Diabetes最新文献

{"title":"Heterogeneity in Phenotype and Early Metabolic Response to Lifestyle Interventions in Type 2 Diabetes in China Using a Tree-Like Representation","authors":"Yi Ding, Qi Zhou, Youjin Jiang, Qiuyu Cao, Xianglin Wu, Xiaoran Li, Yu Xu, Jieli Lu, Min Xu, Tiange Wang, Zhiyun Zhao, Yuhong Chen, Yan Liu, Jie Li, Guang Ning, Weiqing Wang, Yufang Bi, Mian Li","doi":"10.2337/db25-0197","DOIUrl":"https://doi.org/10.2337/db25-0197","url":null,"abstract":"Deciphering the heterogeneity of type 2 diabetes in prognosis and treatment effect is essential. We used a novel dimensionality reduction approach to describe the type 2 diabetes phenotype continuum and visualize the difference in lifestyle intervention efficacy in Chinese patients. Based on 17,816 participants with newly diagnosed type 2 diabetes (aged ≥40 years) from a nationwide cohort, 12 key phenotypes were residualized for age and sex to construct a two-dimensional tree structure. The tree demonstrated the continuous type 2 diabetes spectrum and region-specific characteristics, with a mixed phenotypic trunk and three extreme phenotypic branches. When mapping data from 325 participants with type 2 diabetes from a randomized controlled trial onto the original tree, lifestyle intervention induced a migration toward the left part of tree, indicating an overall metabolic improvement. Specifically, diet intervention was more effective for glycemic control in the upper part of the tree and featured moderate diabesity and elevated insulin, whereas exercise intervention was more effective for glycemic control in the left side of the tree and featured less adiposity and better overall metabolic status. In summary, this analysis depicted the tree structure representing the underlying pathophysiological features of patients with newly diagnosed type 2 diabetes and identified tree regions with different sensitivity to diet or exercise intervention. The results have the potential to aid lifestyle intervention selection. Article Highlights Deciphering the heterogeneity of diabetes is essential for prognosis prediction and treatment guidance, but current classifications are flawed because they lose continuous phenotypic information. We wanted to determine if the novel data reduction method, the data dimensionality reduction tree (DDRTree), is applicable to visualizing the phenotypic continuum, comorbid conditions, and lifestyle intervention effects in Chinese patients with type 2 diabetes. The DDRTree structure demonstrated the region-specific characteristics of type 2 diabetes. Diet intervention was more effective for glycemic control in the upper part of the tree, featuring moderate diabesity, whereas exercise intervention was more effective in the left side of the tree, featuring less adiposity and better overall metabolic status. The Chinese type 2 diabetes tree structure indicates individualized pathophysiology and guides the selection of lifestyle intervention.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"34 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995500","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":"Cell Type–Specific Expression of Long Noncoding RNAs in Human Diabetic Kidneys Identifies TARID as a Key Regulator of Podocyte Function","authors":"Juliette A. de Klerk, Roderick C. Slieker, Wilson C. Parker, Haojia Wu, Yoshiharu Muto, Rudmer J. Postma, Leen M. ’t Hart, Janneke H.D. Peerlings, Floris Herrewijnen, Heein Song, H. Siebe Spijker, Sébastien J. Dumas, Marije Koning, Loïs A.K. van der Pluijm, Hans J. Baelde, Tessa Gerrits, Joris I. Rotmans, Anton Jan van Zonneveld, Coen van Solingen, Benjamin D. Humphreys, Roel Bijkerk","doi":"10.2337/db25-0272","DOIUrl":"https://doi.org/10.2337/db25-0272","url":null,"abstract":"Long noncoding RNAs (lncRNAs) play essential roles in cellular processes, often exhibiting cell type–specific expression and influencing kidney function. While single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cellular specificity, past studies focus solely on protein-coding genes. We hypothesize that lncRNAs, due to their cell-specific nature, have crucial functions within particular renal cells and thereby play essential roles in renal cell function and disease. Using single-nucleus RNA-seq (snRNA-seq) data from kidney samples of five healthy individuals and six patients with diabetic kidney disease (DKD), we explored the noncoding transcriptome. Cell type–specific lncRNAs were identified, and their differential expression in DKD was assessed. Integrative analyses included expression quantitative trait loci (eQTL), genome-wide association studies (GWAS) for estimated glomerular filtration rate (eGFR), and gene regulatory networks. Functional studies focused on TCF21 antisense RNA inducing promoter demethylation (TARID), a lncRNA with podocyte-specific expression, to elucidate its role in podocyte health. We identified 174 lncRNAs with cell type–specific expression across kidney cell types. Of these, 54 lncRNAs were differentially expressed in DKD. Integrative analyses, including eQTL data, GWAS results for eGFR, and gene regulatory networks, pinpointed TARID, a podocyte-specific lncRNA, as a key candidate upregulated in DKD. Functional studies confirmed TARID's podocyte-specific expression and revealed its central role in actin cytoskeleton reorganization. Our study provides a comprehensive resource of single-cell lncRNA expression in the human kidney and highlights the importance of cell type–specific lncRNAs in kidney function and disease. Specifically, we demonstrate the functional relevance of TARID in podocyte health. ARTICLE HIGHLIGHTS This study provides a resource for kidney (cell type–specific) long noncoding (lnc)RNA expression and demonstrates the importance of lncRNAs in renal health. We identified 174 cell type-specific lncRNAs in the human kidney, with 54 showing altered expression in diabetic kidney disease. TCF21 antisense RNA inducing promoter demethylation (TARID), a podocyte-specific lncRNA upregulated in diabetic kidney disease, is crucial for actin cytoskeleton reorganization in podocytes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"33 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987390","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":"Proinflammatory Stress Activates Neutral Sphingomyelinase 2–Based Generation of a Ceramide-Enriched β-Cell EV Subpopulation","authors":"Jerry Xu, Irene Amalaraj, Andre De Oliveira, Arianna Harris-Kawano, Jacob R. Enriquez, Raghavendra G. Mirmira, Josie G. Eder, Meagan C. Burnet, Ivo Diaz Ludovico, Javier E. Flores, Ernesto S. Nakayasu, Emily K. Sims","doi":"10.2337/db24-0341","DOIUrl":"https://doi.org/10.2337/db24-0341","url":null,"abstract":"β-cell extracellular vesicles (EVs) play a role as paracrine effectors in islet health, yet mechanisms connecting β-cell stress to changes in EV cargo and potential impacts on diabetes remain poorly defined. We hypothesized that β-cell inflammatory stress engages neutral sphingomyelinase 2 (nSMase2)–dependent EV formation pathways, generating ceramide-enriched small EVs that could impact surrounding β-cells. Consistent with this, proinflammatory cytokine treatment of INS-1 β-cells and human islets concurrently increased β-cell nSMase2 and ceramide abundance, as well as small EV ceramide species. Direct chemical activation or genetic knockdown of nSMase2, chemical treatment to inhibit cell death pathways, or treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist also modulated β-cell EV ceramide. RNA sequencing of ceramide-enriched EVs identified a distinct set of miRNAs linked to β-cell function and identity. EV treatment from cytokine-exposed parent cells inhibited peak glucose-stimulated insulin secretion in wild-type recipient cells; this effect was abrogated when using EVs from nSMase2 knockdown parent cells. Finally, plasma EVs in children with recent-onset type 1 diabetes showed increases in multiple ceramide species. These findings highlight nSMase2 as a regulator of β-cell EV cargo and identify ceramide-enriched EV populations as a contributor to EV-related paracrine signaling under conditions of β-cell inflammatory stress and death. ARTICLE HIGHLIGHTS Mechanisms connecting β-cell stress to extracellular vesicle (EV) cargo and diabetes are poorly defined. Does β-cell inflammatory stress engage neutral sphingomyelinase 2 (nSMase2)–dependent EV formation to generate ceramide-enriched small EVs? Proinflammatory cytokines increased β-cell small EV ceramide via increases in nSMase2. Ceramide-enriched EVs housed distinct cargo linked to insulin signaling, and ceramide species were enriched in plasma EVs from individuals with type 1 diabetes. Ceramide-enriched EV populations are a potential contributor to β-cell EV-related paracrine signaling.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"14 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930740","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":"Proteogenomic Discovery of Novel Open Reading Frames With HLA Immune Presentation on Human β-Cells","authors":"Kathryn Walters, Roberto Castro-Gutierrez, Soumyadeep Sarkar, Amber Baldwin, Alexandra S. Baker, Ali H. Shilleh, Amanda M. Anderson, Maki Nakayama, Tim Fugman, Ernesto S. Nakayasu, Neelanjan Mukherjee, Holger A. Russ","doi":"10.2337/db24-0527","DOIUrl":"https://doi.org/10.2337/db24-0527","url":null,"abstract":"Ribosome profiling (Ribo-seq) measures translational regulation and reveals novel or unannotated open reading frames (nuORFs) otherwise difficult to identify. Recent reports demonstrate that nuORFs regulate gene expression and immune recognition, highlighting their emerging biological roles. Pancreatic β-cells are critical for maintaining euglycemic conditions, and β-cell impairment contributes to diabetes development. Identification of nuORF and protein/peptide products in human β-cells could reveal novel mechanisms that regulate β-cell function during homeostatic and disease conditions. Here, we applied a proteogenomic approach to human β-cells to define previously unknown protein/peptide products. First, we applied cell type–specific Ribo-seq to map the translatome of human stem cell–derived β-cells (sBCs). Pathways crucial for β-cell function and antigen presentation were subject to translational regulation. We detected a recently described immunogenic neoantigen, INS-DRiP, presumably originating from a downstream start site in INS mRNA. Moreover, our analysis revealed 965 novel nuORFs in sBCs, with a majority showing protein-level support. Comparison with primary human islets further validated nuORF translation and highlighted β-cell specificity. We identified a novel, primate-specific regulatory upstream ORF within TYK2, which is crucial for β-cell function and interferon response and has many variants strongly associated with type 1 diabetes. Finally, we used immunopeptidomics, HLA-binding prediction models, and T-cell coculture assays to validate the presentation and immunogenicity of preproinsulin peptides and nuORFs. Our findings underscore the importance of translational regulation in β-cell function and provide an important resource to the diabetes research community. ARTICLE HIGHLIGHTS We developed a cell type–specific proteogenomic approach to reveal novel or unannotated open reading frames (nuORFs) using transcriptomics, ribosomal profiling, and proteomic analysis of human pancreatic β-cells using stem cell–derived β-cells and/or cadaveric islets. Our analysis revealed translational regulation of β-cell–specific pathways during differentiation and identified 965 nuORFs, with a majority exhibiting protein support and substantial β-cell specificity. A primate-specific ORF located in the 5′ untranslated region of the type 1 diabetes risk gene TYK2 may act as a translational activator. We provide HLA class I immunopeptidomic data from cytokine-stimulated human β-cells and demonstrate their utility in coculture assays with autoreactive T-cell transductants. Taken together, our results define the human β-cell translatome, an important resource to the research field.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"52 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930671","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":"Novel Approach for Assessing Outcomes of Type 1 Diabetes Prevention Trials Over a Fixed Time Interval","authors":"Emily K. Sims, William E. Russell, David Cuthbertson, Jay S. Skyler, Laura M. Jacobsen, Heba M. Ismail, Maria J. Redondo, Brandon M. Nathan, Alice L.J. Carr, Peter N. Taylor, Colin M. Dayan, Alfonso Galderisi, Kevan C. Herold, Jay M. Sosenko","doi":"10.2337/db25-0310","DOIUrl":"https://doi.org/10.2337/db25-0310","url":null,"abstract":"We evaluated whether a binary metabolic end point for change (Δ) from baseline to 1-year postrandomization could be useful in type 1 diabetes (T1D) prevention trials. Using 2-h oral glucose tolerance testing data from the stage 1 participants in the recent abatacept prevention trial and similar participants in the observational TrialNet Pathway to Prevention (PTP) study, we assessed Δmetabolic measures, plotted glucose and C-peptide response curves, and categorized vectors for Δ from baseline to 1 year as metabolic treatment failure versus success. Analyses were validated using the teplizumab prevention study. PTP participants with Δglucose >0 and ΔC-peptide <0 from baseline to 1 year were at substantially higher risk for stage 3 T1D than those with Δglucose <0 and ΔC-peptide >0 (P < 0.0001). Based on this, we compared placebo versus treatment groups in both trials for failure (Δglucose >0 with ΔC-peptide <0) versus success (Δglucose <0 with ΔC-peptide >0) after 1 year. Using this endpoint, a favorable metabolic impact of abatacept was found after 12 months of treatment. An analytic approach using a binary metabolic end point of failure versus success at a fixed time interval appears to detect treatment effects at least as well as standard primary end points with shorter follow-up. ARTICLE HIGHLIGHTS Challenges in time to event type 1 diabetes (T1D) prevention trial design can yield negative results even for treatments that may actually improve disease pathology. We evaluated whether a binary metabolic end point for 12-month change from baseline to 1 year postrandomization could be useful in T1D prevention trials. This approach detected treatment effects at least as well as standard primary end points with shorter follow-up. Fixed interval metabolic end points should be used in combination with traditional T1D end points to better understand treatment effects of preventive agents.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"18 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915480","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":"Lipids Engage a Kidney-Brain GDF15 Axis to Suppress Food Intake","authors":"Ameth N. Garrido, Song-Yang Zhang, Kyla Bruce, Charmaine S.H. Lai, Zeyu Yang, Melissa T. Wang, Tony K.T. Lam","doi":"10.2337/db25-0174","DOIUrl":"https://doi.org/10.2337/db25-0174","url":null,"abstract":"Growth differentiation factor 15 (GDF15) is an anorectic and weight-loss–inducing hormone that responds to stimuli such as endoplasmic reticulum stress, exercise, metformin, and more recently, dietary lipids. Given its potential as an antiobesogenic agent, we examined how endogenous GDF15 responds to an Intralipid infusion in different organs to regulate food intake in vivo. We found that an acute Intralipid infusion into the upper small intestine (USI) inhibited food intake and increased plasma GDF15, as well as kidney and hepatic Gdf15 expression in chow-fed but not high-fat (HF)–induced hyperphagic male rats. Kidney Gdf15 knockdown blunted Intralipid-induced increases in kidney and plasma GDF15 levels as well as its feeding-lowering effects, while hepatic Gdf15 expression remained unaffected. Lastly, we knocked down GDNF family receptor α-like (Gfral) in the area postrema, which negated the feeding-lowering effect of Intralipid despite a rise in plasma GDF15 levels in chow rats. In summary, we report that kidney GDF15 is necessary for USI intralipid sensing to trigger an area postrema axis to inhibit food intake. We propose that HF feeding impairs acute lipid sensing to lower feeding by negating the lipid-regulatory effect on kidney GDF15. ARTICLE HIGHLIGHTS Upper small intestine lipid infusion increases kidney, hepatic, and plasma growth differentiation factor 15 (GDF15) levels in chow but not high-fat rats. Upper small intestine lipid infusion lowers food intake in chow but not high-fat rats. Knockdown of kidney Gdf15 negates lipids to increase plasma GDF15 and lower feeding. Knockdown of GDNF family receptor α-like (Gfral) in the area postrema negates lipid anorectic effect.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915547","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":"Metabolome-Wide Mendelian Randomization and Observational Study Reveal Causal Links Between Circulating Metabolites and Youth-Onset Type 2 Diabetes","authors":"Kaossarath Fagbemi, Raphael Avocegamou, Nahid Yazdanpanah, Mojgan Yazdanpanah, Basile Jumentier, Isabel Gamache, Despoina Manousaki","doi":"10.2337/db25-0093","DOIUrl":"https://doi.org/10.2337/db25-0093","url":null,"abstract":"Despite the increasing prevalence of type 2 diabetes in youth, its causal associations with circulating biomarkers remain elusive. We first aimed to identify circulating metabolites causally linked to youth-onset type 2 diabetes using Mendelian randomization (MR). By analyzing 675 metabolites from large metabolomic European genome-wide association studies (GWAS) and data on youth type 2 diabetes from the multiancestry Progress in Diabetes Genetics in Youth (ProDiGY) consortium, we identified 34 candidate metabolites. Among these, phosphatidylcholine (pc) ae C42:3 and propionylcarnitine provided the strongest evidence of association with youth-onset type 2 diabetes, based also on positive genetic colocalization and sensitivity analyses accounting for adiposity. Among the 34 candidate metabolites, 23 were retained following colocalization and a replication MR using independent metabolomic GWAS and testing effects on adult type 2 diabetes. Furthermore, we validated associations of six of these metabolites with glucose metabolism–related traits in an observational study in the Avon Longitudinal Study of Parents and Children (ALSPAC). Notably, pc ae C42:3 levels at age 7 years were linked to dysglycemia and insulin resistance in adolescence. These findings underscore the dynamic role of metabolites in glucose metabolism in childhood, offering insights for future screening and treatment strategies. ARTICLE HIGHLIGHTS Metabolism is key in the pathogenesis of type 2 diabetes in both children and adults, and large-scale metabolomic studies offer a unique source for discovery of biomarkers for these conditions. Leveraging human genetics, we explored whether altered levels of circulating metabolites in the blood are causally linked to type 2 diabetes in youth across different ancestries. Our Mendelian randomization analysis identified causal associations for 34 metabolites, and, among these, Mendelian randomization replication and colocalization prioritized 23 metabolites. Observational evidence from the Avon Longitudinal Study of Parents and Children (ALSPAC) study validated effects on glucose homeostasis for six of these metabolites, among which phosphatidylcholine ae C42:3 emerged as the most promising biomarker. These findings highlight the role of metabolism in glucose homeostasis pathophysiology in youth.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"23 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144911210","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":"Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis","authors":"Tessa M. Cacciottolo, Katherine Lawler, Kevin M. Méndez-Acevedo, Edson Mendes de Oliveira, Adam Syanda, Elana Henning, Julia M. Keogh, Rebecca Bounds, Miriam Smith, Daniyal Ashraf, David Harman, Adam Duckworth, Edmund M. Godfrey, Laura Watson, Matthew Hoare, Ben Jones, Alastair Baker, Tamir Rashid, I. Sadaf Farooqi","doi":"10.2337/db25-0209","DOIUrl":"https://doi.org/10.2337/db25-0209","url":null,"abstract":"In mice, glucagon regulates lipid metabolism by activating receptors in the liver; however, its role in human lipid metabolism is incompletely understood. Here we describe three normal-weight individuals from a consanguineous family with early-onset hepatic steatosis and/or cirrhosis. Using exome sequencing, we found they were homozygous for two missense variants in the glucagon receptor gene (GCGR). In cells, the double GCGR mutation reduced cell membrane expression and signaling, resulting in an almost complete loss of function. Carriers of pathogenic GCGR mutations had substantially elevated circulating glucagon and amino acid levels and increased adiposity. Introducing the double GCGR mutation into human-induced pluripotent stem cell–derived hepatocytes using clustered regularly interspaced short palindromic repeats ([CRISPR]/CRISPR-associated protein 9) caused increased lipid accumulation. Our results provide an explanation for increased liver fat seen in clinical trials of GCGR antagonists and reduced liver fat in people with obesity and steatotic liver disease treated with GCGR agonists. ARTICLE HIGHLIGHTS In this study, we investigated a consanguineous family in whom normal-weight individuals had hepatic steatosis and cirrhosis. Using whole-exome sequencing we found two rare homozygous variants in the glucagon receptor (GCGR) gene that cosegregated with the phenotype. In cells, the GCGR mutations result in a loss of function and increased lipid accumulation. These results highlight the potential risks associated with GCGR antagonists and the benefits of GCGR agonists, currently in clinical trials.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"178 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898102","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":"SIRT6 Is a Key Regulator of Pancreatic β-Cell Survival and Function During Aging","authors":"Jimin Park, Sandali D. Lokuge, Menghao Huang, Shen Wang, Sheng Liu, Jingru Liang, Ramkumar Katturajan, Corinn Marakovits, Zhihong Yang, Jun Wan, X. Charlie Dong","doi":"10.2337/db25-0116","DOIUrl":"https://doi.org/10.2337/db25-0116","url":null,"abstract":"Pancreatic β-cells undergo senescence and loss during aging; however, the underlying mechanisms remain incompletely understood. This study aimed to investigate what sirtuin 6 (SIRT6) does during β-cell aging. Pancreatic β-cell–specific Sirt6 transgenic (TgSIRT6) mice were generated for this study. DNA damage, cell death, and cell proliferation were analyzed in cell and mouse models. SIRT6 protein levels were decreased in pancreatic β-cells during aging. TgSIRT6 mice exhibited less DNA damage and cell death, including apoptosis, necroptosis, and pyroptosis, in β-cells than control mice. TgSIRT6 mice had increased total islet area and mass in pancreas compared with control mice. As a result, TgSIRT6 mice showed better glucose tolerance and glucose-stimulated insulin secretion than control mice. RRAD and GEM-like GTPase 2 (REM2), an endogenouse inhibitor of high-voltage–activated calcium channels, was negatively regulated by SIRT6. Knockdown of Rem2 in INS-1 cells partially rescued the SIRT6 deficiency– and palmitic acid–induced DNA damage, lipid peroxidation, and cell death. Rem2 β-cell–specific knockout mice had less DNA damage and cell death in β-cells than control mice. Our data suggest that SIRT6 is a critical antiaging factor in pancreatic β-cells and is a potential therapeutic target. ARTICLE HIGHLIGHTS Pancreatic β-cell function declines with age, but the underlying mechanism is poorly understood. In this study, we attempted to address how to reverse β-cell aging. Our data showed that sirtuin 6 (SIRT6) overexpression can reduce age-associated DNA damage, cell death, and functional decline in β-cells. Our findings suggest that improving Sirt6 gene expression and function may slow down β-cell decline in older patients.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"17 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901562","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":"Investigating Late-Stage Diabetic Retinopathy: A Long-term Analysis of Vascular Changes in the Streptozotocin-Induced Mouse Model","authors":"Madison E. Weiss, Milin J. Patel, Brandon H. Watts, Paola E. Parrales, Oscar Alcazar, Isabella M. Pizza, Nicholas Karapelou, Abigail S. Hackam, Midhat H. Abdulreda","doi":"10.2337/db25-0434","DOIUrl":"https://doi.org/10.2337/db25-0434","url":null,"abstract":"Diabetic retinopathy (DR) is characterized by microvascular damage and increased vascular permeability in the retina. The investigation of visual outcomes in late-stage DR is limited by challenges of maintaining chronically hyperglycemic mice, and most reports are restricted to early-stage DR. In this study, we used carefully managed diabetic mice to longitudinally investigate associations between vascular leakage and visual acuity during early- and late-stage DR. Diabetes was induced in C57BL/6J mice with streptozotocin, and fluorescence angiography with dual fluorescence (FA-DF) was used to assess retinal vascular leakage dynamics in chronically hyperglycemic mice for 12 months. Retinal vascular leakage was evident 180 days after diabetes induction and before reduced visual acuity, measured using the optokinetic response, and vascular leakage continued to increase during DR progression. Mice were also treated with intravitreal injections of antiangiogenic aflibercept at late-stage DR, and reduced leakage was reliably measured using FA-DF and was associated with improved visual acuity. Inflammatory and vascular phenotypes were assessed using immunostaining, which revealed significantly lower retinal macrophage and vascular densities and reduced capillary diameter in association with anti-VEGF treatment compared with age-matched diabetic controls. In conclusion, this is the first longitudinal quantification of retinal vascular leakage in early, intermediate, and late stages of DR in the same cohort of mice in a minimally invasive fashion to demonstrate the associated effect of antiangiogenic therapy in vivo. Our findings also further confirmed the sensitivity of FA-DF in assessing retinal vascular leakage in conjunction with other functional measures in longitudinal studies in the same animals. ARTICLE HIGHLIGHTS We use the newly developed fluorescence angiography with dual fluorescence imaging method to longitudinally investigate associations between vascular leakage and visual acuity during early-, intermediate-, and late-stage diabetic retinopathy (DR) in diabetic mice. We demonstrate the onset and progression of vascular leakage, association of leakage with reduced visual acuity, and alteration of macrophage and vascular densities in late-stage DR. We confirm the sensitivity of fluorescence angiography with dual fluorescence in assessing retinal vascular leakage in conjunction with other functional measures in longitudinal studies in the same animals and demonstrate inflammatory changes in late-stage DR.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"41 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898107","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}