Valentina Pita-Grisanti, Flavia Leticia Martins Peçanha, Ruy A. Louzada, Manuel Blandino-Rosano, Camillo Jaramillo, Natalia Arenas, Allison Bayer, Ernesto Bernal-Mizrachi
Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells. Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) and 4E-BP2 are translational repressors and downstream targets of mammalian target of rapamycin complex 1 (mTORC1). Activation of the 4E-BP2/eIF4E pathway by 4E-BP2 deletion promotes translation initiation, inducing β-cell expansion and proliferation and regulating adaptive immunity. However, the involvement of 4E-BP2 in T1D remains unexplored. This study aimed to determine the role of 4E-BP2/eIF4E signaling in T1D prevention. We used the NOD mouse model of T1D and generated mice with global 4E-BP2 deletion in the NOD background (Eif4ebp2−/−). We assessed T1D development, glucose homeostasis, pancreas morphometry, and immune responses in Eif4ebp2−/− and littermate control mice. We found that Eif4ebp2−/− male mice exhibited reduced diabetes incidence, which did not occur in female mice, as well as preserved β-cell mass, improved insulin secretion in vitro, and comparable insulitis. Characterization of T-cell compartments showed decreased splenic CD8+ cytotoxic T-cell proliferation and increased pancreatic regulatory T-cell infiltration in Eif4ebp2−/− mice, potentially resulting from increased proliferation and suppressive capacity. Adoptive transfer studies demonstrated that Eif4ebp2−/− male lymphocytes were less diabetogenic than those of controls. In conclusion, activation of 4E-BP2/eIF4E by 4E-BP2 deletion protected against T1D, supporting 4E-BP2 as a potential therapy target. Article Highlights Mammalian target of rapamycin complex 1 (mTORC1) signaling is essential to β-cell mass, function, and adaptive immunity; however, its specific downstream mediators in type 1 diabetes (T1D) remain poorly defined. We investigated eukaryotic translation initiation factor 4E–binding protein 2 (4E-BP2), a major translational regulator downstream of mTORC1, by using global 4E-BP2–knockout mice on the NOD background. Loss of 4E-BP2 protected male NOD mice from T1D through preservation of β-cell mass and function, coupled with attenuation of autoimmune responses. These findings identify 4E-BP2 as a novel immunometabolic node, highlighting its potential as a therapeutic target for T1D prevention and treatment.
{"title":"Protection Against Type 1 Diabetes Development in Mice With 4E-BP2 Deletion","authors":"Valentina Pita-Grisanti, Flavia Leticia Martins Peçanha, Ruy A. Louzada, Manuel Blandino-Rosano, Camillo Jaramillo, Natalia Arenas, Allison Bayer, Ernesto Bernal-Mizrachi","doi":"10.2337/db25-0348","DOIUrl":"https://doi.org/10.2337/db25-0348","url":null,"abstract":"Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells. Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) and 4E-BP2 are translational repressors and downstream targets of mammalian target of rapamycin complex 1 (mTORC1). Activation of the 4E-BP2/eIF4E pathway by 4E-BP2 deletion promotes translation initiation, inducing β-cell expansion and proliferation and regulating adaptive immunity. However, the involvement of 4E-BP2 in T1D remains unexplored. This study aimed to determine the role of 4E-BP2/eIF4E signaling in T1D prevention. We used the NOD mouse model of T1D and generated mice with global 4E-BP2 deletion in the NOD background (Eif4ebp2−/−). We assessed T1D development, glucose homeostasis, pancreas morphometry, and immune responses in Eif4ebp2−/− and littermate control mice. We found that Eif4ebp2−/− male mice exhibited reduced diabetes incidence, which did not occur in female mice, as well as preserved β-cell mass, improved insulin secretion in vitro, and comparable insulitis. Characterization of T-cell compartments showed decreased splenic CD8+ cytotoxic T-cell proliferation and increased pancreatic regulatory T-cell infiltration in Eif4ebp2−/− mice, potentially resulting from increased proliferation and suppressive capacity. Adoptive transfer studies demonstrated that Eif4ebp2−/− male lymphocytes were less diabetogenic than those of controls. In conclusion, activation of 4E-BP2/eIF4E by 4E-BP2 deletion protected against T1D, supporting 4E-BP2 as a potential therapy target. Article Highlights Mammalian target of rapamycin complex 1 (mTORC1) signaling is essential to β-cell mass, function, and adaptive immunity; however, its specific downstream mediators in type 1 diabetes (T1D) remain poorly defined. We investigated eukaryotic translation initiation factor 4E–binding protein 2 (4E-BP2), a major translational regulator downstream of mTORC1, by using global 4E-BP2–knockout mice on the NOD background. Loss of 4E-BP2 protected male NOD mice from T1D through preservation of β-cell mass and function, coupled with attenuation of autoimmune responses. These findings identify 4E-BP2 as a novel immunometabolic node, highlighting its potential as a therapeutic target for T1D prevention and treatment.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"13 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509210","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}
Aaron J. Deutsch, Andrew S. Bell, Dominika A. Michalek, Adam B. Burkholder, Stella Nam, Raymond J. Kreienkamp, Seth A. Sharp, Alicia Huerta-Chagoya, Ravi Mandla, Ruth Nanjala, Yang Luo, Richard A. Oram, Jose C. Florez, Suna Onengut-Gumuscu, Stephen S. Rich, Maggie C.Y. Ng, Alison A. Motsinger-Reif, Alisa K. Manning, Josep M. Mercader, Miriam S. Udler
Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we leveraged recent multiancestry genome-wide association studies to create a Type 1 Diabetes Multi-Ancestry Polygenic Score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores for European (EUR) and African (AFR) populations: T1D Genetic Risk Score 2 (GRS2EUR) and T1D GRSAFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2EUR and T1D MAPS. Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2EUR (0.82) and T1D GRSAFR (0.82). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2EUR (0.89 vs. 0.91). However, T1D MAPS2 performed equivalently to T1D GRS2EUR in European ancestry (0.91 vs. 0.91) and performed better in non-European ancestry (0.90 vs. 0.82). Overall, these findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations. Article Highlights Type 1 diabetes polygenic scores are highly predictive of disease risk, but their performance varies based on genetic ancestry. Can we develop a polygenic score that accurately predicts type 1 diabetes risk across diverse populations? Our novel polygenic score performs similar to existing scores in European populations, and it demonstrates superior performance in non-European populations. This polygenic score will improve prediction of type 1 diabetes risk in genetically diverse populations.
{"title":"Development and Validation of a Type 1 Diabetes Multi-Ancestry Polygenic Score","authors":"Aaron J. Deutsch, Andrew S. Bell, Dominika A. Michalek, Adam B. Burkholder, Stella Nam, Raymond J. Kreienkamp, Seth A. Sharp, Alicia Huerta-Chagoya, Ravi Mandla, Ruth Nanjala, Yang Luo, Richard A. Oram, Jose C. Florez, Suna Onengut-Gumuscu, Stephen S. Rich, Maggie C.Y. Ng, Alison A. Motsinger-Reif, Alisa K. Manning, Josep M. Mercader, Miriam S. Udler","doi":"10.2337/db25-0772","DOIUrl":"https://doi.org/10.2337/db25-0772","url":null,"abstract":"Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we leveraged recent multiancestry genome-wide association studies to create a Type 1 Diabetes Multi-Ancestry Polygenic Score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores for European (EUR) and African (AFR) populations: T1D Genetic Risk Score 2 (GRS2EUR) and T1D GRSAFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2EUR and T1D MAPS. Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2EUR (0.82) and T1D GRSAFR (0.82). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2EUR (0.89 vs. 0.91). However, T1D MAPS2 performed equivalently to T1D GRS2EUR in European ancestry (0.91 vs. 0.91) and performed better in non-European ancestry (0.90 vs. 0.82). Overall, these findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations. Article Highlights Type 1 diabetes polygenic scores are highly predictive of disease risk, but their performance varies based on genetic ancestry. Can we develop a polygenic score that accurately predicts type 1 diabetes risk across diverse populations? Our novel polygenic score performs similar to existing scores in European populations, and it demonstrates superior performance in non-European populations. This polygenic score will improve prediction of type 1 diabetes risk in genetically diverse populations.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"184 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509211","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}
Alfonso Galderisi, Alice L.J. Carr, Peter Taylor, Jacopo Bonet, David Cuthbertson, Jay Sosenko, Emily K. Sims, Carmella Evans-Molina, Chiara Dalla Man, Heba M. Ismail, Brandon Nathan, Alessandra Petrelli, Peter Senior, Jennifer L. Sherr, Kevan Herold, William E. Russell, Antoinette Moran, Colin Dayan
Abatacept, a cytotoxic T lymphocyte–associated protein 4 immunoglobulin that inhibits T-cell costimulation, was evaluated for 12 months in stage 1 type 1 diabetes (T1D) to delay disease progression. Despite modest preservation of area under the curve C-peptide at 12 months, the primary end point was not met. We adopted the oral minimal model (OMM) to assess β-cell function over 48 months and explored how baseline insulin secretion (ϕtotal) modified treatment response. Using the OMM, ϕtotal was computed from oral glucose tolerance tests conducted at baseline and every 6 months. Participants were stratified into high- and low-secretor groups depending on baseline ϕtotal ≥33rd or <33rd centile, respectively. A sensitivity analysis was performed to validate threshold choice. Among 203 participants (abatacept n = 96; 107 placebo n = 107), 39% receiving abatacept and 47% receiving placebo experienced progression to stage 2 or 3 within 96 months. High secretors receiving abatacept gained 15.8 progression-free months (95% CI 4.85, 26.68; P = 0.005) and had a 54% lower hazard of progression versus those receiving placebo (hazard ratio [HR] 0.46; 95% CI 0.25, 0.84; P = 0.012). Treatment effect differed significantly by secretor status (interaction HR 2.92; 95% CI 1.23, 6.96; P = 0.015). A subgroup of responders to 12 months of abatacept was identified by ϕtotal, providing the first evidence that an immune intervention in stage 1 T1D may delay disease progression. Article Highlights We sought to investigate whether baseline insulin secretion (ϕtotal), quantified using the oral minimal model assessing β-cell function, could identify a subgroup of responders to abatacept (a cytotoxic T lymphocyte–associated protein 4 immunoglobulin that inhibits T-cell costimulation) among those with stage 1 type 1 diabetes (T1D). Abatacept preserved ϕtotal during and up to 1 year after treatment cessation; high baseline secretors treated with abatacept gained ∼16 months of progression-free survival and had a 54% lower hazard of progression versus those receiving placebo, whereas no benefit was observed in low secretors. This is the first evidence of an immune intervention delaying disease progression in those with stage 1 T1D. Continued treatment may result in a greater delay in progression.
Abatacept是一种抑制T细胞共刺激的细胞毒性T淋巴细胞相关蛋白4免疫球蛋白，在1期1型糖尿病（T1D）中进行了为期12个月的评估，以延缓疾病进展。尽管在12个月时c肽曲线下的面积适度保存，但未达到主要终点。我们采用口服最小模型（OMM）来评估超过48个月的β细胞功能，并探讨基线胰岛素分泌（ϕtotal）如何改变治疗反应。使用OMM，从基线和每6个月进行的口服葡萄糖耐量试验中计算出总分。受试者根据基线浓度≥33或&；lt分为高分泌组和低分泌组；分别是33百分位。进行敏感性分析以验证阈值选择。在203名参与者中（abataccept组n = 96；安慰剂组107例n = 107）， 39%接受abataccept组和47%接受安慰剂组在96个月内进展到2期或3期。接受阿巴接受的高分泌组患者获得了15.8个无进展月（95% CI 4.85, 26.68; P = 0.005），与接受安慰剂的患者相比，进展风险降低54%（风险比[HR] 0.46; 95% CI 0.25, 0.84; P = 0.012）。不同分泌状态的治疗效果差异显著（交互作用比2.92;95% CI 1.23, 6.96; P = 0.015）。一个对abataccept治疗12个月有反应的亚组被检测到，这首次提供了1期T1D免疫干预可能延缓疾病进展的证据。我们试图研究基线胰岛素分泌（ϕtotal），使用评估β细胞功能的口服最小模型进行量化，是否可以在1期1型糖尿病（T1D）患者中识别对abatacept（一种抑制T细胞共刺激的细胞毒性T淋巴细胞相关蛋白4免疫球蛋白）有反应的亚组。停药期间及停药后1年内保留的abataccept；与接受安慰剂的患者相比，接受abataccept治疗的高基线分泌者获得了~ 16个月的无进展生存期，并且进展风险降低了54%，而低分泌者没有观察到任何益处。这是免疫干预延缓1期T1D患者疾病进展的第一个证据。继续治疗可能会导致更大的进展延迟。
{"title":"Baseline Insulin Secretion Determines Response to Abatacept in Stage 1 Type 1 Diabetes","authors":"Alfonso Galderisi, Alice L.J. Carr, Peter Taylor, Jacopo Bonet, David Cuthbertson, Jay Sosenko, Emily K. Sims, Carmella Evans-Molina, Chiara Dalla Man, Heba M. Ismail, Brandon Nathan, Alessandra Petrelli, Peter Senior, Jennifer L. Sherr, Kevan Herold, William E. Russell, Antoinette Moran, Colin Dayan","doi":"10.2337/db25-0801","DOIUrl":"https://doi.org/10.2337/db25-0801","url":null,"abstract":"Abatacept, a cytotoxic T lymphocyte–associated protein 4 immunoglobulin that inhibits T-cell costimulation, was evaluated for 12 months in stage 1 type 1 diabetes (T1D) to delay disease progression. Despite modest preservation of area under the curve C-peptide at 12 months, the primary end point was not met. We adopted the oral minimal model (OMM) to assess β-cell function over 48 months and explored how baseline insulin secretion (ϕtotal) modified treatment response. Using the OMM, ϕtotal was computed from oral glucose tolerance tests conducted at baseline and every 6 months. Participants were stratified into high- and low-secretor groups depending on baseline ϕtotal ≥33rd or &lt;33rd centile, respectively. A sensitivity analysis was performed to validate threshold choice. Among 203 participants (abatacept n = 96; 107 placebo n = 107), 39% receiving abatacept and 47% receiving placebo experienced progression to stage 2 or 3 within 96 months. High secretors receiving abatacept gained 15.8 progression-free months (95% CI 4.85, 26.68; P = 0.005) and had a 54% lower hazard of progression versus those receiving placebo (hazard ratio [HR] 0.46; 95% CI 0.25, 0.84; P = 0.012). Treatment effect differed significantly by secretor status (interaction HR 2.92; 95% CI 1.23, 6.96; P = 0.015). A subgroup of responders to 12 months of abatacept was identified by ϕtotal, providing the first evidence that an immune intervention in stage 1 T1D may delay disease progression. Article Highlights We sought to investigate whether baseline insulin secretion (ϕtotal), quantified using the oral minimal model assessing β-cell function, could identify a subgroup of responders to abatacept (a cytotoxic T lymphocyte–associated protein 4 immunoglobulin that inhibits T-cell costimulation) among those with stage 1 type 1 diabetes (T1D). Abatacept preserved ϕtotal during and up to 1 year after treatment cessation; high baseline secretors treated with abatacept gained ∼16 months of progression-free survival and had a 54% lower hazard of progression versus those receiving placebo, whereas no benefit was observed in low secretors. This is the first evidence of an immune intervention delaying disease progression in those with stage 1 T1D. Continued treatment may result in a greater delay in progression.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"92 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516214","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}
Marilyn Arosemena, Karishma Chopra, Maria V. Salguero, Demetra Reyes, Rochelle N. Naylor, Kristen Wroblewski, Esra Tasali, Louis H. Philipson
Obstructive sleep apnea (OSA) is a common condition strongly linked to increased cardiovascular risk and poor glycemic control. Little is known about OSA, cardiovascular risk, and glycemia in maturity-onset diabetes of the young (MODY), an inherited form of diabetes, which is different than both type 1 and type 2 diabetes. We assessed OSA, resting heart rate (RHR), an important prognostic marker of cardiovascular disease, and glycemic variability among the most common subtypes of MODY, glucokinase (GCK)-MODY, and transcription factor (TF)-related MODY (HNF1A, HNF4A, and HNF1B). Adults with GCK-MODY (n = 63) and TF-related MODY (n = 60) and control subjects without diabetes (n = 65) were screened for OSA by home sleep test. Glycemic variability (continuous glucose monitoring) and RHR (wearable sleep-activity tracker) were concomitantly assessed for 2 weeks at home. Data from 188 subjects (2,853 recorded days) were analyzed. Subjects with TF-related MODY, compared with those with GCK-MODY or control subjects, had more OSA (48.3%, 27.0%, and 30.8%, respectively; P = 0.033), higher RHR (72.8 ± 10.8, 65.2 ± 7.9, and 67.3 ± 7.7 bpm, respectively; P < 0.001), and higher glycemic variability (coefficient of variation of glucose 31.6 ± 6.0%, 17.3 ± 4.5%, and 17.5 ± 4.0%, respectively; P < 0.001). Greater severity of OSA and higher RHR were associated with higher glycemic variability. These findings may have important clinical implications for cardiovascular risk assessment in MODY. Article Highlights Obstructive sleep apnea (OSA) has been strongly linked to increased cardiovascular risk and poor glycemic control in the general population. Resting heart rate (RHR) is a prognostic marker of cardiovascular morbidity and mortality and has been linked to dysglycemia. Little is known about OSA, RHR, and glycemia in maturity-onset diabetes of the young (MODY), an inherited form of diabetes with discrete clinical features. Adults with transcription factor–related MODY (HNF1A, HNF4A, and HNF1B) had more OSA and higher RHR and greater glycemic variability compared with those with glucokinase-MODY or control subjects without diabetes, which may have important clinical implications for future cardiovascular risk.
{"title":"Obstructive Sleep Apnea, Resting Heart Rate, and Glycemic Variability in Adults With Maturity-Onset Diabetes of the Young","authors":"Marilyn Arosemena, Karishma Chopra, Maria V. Salguero, Demetra Reyes, Rochelle N. Naylor, Kristen Wroblewski, Esra Tasali, Louis H. Philipson","doi":"10.2337/db24-0787","DOIUrl":"https://doi.org/10.2337/db24-0787","url":null,"abstract":"Obstructive sleep apnea (OSA) is a common condition strongly linked to increased cardiovascular risk and poor glycemic control. Little is known about OSA, cardiovascular risk, and glycemia in maturity-onset diabetes of the young (MODY), an inherited form of diabetes, which is different than both type 1 and type 2 diabetes. We assessed OSA, resting heart rate (RHR), an important prognostic marker of cardiovascular disease, and glycemic variability among the most common subtypes of MODY, glucokinase (GCK)-MODY, and transcription factor (TF)-related MODY (HNF1A, HNF4A, and HNF1B). Adults with GCK-MODY (n = 63) and TF-related MODY (n = 60) and control subjects without diabetes (n = 65) were screened for OSA by home sleep test. Glycemic variability (continuous glucose monitoring) and RHR (wearable sleep-activity tracker) were concomitantly assessed for 2 weeks at home. Data from 188 subjects (2,853 recorded days) were analyzed. Subjects with TF-related MODY, compared with those with GCK-MODY or control subjects, had more OSA (48.3%, 27.0%, and 30.8%, respectively; P = 0.033), higher RHR (72.8 ± 10.8, 65.2 ± 7.9, and 67.3 ± 7.7 bpm, respectively; P &lt; 0.001), and higher glycemic variability (coefficient of variation of glucose 31.6 ± 6.0%, 17.3 ± 4.5%, and 17.5 ± 4.0%, respectively; P &lt; 0.001). Greater severity of OSA and higher RHR were associated with higher glycemic variability. These findings may have important clinical implications for cardiovascular risk assessment in MODY. Article Highlights Obstructive sleep apnea (OSA) has been strongly linked to increased cardiovascular risk and poor glycemic control in the general population. Resting heart rate (RHR) is a prognostic marker of cardiovascular morbidity and mortality and has been linked to dysglycemia. Little is known about OSA, RHR, and glycemia in maturity-onset diabetes of the young (MODY), an inherited form of diabetes with discrete clinical features. Adults with transcription factor–related MODY (HNF1A, HNF4A, and HNF1B) had more OSA and higher RHR and greater glycemic variability compared with those with glucokinase-MODY or control subjects without diabetes, which may have important clinical implications for future cardiovascular risk.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"88 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509218","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}
Masaya Oshima, Clémentine Halliez, Farah Kobaisi, Nina Modé, Alexis Fouque, Barbara Brandao, Océane Mayer, Diego Balboa, Roberto Mallone, Raphael Scharfmann
Type 1 diabetes is a progressive autoimmune disease characterized by the selective destruction of insulin-producing β-cells by CD8+ T cells. Although the mechanisms of antigen-specific β-cell killing are well established, the broader consequences of this targeted destruction on neighboring β-cells that escape direct T-cell receptor (TCR)–mediated attack remain poorly understood. Here, we developed a coculture model of HLA-A2–expressing human β-cells cultured as pseudoislets and CD8+ T cells specific for the INS15-24 epitope. Using this new in vitro model, we demonstrate that 1) β-cell death induced by CD8+ T cells strictly depends on TCR-HLA class I interactions; and 2) neighboring β-cells that evade direct T-cell contact do not alter β-cell identity or glucose-stimulated insulin secretion. However, they exhibit increased expression of inflammatory markers, reduced insulin content, and impaired protein translation. The robust, versatile, and readily applicable model described here represents a strong basis to further address paracrine signaling that extend beyond direct cytotoxicity. Article Highlights In type 1 diabetes, CD8+ T cells destroy pancreatic β-cells. Since most β-cells avoid direct T-cell contact, we asked whether bystander effects drive their dysfunction and loss. We asked whether CD8+ T cells can damage β-cells indirectly via bystander inflammation. By developing and using a chimeric pseudoislet model, we show that β-cell killing requires direct CD8+ T-cell contact, contact-free β-cells are impacted by inflammation, that these effects are reproduced using conditioned medium from activated CD8+ T cells, and that insulin secretion is preserved with reduced storage and impaired protein translation. Our model provides a platform to dissect type 1 diabetes pathogenesis and test therapies to preserve β cells.
{"title":"Killing of Human β-Cells by CD8+ T Cells Triggers Inflammatory Paracrine Signaling and Neighboring β-Cell Dysfunction","authors":"Masaya Oshima, Clémentine Halliez, Farah Kobaisi, Nina Modé, Alexis Fouque, Barbara Brandao, Océane Mayer, Diego Balboa, Roberto Mallone, Raphael Scharfmann","doi":"10.2337/db25-0473","DOIUrl":"https://doi.org/10.2337/db25-0473","url":null,"abstract":"Type 1 diabetes is a progressive autoimmune disease characterized by the selective destruction of insulin-producing β-cells by CD8+ T cells. Although the mechanisms of antigen-specific β-cell killing are well established, the broader consequences of this targeted destruction on neighboring β-cells that escape direct T-cell receptor (TCR)–mediated attack remain poorly understood. Here, we developed a coculture model of HLA-A2–expressing human β-cells cultured as pseudoislets and CD8+ T cells specific for the INS15-24 epitope. Using this new in vitro model, we demonstrate that 1) β-cell death induced by CD8+ T cells strictly depends on TCR-HLA class I interactions; and 2) neighboring β-cells that evade direct T-cell contact do not alter β-cell identity or glucose-stimulated insulin secretion. However, they exhibit increased expression of inflammatory markers, reduced insulin content, and impaired protein translation. The robust, versatile, and readily applicable model described here represents a strong basis to further address paracrine signaling that extend beyond direct cytotoxicity. Article Highlights In type 1 diabetes, CD8+ T cells destroy pancreatic β-cells. Since most β-cells avoid direct T-cell contact, we asked whether bystander effects drive their dysfunction and loss. We asked whether CD8+ T cells can damage β-cells indirectly via bystander inflammation. By developing and using a chimeric pseudoislet model, we show that β-cell killing requires direct CD8+ T-cell contact, contact-free β-cells are impacted by inflammation, that these effects are reproduced using conditioned medium from activated CD8+ T cells, and that insulin secretion is preserved with reduced storage and impaired protein translation. Our model provides a platform to dissect type 1 diabetes pathogenesis and test therapies to preserve β cells.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"2 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491789","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}
Cuizhe Wang, Yanting Hou, Meixiu Zhang, Jingzhou Wang, Xiaolong Chu, Maodi Liang, Chaoyue Sun, Jianxin Xie, Jun Zhang, Cong-Yi Wang
miRNAs are key regulators of metabolic homeostasis, yet their role in obesity-associated dysfunction remains incompletely understood. Here, we identify miR-432 as a driver of systemic metabolic dysregulation. Serum miRNA profiling revealed a positive correlation between miR-432 expression and obesity/type 2 diabetes mellitus. Functionally, adipose-specific miR-432 exacerbated high-fat diet–induced obesity and insulin resistance. Similarly, hepatic-specific miR-432 aggravated hepatic steatosis and systemic glucose dysregulation, while skeletal muscle–specific miR-432 disrupted glucose homeostasis without affecting body composition. Mechanistically, miR-432 disrupted insulin sensitivity by inhibiting the PIK3R3/AKT pathway and perturbed lipid homeostasis by suppressing the PIK3R3/PPAR-α axis. Notably, obesity-induced miR-432 upregulation was predominantly localized in adipocytes and driven by the CDK5/PPAR-γ axis. Furthermore, adipocyte-derived exosomal miR-432 was identified as a mediator of systemic metabolic dysfunction, facilitating intertissue cross talk in obesity. Collectively, our data demonstrate that miR-432 exacerbates obesity-induced dysregulation of glucose and lipid metabolism. Article Highlights miR-432 overexpression in adipose tissue, liver, and skeletal muscle exacerbates high-fat diet–induced disruption of metabolic homeostasis. miR-432 impairs glucose homeostasis by suppressing the PIK3R3/AKT pathway and disrupts lipid homeostasis via inhibition of the PIK3R3/PPAR-α axis or directly suppressing PPAR-α. Obesity-induced elevation of miR-432 is predominantly localized in adipocytes and driven by the CDK5/PPAR-γ axis. Adipocyte-derived exosomal miR-432 mediates systemic metabolic dysfunction, establishing an intertissue regulatory network.
{"title":"miR-432 Exacerbates Obesity-Induced Dysregulation of Glucose and Lipid Homeostasis","authors":"Cuizhe Wang, Yanting Hou, Meixiu Zhang, Jingzhou Wang, Xiaolong Chu, Maodi Liang, Chaoyue Sun, Jianxin Xie, Jun Zhang, Cong-Yi Wang","doi":"10.2337/db25-0295","DOIUrl":"https://doi.org/10.2337/db25-0295","url":null,"abstract":"miRNAs are key regulators of metabolic homeostasis, yet their role in obesity-associated dysfunction remains incompletely understood. Here, we identify miR-432 as a driver of systemic metabolic dysregulation. Serum miRNA profiling revealed a positive correlation between miR-432 expression and obesity/type 2 diabetes mellitus. Functionally, adipose-specific miR-432 exacerbated high-fat diet–induced obesity and insulin resistance. Similarly, hepatic-specific miR-432 aggravated hepatic steatosis and systemic glucose dysregulation, while skeletal muscle–specific miR-432 disrupted glucose homeostasis without affecting body composition. Mechanistically, miR-432 disrupted insulin sensitivity by inhibiting the PIK3R3/AKT pathway and perturbed lipid homeostasis by suppressing the PIK3R3/PPAR-α axis. Notably, obesity-induced miR-432 upregulation was predominantly localized in adipocytes and driven by the CDK5/PPAR-γ axis. Furthermore, adipocyte-derived exosomal miR-432 was identified as a mediator of systemic metabolic dysfunction, facilitating intertissue cross talk in obesity. Collectively, our data demonstrate that miR-432 exacerbates obesity-induced dysregulation of glucose and lipid metabolism. Article Highlights miR-432 overexpression in adipose tissue, liver, and skeletal muscle exacerbates high-fat diet–induced disruption of metabolic homeostasis. miR-432 impairs glucose homeostasis by suppressing the PIK3R3/AKT pathway and disrupts lipid homeostasis via inhibition of the PIK3R3/PPAR-α axis or directly suppressing PPAR-α. Obesity-induced elevation of miR-432 is predominantly localized in adipocytes and driven by the CDK5/PPAR-γ axis. Adipocyte-derived exosomal miR-432 mediates systemic metabolic dysfunction, establishing an intertissue regulatory network.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491788","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}
Haoran Jing, Meixin Shi, Ye Wang, Rongyi Cao, Xiaoxue Li, Xin Zhong, Shiyun Dong, Can Wei
Diabetic cardiomyopathy (DbCM) is characterized by metabolic remodeling and energetic stress independent of coronary artery disease. Increased reliance on fatty acid and ketone body metabolism has been observed in DbCM, but the regulatory mechanisms linking altered substrate use to myocardial dysfunction remain poorly understood. In particular, lysine β-hydroxybutyrate (Kbhb), a ketone body–derived, posttranslational modification, has emerged as a potentially critical regulator but has not been fully investigated. We conducted a comprehensive multiomics study integrating metabolomics, transcriptomics, proteomics, and Kbhb-specific proteomics on myocardial tissues in a well-established mouse model of DbCM. Kbhb-modified proteins were systematically mapped and quantified, followed by motif, subcellular localization, and protein-protein interaction analyses. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Kbhb profiling revealed extensive mitochondrial protein modification, with Atp5f1a-K239 identified as a key modification site strongly correlated with β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb as a potential metabolic-epigenetic modifier linking ketone body availability to the regulation of mitochondrial proteins in DbCM. Our findings provide novel insights into metabolic-epigenetic cross talk and identify potential therapeutic targets for interventions to restore mitochondrial function in alleviating diabetic heart disease. Article Highlights We performed a multiomics study to better understand dysfunctions in diabetic cardiomyopathy (DbCM) and specifically identify links between lysine β-hydroxybutyrylation (Kbhb), a ketone body–derived, posttranslational modification, and cardiac dysfunction. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Mitochondrial proteins showed that high Kbhb modification and modification of the Atp5f1a-K239 site were strongly correlated with high β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb modification of mitochondrial proteins as a potential mechanism linking ketone body availability to mitochondrial function in DbCM.
{"title":"β-Hydroxybutyrylation Links Ketone Metabolism to Mitochondrial Remodeling in Diabetic Cardiomyopathy","authors":"Haoran Jing, Meixin Shi, Ye Wang, Rongyi Cao, Xiaoxue Li, Xin Zhong, Shiyun Dong, Can Wei","doi":"10.2337/db25-0496","DOIUrl":"https://doi.org/10.2337/db25-0496","url":null,"abstract":"Diabetic cardiomyopathy (DbCM) is characterized by metabolic remodeling and energetic stress independent of coronary artery disease. Increased reliance on fatty acid and ketone body metabolism has been observed in DbCM, but the regulatory mechanisms linking altered substrate use to myocardial dysfunction remain poorly understood. In particular, lysine β-hydroxybutyrate (Kbhb), a ketone body–derived, posttranslational modification, has emerged as a potentially critical regulator but has not been fully investigated. We conducted a comprehensive multiomics study integrating metabolomics, transcriptomics, proteomics, and Kbhb-specific proteomics on myocardial tissues in a well-established mouse model of DbCM. Kbhb-modified proteins were systematically mapped and quantified, followed by motif, subcellular localization, and protein-protein interaction analyses. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Kbhb profiling revealed extensive mitochondrial protein modification, with Atp5f1a-K239 identified as a key modification site strongly correlated with β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb as a potential metabolic-epigenetic modifier linking ketone body availability to the regulation of mitochondrial proteins in DbCM. Our findings provide novel insights into metabolic-epigenetic cross talk and identify potential therapeutic targets for interventions to restore mitochondrial function in alleviating diabetic heart disease. Article Highlights We performed a multiomics study to better understand dysfunctions in diabetic cardiomyopathy (DbCM) and specifically identify links between lysine β-hydroxybutyrylation (Kbhb), a ketone body–derived, posttranslational modification, and cardiac dysfunction. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Mitochondrial proteins showed that high Kbhb modification and modification of the Atp5f1a-K239 site were strongly correlated with high β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb modification of mitochondrial proteins as a potential mechanism linking ketone body availability to mitochondrial function in DbCM.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"140 1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485751","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}
Mahesh Agarwal, Sathishkumar Chandrakumar, Irene Santiago Tierno, Emma M. Lessieur, Zak R. Bollinger, Timothy S. Kern, Kaustabh Ghosh
Activated neutrophils contribute to retinal endothelial cell (EC) death and capillary degeneration associated with early diabetic retinopathy (DR), a major vision-threatening complication of diabetes. However, the factors and mechanisms driving neutrophil activation and cytotoxicity in diabetes remain insufficiently understood. Here, we show that lysyl oxidase (LOX), a matrix cross-linking and stiffening enzyme that increases retinal EC susceptibility to activated neutrophils, simultaneously activates neutrophils in its soluble form. Specifically, treatment of diabetic mice with LOX inhibitor β-aminopropionitrile (BAPN) prevented the diabetes-induced increase in neutrophil activation (extracellular release of neutrophil elastase and superoxide) and cytotoxicity toward cocultured mouse retinal ECs. Mouse neutrophils and differentiated (neutrophil-like) human HL-60 cells treated with recombinant LOX alone exhibited significant activation and cytotoxicity. Mechanistically, this LOX-induced neutrophil activation was associated with biphasic F-actin remodeling, with the initial and rapid (∼10 min) F-actin depolymerization followed by a significant increase in F-actin polymerization and polarization. Preventing the initial F-actin depolymerization blocked LOX-induced neutrophil activation and cytotoxicity toward cocultured retinal ECs. Finally, this biphasic F-actin remodeling was found to be essential for LOX-induced membrane aggregation of azurophilic granule marker CD63 and NADPH organizer p47phox, which are associated with extracellular release of neutrophil elastase and superoxide, respectively. By revealing a previously unrecognized causal link between LOX and actin-dependent neutrophil activation in diabetes, these findings provide fresh mechanistic insights into the proinflammatory role of LOX in early DR that goes beyond its canonical matrix-stiffening effects. ARTICLE HIGHLIGHTS Activated neutrophils kill retinal endothelial cells (ECs) in early diabetic retinopathy, but how neutrophils become activated in diabetes is not well understood. We found that lysyl oxidase (LOX), whose matrix-localized form activates retinal ECs, can also directly activate neutrophils in its soluble form. LOX-induced release of neutrophil elastase and superoxide is mediated by actin remodeling and membrane aggregation of azurophilic granules. The dual ability of LOX to activate neutrophils (in its soluble form) and retinal ECs (in its matrix-localized form) implicates it as a key proinflammatory target for early diabetic retinopathy.
{"title":"Lysyl Oxidase Promotes Actin-Dependent Neutrophil Activation and Cytotoxicity Toward Retinal Endothelial Cells in Diabetes","authors":"Mahesh Agarwal, Sathishkumar Chandrakumar, Irene Santiago Tierno, Emma M. Lessieur, Zak R. Bollinger, Timothy S. Kern, Kaustabh Ghosh","doi":"10.2337/db25-0541","DOIUrl":"https://doi.org/10.2337/db25-0541","url":null,"abstract":"Activated neutrophils contribute to retinal endothelial cell (EC) death and capillary degeneration associated with early diabetic retinopathy (DR), a major vision-threatening complication of diabetes. However, the factors and mechanisms driving neutrophil activation and cytotoxicity in diabetes remain insufficiently understood. Here, we show that lysyl oxidase (LOX), a matrix cross-linking and stiffening enzyme that increases retinal EC susceptibility to activated neutrophils, simultaneously activates neutrophils in its soluble form. Specifically, treatment of diabetic mice with LOX inhibitor β-aminopropionitrile (BAPN) prevented the diabetes-induced increase in neutrophil activation (extracellular release of neutrophil elastase and superoxide) and cytotoxicity toward cocultured mouse retinal ECs. Mouse neutrophils and differentiated (neutrophil-like) human HL-60 cells treated with recombinant LOX alone exhibited significant activation and cytotoxicity. Mechanistically, this LOX-induced neutrophil activation was associated with biphasic F-actin remodeling, with the initial and rapid (∼10 min) F-actin depolymerization followed by a significant increase in F-actin polymerization and polarization. Preventing the initial F-actin depolymerization blocked LOX-induced neutrophil activation and cytotoxicity toward cocultured retinal ECs. Finally, this biphasic F-actin remodeling was found to be essential for LOX-induced membrane aggregation of azurophilic granule marker CD63 and NADPH organizer p47phox, which are associated with extracellular release of neutrophil elastase and superoxide, respectively. By revealing a previously unrecognized causal link between LOX and actin-dependent neutrophil activation in diabetes, these findings provide fresh mechanistic insights into the proinflammatory role of LOX in early DR that goes beyond its canonical matrix-stiffening effects. ARTICLE HIGHLIGHTS Activated neutrophils kill retinal endothelial cells (ECs) in early diabetic retinopathy, but how neutrophils become activated in diabetes is not well understood. We found that lysyl oxidase (LOX), whose matrix-localized form activates retinal ECs, can also directly activate neutrophils in its soluble form. LOX-induced release of neutrophil elastase and superoxide is mediated by actin remodeling and membrane aggregation of azurophilic granules. The dual ability of LOX to activate neutrophils (in its soluble form) and retinal ECs (in its matrix-localized form) implicates it as a key proinflammatory target for early diabetic retinopathy.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441390","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}
Huguet V. Landa-Galvan, Thalia A. Castro, Jahi J. Noel, Gabriel Avila Llamas, Rohit B. Sharma, Laura C. Alonso
Finding ways to increase β-cell mass is a key goal of diabetes research. During elevated insulin demand, β-cells turn on endoplasmic reticulum (ER) stress response pathways, and some β-cells enter the cell cycle. ER stress response protein activating transcription factor 6 (ATF6α) induces β-cell proliferation, but only in high glucose. The mechanism by which ATF6α increases proliferation, and the reasons for glucose dependence, remain unknown. Here we show that ATF6α activation in mouse and human islet cells increases expression of E2F1, a key cell cycle driver. E2F1 was required for ATF6α-induced proliferation in high glucose. However, E2F1 remained inactive in normal glucose, possibly because retinoblastoma (Rb), a direct E2F1 inhibitor, was in its dephosphorylated, active state. Indeed, inducing Rb phosphorylation by overexpressing cyclin-dependent kinase 4 (CDK4) allowed ATF6α to increase E2F1 activity and β-cell proliferation in normal glucose. E2F1 expression increased in an ATF6α-dependent manner during generalized ER stress by thapsigargin treatment. Importantly, in human β-cells, ATF6α failed to synergize with high glucose to induce proliferation, but the synergy was rescued by adding back CDK6. Taken together, this study establishes a new dual-input β-cell proliferation regulatory mechanism integrating ER load with current glycemic conditions via CDK4/6, in which Rb phosphorylation serves as a glucose sensor that permits ATF6α-driven proliferation. ARTICLE HIGHLIGHTS Endoplasmic reticulum stress response mediator activating transcription factor 6 (ATF6α) increases pancreatic β-cell proliferation in a glucose-dependent manner, but the mechanism remains unknown. ATF6α activation upregulated mRNA and protein expression of E2F1, a key G1/S phase transition regulator; however, E2F1 activity only increased in high glucose. Glucose dependence of E2F1 activity was mediated by cyclin-dependent kinase 4/6 phosphorylation of retinoblastoma (Rb) protein, derepressing E2F1 in high glucose. Generalized endoplasmic reticulum stressor thapsigargin increased E2F1 abundance in an ATF6-dependent manner. ATF6α increased E2F1 expression in human β-cells and increased human β-cell proliferation when cyclin-dependent kinase 6 (CDK6) was coexpressed.
{"title":"Dual-Input Regulation of β-Cell Proliferation by ATF6α and Glucose via E2F1","authors":"Huguet V. Landa-Galvan, Thalia A. Castro, Jahi J. Noel, Gabriel Avila Llamas, Rohit B. Sharma, Laura C. Alonso","doi":"10.2337/db25-0279","DOIUrl":"https://doi.org/10.2337/db25-0279","url":null,"abstract":"Finding ways to increase β-cell mass is a key goal of diabetes research. During elevated insulin demand, β-cells turn on endoplasmic reticulum (ER) stress response pathways, and some β-cells enter the cell cycle. ER stress response protein activating transcription factor 6 (ATF6α) induces β-cell proliferation, but only in high glucose. The mechanism by which ATF6α increases proliferation, and the reasons for glucose dependence, remain unknown. Here we show that ATF6α activation in mouse and human islet cells increases expression of E2F1, a key cell cycle driver. E2F1 was required for ATF6α-induced proliferation in high glucose. However, E2F1 remained inactive in normal glucose, possibly because retinoblastoma (Rb), a direct E2F1 inhibitor, was in its dephosphorylated, active state. Indeed, inducing Rb phosphorylation by overexpressing cyclin-dependent kinase 4 (CDK4) allowed ATF6α to increase E2F1 activity and β-cell proliferation in normal glucose. E2F1 expression increased in an ATF6α-dependent manner during generalized ER stress by thapsigargin treatment. Importantly, in human β-cells, ATF6α failed to synergize with high glucose to induce proliferation, but the synergy was rescued by adding back CDK6. Taken together, this study establishes a new dual-input β-cell proliferation regulatory mechanism integrating ER load with current glycemic conditions via CDK4/6, in which Rb phosphorylation serves as a glucose sensor that permits ATF6α-driven proliferation. ARTICLE HIGHLIGHTS Endoplasmic reticulum stress response mediator activating transcription factor 6 (ATF6α) increases pancreatic β-cell proliferation in a glucose-dependent manner, but the mechanism remains unknown. ATF6α activation upregulated mRNA and protein expression of E2F1, a key G1/S phase transition regulator; however, E2F1 activity only increased in high glucose. Glucose dependence of E2F1 activity was mediated by cyclin-dependent kinase 4/6 phosphorylation of retinoblastoma (Rb) protein, derepressing E2F1 in high glucose. Generalized endoplasmic reticulum stressor thapsigargin increased E2F1 abundance in an ATF6-dependent manner. ATF6α increased E2F1 expression in human β-cells and increased human β-cell proliferation when cyclin-dependent kinase 6 (CDK6) was coexpressed.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"30 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411966","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}
Christiane S. Hampe, Varun Kamat, Caeley L. Bryan, Laura Pyle, Gregory J. Morton, Ian R. Sweet
An intrinsic hallmark of type 1 diabetes is the correlation between appearance of autoantibodies directed against islet cell autoantigens with subsequent development of the disease. We recently studied effects of human monoclonal autoantibodies (mAbs) derived from a patient with prediabetes and demonstrated that a GAD65mAb penetrated and accumulated in β-cells and significantly reduced the insulin secretion rate (ISR). Accordingly, in the current study, we performed more detailed analyses of the effects of this GAD65mAb on rat and human islets. ISR was suppressed by ∼40% after 3 days of exposure. Mechanisms mediating the effects were found to involve inhibition of mitochondrial generation of ATP, which decreased in parallel with that of ISR. As expected, the GAD65mAb inhibited γ-aminobutyric acid secretion. The effects of GAD65mAb were observed in rat and human islets but not in mouse islets, which do not express GAD65. GAD65mAb also reduced insulin secretion in vivo, where decreased insulin levels after intraperitoneal (i.p.) injection of glucose were observed in rats after i.p. injection of GAD65mAb. Thus, it appears that an islet cell autoantibody against GAD65 can directly impact and impair secretory function in islets in vitro and in vivo through a mechanism that involves inhibition of mitochondrial energetics. ARTICLE HIGHLIGHTS This study was undertaken to further investigate the ability of a monoclonal autoantibody to GAD65 from a patient with pre–type 1 diabetes to be deleterious to islet function. The study was designed to further characterize the effects, understand the mechanism mediating the effects, and demonstrate that the effects were operational in vivo. The effects of the GAD65 monoclonal antibody reduced ATP, γ-aminobutyric acid secretion, and insulin secretion with a similar time course and concentration dependency, which appeared to be mediated by effects on mitochondrial energetics and were similar in vivo in rats as in vitro. These findings raise the possibility that autoantibodies could play a pathogenic role in the development of type 1 diabetes.
{"title":"Deleterious Effects of a GAD65 Monoclonal Autoantibody on Islet Function","authors":"Christiane S. Hampe, Varun Kamat, Caeley L. Bryan, Laura Pyle, Gregory J. Morton, Ian R. Sweet","doi":"10.2337/db25-0475","DOIUrl":"https://doi.org/10.2337/db25-0475","url":null,"abstract":"An intrinsic hallmark of type 1 diabetes is the correlation between appearance of autoantibodies directed against islet cell autoantigens with subsequent development of the disease. We recently studied effects of human monoclonal autoantibodies (mAbs) derived from a patient with prediabetes and demonstrated that a GAD65mAb penetrated and accumulated in β-cells and significantly reduced the insulin secretion rate (ISR). Accordingly, in the current study, we performed more detailed analyses of the effects of this GAD65mAb on rat and human islets. ISR was suppressed by ∼40% after 3 days of exposure. Mechanisms mediating the effects were found to involve inhibition of mitochondrial generation of ATP, which decreased in parallel with that of ISR. As expected, the GAD65mAb inhibited γ-aminobutyric acid secretion. The effects of GAD65mAb were observed in rat and human islets but not in mouse islets, which do not express GAD65. GAD65mAb also reduced insulin secretion in vivo, where decreased insulin levels after intraperitoneal (i.p.) injection of glucose were observed in rats after i.p. injection of GAD65mAb. Thus, it appears that an islet cell autoantibody against GAD65 can directly impact and impair secretory function in islets in vitro and in vivo through a mechanism that involves inhibition of mitochondrial energetics. ARTICLE HIGHLIGHTS This study was undertaken to further investigate the ability of a monoclonal autoantibody to GAD65 from a patient with pre–type 1 diabetes to be deleterious to islet function. The study was designed to further characterize the effects, understand the mechanism mediating the effects, and demonstrate that the effects were operational in vivo. The effects of the GAD65 monoclonal antibody reduced ATP, γ-aminobutyric acid secretion, and insulin secretion with a similar time course and concentration dependency, which appeared to be mediated by effects on mitochondrial energetics and were similar in vivo in rats as in vitro. These findings raise the possibility that autoantibodies could play a pathogenic role in the development of type 1 diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"10 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260751","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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