Diabetes最新文献

{"title":"Effects of Pancreatic Resection on Liver Fat Content and Amino Acid, Lipid, and Glucose Metabolism: A Prospective 1-Year Follow-up Study","authors":"Magnus F.G. Grøndahl, Iben Rix, Lars F. Garvey, Casper K. Nielsen, Malte P. Suppli, Gro L. Willemoe, Merete J. Kønig, Elizaveta Chabanova, Samuel A.J. Trammell, Trisha J. Grevengoed, Bolette Hartmann, Jens J. Holst, Carsten P. Hansen, Asger B. Lund, Filip K. Knop","doi":"10.2337/db25-0902","DOIUrl":"https://doi.org/10.2337/db25-0902","url":null,"abstract":"Individuals who undergo pancreatic resection are at increased risk of developing hepatic steatosis. Glucagon is a key regulator of hepatic glucose, amino acids, and lipid metabolism, and the change in circulating glucagon is suggested to contribute to the pathogenesis of postoperative steatotic liver disease. Here, we aimed to elucidate hepatic and metabolic changes induced by pancreatic resection. Fifty individuals scheduled to undergo pancreatic surgery were recruited and evaluated by blood samples and a liver biopsy obtained during surgery. One year after surgery, 21 eligible participants (15 following pancreaticoduodenectomy, 6 following total pancreatectomy) met for a follow-up visit, with the remaining being excluded because of recurrent disease, comorbidities, or death. Follow-up MRS indicated increased liver fat in 12 of 19 participants despite a mean numerical decrease in body weight. Five eligible participants underwent a liver biopsy at follow-up, demonstrating increased liver fat content (largest individual increase: 80 percentage points). Circulating glucagon and C-peptide were significantly reduced at follow-up, with no detection of either following total pancreatectomy. No significant changes in fasting plasma glucose or HbA1c were observed, attributed to relevant exogenous insulin supplementation. Amino acids were markedly increased after both pancreaticoduodenectomy and total pancreatectomy, correlating negatively with remnant endocrine pancreatic function. In conclusion, our data suggest that reduced circulating glucagon levels may contribute to the increased liver fat content and hyperaminoacidemia observed after pancreatic resection. Article Highlights Previous studies have demonstrated increased risk of hepatic steatosis in patients following pancreatic resection, which might be linked to decreased pancreatic function. Here, we evaluated liver fat content, circulating pancreatic hormones, amino acids, and more, before and 1 year after either total pancreatectomy or pancreaticoduodenectomy. At 1-year follow-up, we found increased liver fat content in more than half (63%) of the participants, evaluated both by liver histology and magnetic resonance imaging. The participants were characterized by hyperaminoacidemia, which correlated negatively with remnant endocrine pancreatic function. These findings further elucidate the relationship between glucagon, circulating amino acids, and hepatic metabolism.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"53 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Memory Regulatory T Cells as a Biomarker of Early Type I Diabetes","authors":"Davide Raineri, Silvia Savastio, Simonetta Bellone, Lorenza Scotti, Camilla Barbero-Mazzucca, Giuseppe Cappellano, Flavia Prodam, Erica Pozzi, Ivana Rabbone, Annalisa Chiocchetti","doi":"10.2337/db25-0161","DOIUrl":"https://doi.org/10.2337/db25-0161","url":null,"abstract":"Type 1 diabetes (T1D) is the most common chronic autoimmune disease in children, driven by a breakdown in self-tolerance and T cell–mediated immune attack of pancreatic β-cells. There are no biomarkers to effectively diagnose autoimmunity before disease onset and clinical symptom development. Here, we applied deep multiparametric immunophenotyping to compare immune landscapes in 38 patients with new-onset T1D, 24 siblings, and 18 healthy control participants (HCs). Patients with T1D underwent clinical and metabolic evaluations. Immune populations in fresh whole-blood samples were analyzed using a panel of 26 antibodies, detecting 39 different cell populations. Memory regulatory T cells (memory Tregs) were significantly increased in patients with T1D (P < 0.05) and their siblings (P < 0.01) compared with HCs but not between patients with T1D and siblings. Memory Tregs were associated with disease status and age in multivariable analysis. There was a positive correlation between age and memory Tregs in the HC and sibling groups but not in patients with T1D. Baseline memory Treg levels in siblings resembled those of patients with T1D. These findings highlight the existence of an age-independent, disease-specific immune fingerprint that could serve as a minimally invasive biomarker for early diagnosis and personalized immunotherapy. Further studies using functional and single-cells analysis are needed to confirm memory Tregs as a pathogenic trait. Article Highlights There are more memory regulatory T cells (Tregs) in individuals with type 1 diabetes (T1D) and siblings than in healthy control (HC) individuals. Individuals with T1D and their siblings share an immunological profile, with siblings displaying an intermediate phenotype that overlaps with both T1D and HC individuals. Memory Tregs increased with age in HC individuals and siblings but not in individuals with T1D. Diabetic ketoacidosis status had no impact on immune cell populations in patients with T1D.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"67 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147274321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Signature of Gestational Diabetes Mellitus and Risk of Adverse Birth Outcomes: A Prospective Birth Cohort Study","authors":"Jinghan Wang, Yue Jiang, Hong Lv, Di Pi, Xiumei Han, Bo Xu, Xiaoyu Liu, Kun Zhou, Yangqian Jiang, Xiaolin Yang, Xin Xu, Yuanyan Dou, Tao Jiang, Jiangbo Du, Guangfu Jin, Hongxia Ma, Zhibin Hu, Hongbing Shen, Yuan Lin","doi":"10.2337/db25-0920","DOIUrl":"https://doi.org/10.2337/db25-0920","url":null,"abstract":"Gestational diabetes mellitus (GDM) is a heterogeneous condition diagnosed solely through glucose. It is characterized by profound perturbations in the metabolome, with specific metabolic profiles linked to adverse birth outcomes. Metabolomics can reveal population heterogeneity in health and disease. Here, we used nontargeted metabolomics to systematically profile the circulating metabolome in 2,050 pregnant women during midpregnancy, identifying 30 metabolites that define the GDM metabolic signature (mGDM). Participants were stratified into four groups by distinct glycemic and metabolic profiles, namely normoglycemic non-mGDM, hyperglycemic non-mGDM, normoglycemic mGDM, and hyperglycemic mGDM, and associations with subsequent adverse birth outcomes were assessed. Compared with normoglycemic non-mGDM, normoglycemic mGDM demonstrated nearly a twofold increased risk of preterm birth (odds ratio [OR] 1.93, 95% CI 1.02–3.65) and large for gestational age (OR 2.11, 95% CI 1.53–2.92). Conversely, the hyperglycemic non-mGDM group did not show elevated risks in adverse birth outcomes versus the normoglycemic group. The hyperglycemic mGDM profile was associated with higher risks of preterm birth (OR 2.37, 95% CI 1.04–5.39), large for gestational age (OR 2.28, 95% CI 1.50–3.47), congenital malformations (OR 1.87, 95% CI 1.03–3.39), and neonatal intensive care unit (NICU) admissions (OR 1.69, 95% CI 1.09–2.61). We observed a stepwise increase in adverse outcome risk across the four-level metabolic-glycemic categories (P for trend < 0.001 for large for gestational age, 0.013 for preterm birth, and 0.018 for NICU admission). Taken together, our study outlines the metabolic profile of GDM and reveals clinically relevant heterogeneity in adverse pregnancy outcomes by metabolic signature. Integrating blood glucose and metabolomics may improve risk stratification and advance precision maternal care. Article Highlights Women diagnosed with gestational diabetes mellitus (GDM) exhibit variability in symptom presentation and pregnancy outcomes. The heterogeneity in metabolic features beyond a GDM diagnosis and their influences on health outcomes is less studied. We aimed to identify the metabolic signatures of GDM, stratify pregnant women by glycemic and metabolic profiles, and further investigate the intergroup heterogeneity and their respective associations with adverse birth outcomes. Maternal metabolic dysregulation, rather than blood glucose alone, exerts more profound associations with adverse outcomes in pregnant women and their offspring. Targeted risk stratification using metabolomics offers a novel opportunity for precision medicine in GDM, potentially improving health management of pregnant women.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"50 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Regulation of VCAM-1 by Lipoxin A4 Is Renoprotective Against Diabetic Kidney Disease","authors":"Madhura Bose, Muthukumar Mohan, Jun Okabe, Harikrishnan Kaipananickal, Victoria Priori, Carolyn Chhor, Karly C. Sourris, Ramtin Radman, Christos Tikellis, Yvonne Zhang, Assam El-Osta, Eoin Brennan, Patrick J. Guiry, Kevin Gahan, Catherine Tighe, Merlin Thomas, Karin Jandeleit-Dahm, Catherine Godson, Phillip Kantharidis, Mark E. Cooper","doi":"10.2337/db25-0970","DOIUrl":"https://doi.org/10.2337/db25-0970","url":null,"abstract":"Chronic low-grade inflammation underlies many microvascular complications of diabetes, including diabetic kidney disease (DKD). Lipoxins (LXs), an endogenously produced family of lipid mediators, resolve inflammation and protect against renal scarring as occurs in DKD. This study examined the mechanism by which LXs protect against DKD, focusing on the regulation of VCAM-1 and the recruitment of macrophages to the diabetic glomerulus. LXA4 and two fourth-generation mimetics were assessed in diabetic ApoE knockout mice, followed by in vitro studies in the main renal cell populations, including podocytes, proximal tubular, mesangial, and glomerular endothelial cells. LXs attenuated albuminuria, mesangial expansion, and collagen and fibronectin deposition as both a preventive and delayed intervention in experimental DKD. LXs also consistently attenuated the TNF-α–induced expression of VCAM-1 in all the human and mouse renal cell populations examined. Further analysis identified that the renoprotection was in part mediated by an epigenetic modification of the VCAM-1 gene through H3K4 monomethylation, which did not appear to be dependent on NF-κB activation in human glomerular endothelial cells. LXs protect against DKD by modulating glomerular endothelial cell inflammation and via a novel LX-mediated epigenetic mechanism regulating the VCAM-1 promoter in these cells. Article Highlights Lipoxins (LXs) protect against diabetic kidney disease (DKD) by resolving chronic low-grade inflammation, but the exact mechanism by which this occurs is not known. We investigated the effect of LXs on inflammatory markers and the recruitment of macrophages to the diabetic glomerulus by using LXs as both a preventive and delayed interventional treatment in streptozotocin-induced diabetic ApoE knockout mice. Protection against DKD was associated with reduced glomerular macrophage accumulation. LXs also attenuated the expression of VCAM1 in glomerular endothelial cells. LXs protect against DKD in part by a mechanism that reduces VCAM1 gene expression via H3K4 monomethylation on the VCAM1 gene.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Staying Functional Through Connection and Adaptation: When Islets Inspire Islet Biologists","authors":"Sangeeta Dhawan, Jing Hughes, Aleksey V. Matveyenko, Vincent Poitout","doi":"10.2337/dbi25-0036","DOIUrl":"https://doi.org/10.2337/dbi25-0036","url":null,"abstract":"In response to the lockdowns and travel bans during the coronavirus disease 2019 pandemic, Peter C. Butler at the University of California, Los Angeles (UCLA), started a virtual islet biology seminar series. After the authors of this article joined him as co-organizers, this initiative became the Islet Research Seminar Series (IRSS). Like islets of Langerhans adapt to their changing environment, the islet biology community quickly embraced this new format. The IRSS evolved into a lasting scientific forum that convenes weekly and is attended by islet biologists from the U.S., Canada, Europe, and Israel. The series covers a range of topics in islet biology, with presentations from scientists representing all career stages. It has proven particularly valuable for trainees and early-stage investigators in exposing them to a variety of topics in islet biology without travel required and facilitating more spontaneous interactions with senior scientists than at in-person meetings. While the online format is not meant to replace live scientific conferences, we believe that the IRSS plays a unique role in keeping the islet biology community connected and abreast of the most recent scientific discoveries in our field. The success of this platform stands as a testament to the scientific community to adapt and thrive through challenges. This article is dedicated to Peter C. Butler, UCLA, who initiated the IRSS.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"7 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the Pancreatic “Metabolic Synapse” Aggravates Type 2 Diabetes Mellitus by Inducing PANoptosis in β-Cells","authors":"Zhao Xiang, Liu Zitian, Yang Guangwei, Dong Shuohui, Wang Kexin","doi":"10.2337/db25-0863","DOIUrl":"https://doi.org/10.2337/db25-0863","url":null,"abstract":"Pancreatic β-cells play a central role in type 2 diabetes mellitus (T2DM), yet the interactions between β-cells and stromal components within the islet microenvironment remain poorly defined. We investigated the contribution of pancreatic fibroblasts to β-cell dysfunction and T2DM progression. We used single-cell sequencing technology and in vitro experiments to investigate the mechanisms by which bariatric surgery ameliorates T2DM. We introduce the novel concept of a “metabolic synapse” to describe the interaction between pancreatic fibroblasts and β-cells. Our findings reveal that pancreatic fibroblasts secrete excessive glutamate in the early stages of T2DM. Elevated glutamate concentrations within the islet microenvironment subsequently activate N-methyl-d-aspartic acid receptors (NMDARs), triggering PANoptosis in pancreatic β-cells and accelerating T2DM progression. Consistent with this, significant changes in NMDAR expression were observed in human pancreatic samples from patients with T2DM. These findings uncover a previously unrecognized fibroblast-β-cell communication pathway in the islet niche, provide mechanistic insights into T2DM pathogenesis, and highlight the glutamate–NMDAR axis as a potential therapeutic target for nonsurgical intervention. Article Highlights We identify a fibroblast-β-cell “metabolic synapse” in type 2 diabetes that couples stromal glutamate overflow to β-cell N-methyl-d-aspartic acid receptor (NMDAR) activation. Single-cell maps and coculture assays show diabetogenic stress drives fibroblasts to hypersecrete glutamate, whereas β-cells upregulate NMDARs, triggering PANoptosis. In rodents, pharmacologic NMDAR blockade attenuates β-cell PANoptosis, preserves islet function, and improves glycemic control. Human pancreatic samples cohorts reveal fibrosis regression and stage-wise NMDAR upregulation, highlighting the glutamate–NMDAR axis as a therapeutic target.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"87 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interrupting T-Cell Memory Ameliorates Exaggerated Metabolic Response to Weight Cycling","authors":"Jamie N. Garcia, Matthew A. Cottam, Alec S. Rodriguez, Anwar F. Hussein Agha, Heather L. Caslin, Nathan C. Winn, Alyssa H. Hasty","doi":"10.2337/db25-0605","DOIUrl":"https://doi.org/10.2337/db25-0605","url":null,"abstract":"Weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Both obesity itself and weight cycling cause adipose tissue inflammation and metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid-associated macrophages and memory T cells persist in adipose tissue and become more inflammatory on weight regain. This suggests that the immune system retains an obesogenic memory, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. We show that blocking the CD70–CD27 axis, critical for the formation of immunologic memory, decreases the number of memory T cells and T-cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, although CD70−/− mice have metabolic responses to stable obesity similar to those of wild-type mice, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to support mitigating the metabolic consequences of weight cycling through an immunomodulatory mechanism. We propose a new avenue of therapeutic intervention targeting memory T cells to minimize the adverse consequences of weight cycling. These findings are timely, given the increasing use of weight-loss drugs, which may lead to more instances of human weight cycling. Article Highlights We aimed to address a critical gap in understanding how persistent immune changes with weight cycling contribute to worsened metabolic health. We wanted to determine whether disrupting immune memory formation could prevent the accumulation and reactivation of memory T cells in adipose tissue and thereby protect against the metabolic dysfunction associated with weight cycling. In targeting the CD70–CD27 axis, thereby inhibiting T-cell memory formation, we were able to mitigate the exacerbated glucose intolerance observed in wild-type weight-cycled mice. This study highlights the potential to address the negative metabolic effects of weight cycling through an immunomodulatory approach, offering a novel therapeutic target by disrupting obesogenic immune memory.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"59 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose Tissue Resistance to the Antilipolytic Effect of Insulin and Niacin in Humans With Obesity","authors":"Shuhao Lin, Kelli A. Lytle, Nicola Fink, Michael D. Jensen","doi":"10.2337/db25-0979","DOIUrl":"https://doi.org/10.2337/db25-0979","url":null,"abstract":"Adipose tissue (AT) lipolysis insulin resistance results in excess free fatty acid (FFA) release. We tested the hypothesis that the ability of insulin to suppress AT lipolysis is unrelated to the ability of niacin to suppress lipolysis, because niacin acts through a different proximal signaling pathway. Ten volunteers (5 women/5 men) with upper body obesity and/or type 2 diabetes mellitus (T2DM) underwent two study visits with overnight intravenous infusions of niacin (1.4 mg/min) or saline, followed by a hyperinsulinemic-euglycemic clamp. FFA-palmitate Ra was measured using [U-13C] and [2H9]palmitate infusions; abdominal AT biopsies were performed before and during the insulin clamp. The suppression of FFA-palmitate Ra by insulin on the saline control day and by niacin after an overnight infusion were highly correlated (r = −0.93, P < 0.001). Fasting AT Akt (pAktS473/474-to-panAkt ratio, P = 0.01) and perilipin 1 (PLN 1) (pPLN1S552-to-panPLN1 ratio, P = 0.02) phosphorylation were less during niacin than the saline control study. Because the suppression of lipolysis by insulin and niacin are highly correlated within individuals and because niacin and insulin act through different proximal signaling pathways, we propose dysregulated AT lipolysis in obesity/T2DM is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.” Article Highlights We undertook this study to compare adipose tissue lipolysis responses to insulin and niacin in humans. We tested the hypothesis that adipose tissue insulin resistance would be unrelated to adipose tissue niacin resistance. The suppression of lipolysis by insulin and niacin were highly correlated. Dysregulated adipose tissue lipolysis in obesity/type 2 diabetes is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.”","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"17 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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}

{"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}