body energy expenditure by promoting adipose tissue browning and thermogenesis. Knockdown of hepatic FGF21 expression partially counteracts the protective effect conferred by PPA1 deficiency. Mechanistically, hepatic PPA1 deficiency elevates FGF21 through the GCN2/eIF2α/ATF4 pathway, a process that is dependent on the loss of its enzymatic activity. Our findings not only establish PPA1 as a critical regulator of systemic energy metabolism but also identify it as a novel modulator of FGF21, highlighting its potential as a therapeutic target for obesity and related metabolic disorders. ARTICLE HIGHLIGHTS Pyrophosphatase 1 (PPA1) is upregulated in livers of high-fat diet–induced obese mice and metabolic dysfunction–associated steatotic liver disease patients. Hepatic PPA1 deletion protects mice against high-fat diet–induced obesity and related metabolic disorders by promoting whole-body energy expenditure. Deficiency of hepatic PPA1 expression facilitates fibroblast growth factor 21 production by activating the GCN2/eIF2α/ATF4 signaling pathway.
{"title":"Down-Regulation of Hepatic PPA1 Protects Against Obesity by Elevating FGF21 Production via eIF2α Phosphorylation","authors":"Yue Sun, Jinfu Zhang, Yuanyuan Su, Tiancheng Wu, Jiaqi Chen, Nan Yang, Xiao Han, Haiyan Lin, Ye Yin","doi":"10.2337/db25-0655","DOIUrl":"https://doi.org/10.2337/db25-0655","url":null,"abstract":"Chronic overnutrition promotes excessive hepatic triglyceride accumulation, subsequently leading to insulin resistance and systemic metabolic dysfunction. Inorganic pyrophosphatase 1 (PPA1), an enzyme that hydrolyzes inorganic pyrophosphate, plays a key role in driving synthetic biochemical reactions. Here, we identified PPA1 as a novel regulator of systemic energy expenditure that functions by controlling hepatic production of fibroblast growth factor 21 (FGF21). FGF21 is a hormone predominantly secreted by the liver that protects against obesity by enhancing whole-body energy expenditure. Although nutritional states and various transcription factors are known to regulate hepatic FGF21 expression, the underlying mechanisms remain elusive. In this study, we demonstrate that hepatic-specific deletion of PPA1 effectively attenuates high-fat diet–induced obesity, reduces hepatic lipid deposition, and improves systemic insulin sensitivity in vivo. PPA1 ablation in the liver significantly elevates circulating FGF21 levels and increases whole-body energy expenditure by promoting adipose tissue browning and thermogenesis. Knockdown of hepatic FGF21 expression partially counteracts the protective effect conferred by PPA1 deficiency. Mechanistically, hepatic PPA1 deficiency elevates FGF21 through the GCN2/eIF2α/ATF4 pathway, a process that is dependent on the loss of its enzymatic activity. Our findings not only establish PPA1 as a critical regulator of systemic energy metabolism but also identify it as a novel modulator of FGF21, highlighting its potential as a therapeutic target for obesity and related metabolic disorders. ARTICLE HIGHLIGHTS Pyrophosphatase 1 (PPA1) is upregulated in livers of high-fat diet–induced obese mice and metabolic dysfunction–associated steatotic liver disease patients. Hepatic PPA1 deletion protects mice against high-fat diet–induced obesity and related metabolic disorders by promoting whole-body energy expenditure. Deficiency of hepatic PPA1 expression facilitates fibroblast growth factor 21 production by activating the GCN2/eIF2α/ATF4 signaling pathway.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"5 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972254","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}
Eftychia Kontidou, Aida Collado, Rawan Humoud, Kesavan Manickam, John Tengbom, Tong Jiao, Michael Alvarsson, Jiangning Yang, Linda Mellbin, Ali Mahdi, John Pernow, Zhichao Zhou
Type 2 diabetes increases cardiovascular risk, with endothelial dysfunction playing a key role. Prolonged disease duration exacerbates cardiovascular risk, but the underlying mechanisms remain unclear. We previously demonstrated that red blood cells (RBCs) from individuals with type 2 diabetes impair endothelial function via reduced miRNA (miR)-210-3p. We investigated whether disease duration influences RBC-induced endothelial dysfunction and its link to miR-210-3p. RBCs were isolated from diabetic db/db mice of various ages and from humans with newly diagnosed (<1 year) or long-lasting type 2 diabetes (>7 years). Endothelial-dependent relaxation (EDR), miR-210-3p levels, its target protein glycerol-3-phosphate dehydrogenase 2 (GPD2), and oxidative stress marker 4-hydroxynonenal (4-HNE) were assessed. RBCs from 14- and 22-week-old, but not 7-week-old, db/db mice impaired EDR. These RBCs showed similarly reduced miR-210-3p levels and increased vascular GPD2 and 4-HNE expression. RBCs from individuals with long-lasting type 2 diabetes, but not from the newly diagnosed group, impaired EDR. After ≥7 years, RBCs from initially newly diagnosed individuals impaired EDR, which was rescued by miR-210-3p mimic transfection. In contrast, RBCs from healthy subjects did not impair EDR after follow-up. These findings underscore the pivotal role of disease duration for RBC-mediated vascular dysfunction, linked to miR-210-3p downregulation. RBC miR-210-3p may serve as a biomarker for diabetes-related vascular disease. Article Highlights Red blood cells (RBCs) from older (representing longer duration of diabetes) but not young diabetic mice induce endothelial dysfunction. Protective miRNA-210-3p levels in RBCs are reduced in older diabetic mice compared with young ones. RBCs from individuals with long-lasting (>7 years) but not newly diagnosed type 2 diabetes (<1 year) induce endothelial dysfunction. RBCs from individuals with newly diagnosed type 2 diabetes induce endothelial dysfunction at a >7-year follow up, which is rescued by miRNA-210-3p mimic.
{"title":"Long Duration of Type 2 Diabetes Drives Erythrocyte-Induced Vascular Endothelial Dysfunction: A Link to miRNA-210-3p","authors":"Eftychia Kontidou, Aida Collado, Rawan Humoud, Kesavan Manickam, John Tengbom, Tong Jiao, Michael Alvarsson, Jiangning Yang, Linda Mellbin, Ali Mahdi, John Pernow, Zhichao Zhou","doi":"10.2337/db25-0463","DOIUrl":"https://doi.org/10.2337/db25-0463","url":null,"abstract":"Type 2 diabetes increases cardiovascular risk, with endothelial dysfunction playing a key role. Prolonged disease duration exacerbates cardiovascular risk, but the underlying mechanisms remain unclear. We previously demonstrated that red blood cells (RBCs) from individuals with type 2 diabetes impair endothelial function via reduced miRNA (miR)-210-3p. We investigated whether disease duration influences RBC-induced endothelial dysfunction and its link to miR-210-3p. RBCs were isolated from diabetic db/db mice of various ages and from humans with newly diagnosed (&lt;1 year) or long-lasting type 2 diabetes (&gt;7 years). Endothelial-dependent relaxation (EDR), miR-210-3p levels, its target protein glycerol-3-phosphate dehydrogenase 2 (GPD2), and oxidative stress marker 4-hydroxynonenal (4-HNE) were assessed. RBCs from 14- and 22-week-old, but not 7-week-old, db/db mice impaired EDR. These RBCs showed similarly reduced miR-210-3p levels and increased vascular GPD2 and 4-HNE expression. RBCs from individuals with long-lasting type 2 diabetes, but not from the newly diagnosed group, impaired EDR. After ≥7 years, RBCs from initially newly diagnosed individuals impaired EDR, which was rescued by miR-210-3p mimic transfection. In contrast, RBCs from healthy subjects did not impair EDR after follow-up. These findings underscore the pivotal role of disease duration for RBC-mediated vascular dysfunction, linked to miR-210-3p downregulation. RBC miR-210-3p may serve as a biomarker for diabetes-related vascular disease. Article Highlights Red blood cells (RBCs) from older (representing longer duration of diabetes) but not young diabetic mice induce endothelial dysfunction. Protective miRNA-210-3p levels in RBCs are reduced in older diabetic mice compared with young ones. RBCs from individuals with long-lasting (&gt;7 years) but not newly diagnosed type 2 diabetes (&lt;1 year) induce endothelial dysfunction. RBCs from individuals with newly diagnosed type 2 diabetes induce endothelial dysfunction at a &gt;7-year follow up, which is rescued by miRNA-210-3p mimic.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"76 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920332","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}
Noah J. Levi, Alejandro Tamayo Garcia, Madina Sokolov, Rene Barro-Soria, Alejandro Caicedo
The parasympathetic nervous system modulates hormone and digestive enzyme secretion from the pancreas. However, the mechanisms of neuroeffector transmission within the final parasympathetic pathway in the pancreas have not been elucidated. Here, we demonstrate that intrapancreatic cholinergic neurons are bona fide postganglionic neurons that functionally couple vagal input to target cells in the pancreas. In living pancreatic slices from various mice expressing genetically encoded sensors and actuators, we found that intrapancreatic neurons responded to cholinergic input via nicotinic and muscarinic M1 acetylcholine receptors. However, only muscarinic receptor signaling was necessary and sufficient to elicit responses in exocrine and endocrine target cells. We established that muscarinic receptor signaling in intrapancreatic neurons is linked to the potassium M-current, thus producing the sustained reverberating activity required to efficiently modulate insulin and glucagon secretion and elicit oscillatory responses in acinar cells. Whereas intrapancreatic neurons triggered responses in acinar cells without additional stimulation, they only primed and amplified hormone secretion already stimulated by changes in glucose levels. This mechanistic insight into how intrapancreatic neurons regulate pancreas function challenges canonical models of parasympathetic neurotransmission and is critical to understanding autonomic control of the pancreas. Article Highlights Neurotransmission mechanisms at the final parasympathetic pathway in the pancreas have not been elucidated. We manipulated and recorded neuronal and target cell responses in living pancreatic slices to assess how intrapancreatic neurons affect pancreatic cell function. Activating muscarinic receptor signaling in intrapancreatic neurons was required to trigger exocrine cell activity and modulate endocrine cell secretion. Our findings revise conventional models of parasympathetic neuronal control of pancreatic function.
{"title":"Activating Muscarinic Receptor Signaling in Intrapancreatic Neurons Is Required for Parasympathetic Cholinergic Control of Pancreatic Cell Function","authors":"Noah J. Levi, Alejandro Tamayo Garcia, Madina Sokolov, Rene Barro-Soria, Alejandro Caicedo","doi":"10.2337/db25-0604","DOIUrl":"https://doi.org/10.2337/db25-0604","url":null,"abstract":"The parasympathetic nervous system modulates hormone and digestive enzyme secretion from the pancreas. However, the mechanisms of neuroeffector transmission within the final parasympathetic pathway in the pancreas have not been elucidated. Here, we demonstrate that intrapancreatic cholinergic neurons are bona fide postganglionic neurons that functionally couple vagal input to target cells in the pancreas. In living pancreatic slices from various mice expressing genetically encoded sensors and actuators, we found that intrapancreatic neurons responded to cholinergic input via nicotinic and muscarinic M1 acetylcholine receptors. However, only muscarinic receptor signaling was necessary and sufficient to elicit responses in exocrine and endocrine target cells. We established that muscarinic receptor signaling in intrapancreatic neurons is linked to the potassium M-current, thus producing the sustained reverberating activity required to efficiently modulate insulin and glucagon secretion and elicit oscillatory responses in acinar cells. Whereas intrapancreatic neurons triggered responses in acinar cells without additional stimulation, they only primed and amplified hormone secretion already stimulated by changes in glucose levels. This mechanistic insight into how intrapancreatic neurons regulate pancreas function challenges canonical models of parasympathetic neurotransmission and is critical to understanding autonomic control of the pancreas. Article Highlights Neurotransmission mechanisms at the final parasympathetic pathway in the pancreas have not been elucidated. We manipulated and recorded neuronal and target cell responses in living pancreatic slices to assess how intrapancreatic neurons affect pancreatic cell function. Activating muscarinic receptor signaling in intrapancreatic neurons was required to trigger exocrine cell activity and modulate endocrine cell secretion. Our findings revise conventional models of parasympathetic neuronal control of pancreatic function.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903708","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}
Angiotensin II (AngII) activation, a key driver of diabetes pathogenesis and associated complications, induces kidney injury by promoting oxidative stress and inflammation. Ferroptosis is an iron-dependent regulated cell death, playing a crucial role in kidney injury. This study aimed to explore the contribution of ferroptosis to AngII-induced kidney injury and its regulatory mechanisms. Our findings reveal that chronic AngII stimulation leads to renal dysfunction, characterized by elevated serum creatinine levels, increased urinary protein-to-creatinine ratio, and tubular injury. These changes are associated with ferroptosis in renal tubular epithelial cells (TECs) and a marked upregulation of dipeptidase 1 (DPEP1) expression. Notably, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reversed ferroptosis in TECs, restored tubular integrity, and improved renal function. DPEP1 gene silencing and the DPEP1 inhibitor cilastatin significantly inhibited AngII-induced ferroptosis in TECs. Mechanistically, AngII upregulated DPEP1 expression via the transcription factor SP1. Elevated DPEP1 enhanced ubiquitination of SLC3A2, a key cystine/glutathione transporter. Furthermore, inhibiting DPEP1 with cilastatin in a mouse model effectively reversed ferroptosis and alleviated kidney injury. These findings highlight ferroptosis’ key role in AngII-induced kidney injury and suggest DPEP1 targeting as a therapeutic strategy against AngII-driven renal damage. Article Highlights This study investigated the role of ferroptosis in angiotensin II (AngII)-induced kidney injury, addressing a critical gap in understanding AngII-mediated nephropathy mechanisms. We asked whether dipeptidase 1 (DPEP1)-mediated SLC3A2 degradation drives ferroptosis and renal damage under AngII activation. AngII upregulates DPEP1 via SP1, promoting SLC3A2 ubiquitination and glutathione depletion, ultimately triggering tubular ferroptosis. DPEP1 inhibition rescues renal function. Targeting the SP1-DPEP1-SLC3A2 axis offers a novel therapeutic strategy against ferroptosis-dependent kidney injury in hypertension and metabolic disorders.
{"title":"Angiotensin II–Induced Ferroptosis in Epithelial Cells Contributes to Kidney Injury via SP1-DPEP1–Mediated SLC3A2 Degradation","authors":"Yuan Tian, Ge Yang, Qihe Zhang, Chao Dong, Yanru Li, Shuang Lv, Shuang Li, Haiying Zhang, Xin Jiang, Ying Xin","doi":"10.2337/db25-0619","DOIUrl":"https://doi.org/10.2337/db25-0619","url":null,"abstract":"Angiotensin II (AngII) activation, a key driver of diabetes pathogenesis and associated complications, induces kidney injury by promoting oxidative stress and inflammation. Ferroptosis is an iron-dependent regulated cell death, playing a crucial role in kidney injury. This study aimed to explore the contribution of ferroptosis to AngII-induced kidney injury and its regulatory mechanisms. Our findings reveal that chronic AngII stimulation leads to renal dysfunction, characterized by elevated serum creatinine levels, increased urinary protein-to-creatinine ratio, and tubular injury. These changes are associated with ferroptosis in renal tubular epithelial cells (TECs) and a marked upregulation of dipeptidase 1 (DPEP1) expression. Notably, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reversed ferroptosis in TECs, restored tubular integrity, and improved renal function. DPEP1 gene silencing and the DPEP1 inhibitor cilastatin significantly inhibited AngII-induced ferroptosis in TECs. Mechanistically, AngII upregulated DPEP1 expression via the transcription factor SP1. Elevated DPEP1 enhanced ubiquitination of SLC3A2, a key cystine/glutathione transporter. Furthermore, inhibiting DPEP1 with cilastatin in a mouse model effectively reversed ferroptosis and alleviated kidney injury. These findings highlight ferroptosis’ key role in AngII-induced kidney injury and suggest DPEP1 targeting as a therapeutic strategy against AngII-driven renal damage. Article Highlights This study investigated the role of ferroptosis in angiotensin II (AngII)-induced kidney injury, addressing a critical gap in understanding AngII-mediated nephropathy mechanisms. We asked whether dipeptidase 1 (DPEP1)-mediated SLC3A2 degradation drives ferroptosis and renal damage under AngII activation. AngII upregulates DPEP1 via SP1, promoting SLC3A2 ubiquitination and glutathione depletion, ultimately triggering tubular ferroptosis. DPEP1 inhibition rescues renal function. Targeting the SP1-DPEP1-SLC3A2 axis offers a novel therapeutic strategy against ferroptosis-dependent kidney injury in hypertension and metabolic disorders.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"177 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903705","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}
Yoichi Ono, Simone Kennard, Benjamin T. Wall, Jing Ma, Eric J. Belin de Chantemèle
Although control of metabolism by leptin is primarily viewed as centrally mediated, leptin has also been shown to directly regulate adipocyte function. However, the impact of the peripheral effects of leptin on systemic metabolism, especially in the context of obesity, remains unclear. To address this question, we selectively restored adipocyte leptin receptor (LEPR) expression in obese male and female LEPR–conditional knockout mice. Adipocyte LEPR restoration did not affect body weight but selectively increased brown adipose tissue (BAT) mass in male mice. This was associated with increased energy expenditure, smaller BAT adipocytes, lower triglycerides content, and increased markers of browning and lipolysis exclusively in males. Additionally, adipocyte LEPR restoration enhanced the expression of markers of endothelial cells and angiogenesis in male mouse BAT, supporting increased local vascularization. Improved BAT function in males was also associated with lower HbA1c, better insulin sensitivity, reduced systolic blood pressure, decreased arterial stiffness, and improved endothelial function. Lastly, adipocyte LEPR restoration lowered circulating proinflammatory cytokines and reduced tissue inflammation in the aorta and heart, again in males only. These findings reveal a critical role for adipocyte leptin signaling in regulating BAT function and emphasize its importance in maintaining glycemic and cardiovascular health in males with obesity. Article Highlights Leptin is known to enhance brown adipose tissue (BAT) activity through sympathetic stimulation. However, in vitro studies suggest leptin could also act directly on adipocytes to promote lipolysis. Whether these peripheral effects of leptin are relevant to systemic metabolic control in obesity remains unclear. We addressed this question by selectively restoring leptin receptor (LEPR) expression in adipocytes of obese LEPR–conditional knockout mice. LEPR restoration selectively enhanced BAT activity in male mice, which led to improved glycemic control and cardiovascular function. These findings reveal a crucial role for BAT leptin signaling in regulating energy expenditure and glycemic and cardiovascular health, primarily in males.
{"title":"Adipocyte Leptin Signaling Regulates Glycemia and Cardiovascular Function by Enhancing Brown Adipose Tissue Thermogenesis in Obese Male Mice","authors":"Yoichi Ono, Simone Kennard, Benjamin T. Wall, Jing Ma, Eric J. Belin de Chantemèle","doi":"10.2337/db25-0388","DOIUrl":"https://doi.org/10.2337/db25-0388","url":null,"abstract":"Although control of metabolism by leptin is primarily viewed as centrally mediated, leptin has also been shown to directly regulate adipocyte function. However, the impact of the peripheral effects of leptin on systemic metabolism, especially in the context of obesity, remains unclear. To address this question, we selectively restored adipocyte leptin receptor (LEPR) expression in obese male and female LEPR–conditional knockout mice. Adipocyte LEPR restoration did not affect body weight but selectively increased brown adipose tissue (BAT) mass in male mice. This was associated with increased energy expenditure, smaller BAT adipocytes, lower triglycerides content, and increased markers of browning and lipolysis exclusively in males. Additionally, adipocyte LEPR restoration enhanced the expression of markers of endothelial cells and angiogenesis in male mouse BAT, supporting increased local vascularization. Improved BAT function in males was also associated with lower HbA1c, better insulin sensitivity, reduced systolic blood pressure, decreased arterial stiffness, and improved endothelial function. Lastly, adipocyte LEPR restoration lowered circulating proinflammatory cytokines and reduced tissue inflammation in the aorta and heart, again in males only. These findings reveal a critical role for adipocyte leptin signaling in regulating BAT function and emphasize its importance in maintaining glycemic and cardiovascular health in males with obesity. Article Highlights Leptin is known to enhance brown adipose tissue (BAT) activity through sympathetic stimulation. However, in vitro studies suggest leptin could also act directly on adipocytes to promote lipolysis. Whether these peripheral effects of leptin are relevant to systemic metabolic control in obesity remains unclear. We addressed this question by selectively restoring leptin receptor (LEPR) expression in adipocytes of obese LEPR–conditional knockout mice. LEPR restoration selectively enhanced BAT activity in male mice, which led to improved glycemic control and cardiovascular function. These findings reveal a crucial role for BAT leptin signaling in regulating energy expenditure and glycemic and cardiovascular health, primarily in males.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"36 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903707","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}
Current imaging technologies cannot detect diabetic retinopathy until there has been significant permanent damage to patients’ vision. We hypothesized that hyperglycemia causes retinal hypoxia, and hypoxia may lead to apoptosis of retinal cells. We performed experiments using a mouse model of streptozotocin (STZ)-induced diabetes to investigate the role of hyperglycemia in diabetic eye disease. Our experimental results indicate that diabetic retinas are significantly hypoxic compared with nondiabetic controls. Retinal hypoxia can be detected using HYPOX-4, an early-detection imaging probe, potentially before any detectable changes in the diabetic retina. In the early stages of diabetes, we did not observe any detectable changes in electroretinography response, vascular permeability in fluorescein angiography, or retinal thickness in optical coherence tomographic imaging. In addition, increased HYPOX-4 fluorescence in the diabetic retina was not associated with focal ischemia; rather, increased levels of HYPOX-4 fluorescence were observed throughout the entire diabetic retina. Moreover, hypoxia profiles in STZ-induced diabetic retinas were colocalized with TUNEL-positive apoptotic cells. To confirm the role of hyperglycemia in the diabetic retina, human retinal cells were treated under hyperglycemic conditions, and hypoxia was monitored using the pimonidazole-adduct immunostaining method. Surprisingly, retinal cells became hypoxic under hyperglycemic conditions within the first few hours. We conclude that the diabetic retina becomes hypoxic as a result of hyperglycemia in the early stage of diabetes, which could lead to the degeneration of retinal cells at later stages of the disease. In addition, HYPOX-4 could be used as a powerful early diagnostic imaging method to detect retinal hypoxia in the diabetic retina before any detectable retinopathy. ARTICLE HIGHLIGHTS Hyperglycemia causes retinal hypoxia. Hypoxia may lead to apoptosis of retinal cells. Retinal hypoxia can be detected before any detectable changes in the diabetic retina. HYPOX-4 is a powerful early diagnostic imaging method to detect hypoxia in the diabetic retinas of living patients.
{"title":"Imaging Hypoxia in the Diabetic Retina: A Potential Early-Detection Imaging Biomarker Before Detectable Retinopathy in Diabetes","authors":"MD Imam Uddin, Blake Dieckmann, David E. Burgos","doi":"10.2337/db25-0394","DOIUrl":"https://doi.org/10.2337/db25-0394","url":null,"abstract":"Current imaging technologies cannot detect diabetic retinopathy until there has been significant permanent damage to patients’ vision. We hypothesized that hyperglycemia causes retinal hypoxia, and hypoxia may lead to apoptosis of retinal cells. We performed experiments using a mouse model of streptozotocin (STZ)-induced diabetes to investigate the role of hyperglycemia in diabetic eye disease. Our experimental results indicate that diabetic retinas are significantly hypoxic compared with nondiabetic controls. Retinal hypoxia can be detected using HYPOX-4, an early-detection imaging probe, potentially before any detectable changes in the diabetic retina. In the early stages of diabetes, we did not observe any detectable changes in electroretinography response, vascular permeability in fluorescein angiography, or retinal thickness in optical coherence tomographic imaging. In addition, increased HYPOX-4 fluorescence in the diabetic retina was not associated with focal ischemia; rather, increased levels of HYPOX-4 fluorescence were observed throughout the entire diabetic retina. Moreover, hypoxia profiles in STZ-induced diabetic retinas were colocalized with TUNEL-positive apoptotic cells. To confirm the role of hyperglycemia in the diabetic retina, human retinal cells were treated under hyperglycemic conditions, and hypoxia was monitored using the pimonidazole-adduct immunostaining method. Surprisingly, retinal cells became hypoxic under hyperglycemic conditions within the first few hours. We conclude that the diabetic retina becomes hypoxic as a result of hyperglycemia in the early stage of diabetes, which could lead to the degeneration of retinal cells at later stages of the disease. In addition, HYPOX-4 could be used as a powerful early diagnostic imaging method to detect retinal hypoxia in the diabetic retina before any detectable retinopathy. ARTICLE HIGHLIGHTS Hyperglycemia causes retinal hypoxia. Hypoxia may lead to apoptosis of retinal cells. Retinal hypoxia can be detected before any detectable changes in the diabetic retina. HYPOX-4 is a powerful early diagnostic imaging method to detect hypoxia in the diabetic retinas of living patients.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"29 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777593","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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