Diabetes最新文献

{"title":"Unraveling Diabetic Cardiomyopathy (DCM): The Critical Role of the Yap-miR-22-3p-Sirt1 Axis in the Pathogenesis of DCM.","authors":"Yilang Li, Yue Zeng, Yuling Lian, Chi Zhang, Xiaoqing Chen, Siyu Zhang, Yipu Huang, Wenchang Yuan, Yuan Qin, Ducai Liu, Yun Liu, Yilin Chen, Yongying Shi, Xun Yuan, Ning Hou","doi":"10.2337/db25-0435","DOIUrl":"10.2337/db25-0435","url":null,"abstract":"<p><p>Diabetic cardiomyopathy (DCM), characterized by myocardial hypertrophy and fibrosis, is a severe complication of diabetes. Activation of Yes-associated protein (Yap) has been implicated in myocardial remodeling and cardiac dysfunction. This study aimed to elucidate the role and underlying molecular mechanisms of Yap in DCM. Yap expression was evaluated in mice with type 2 diabetes mellitus (T2DM) and in neonatal rat cardiomyocytes (NRCMs) treated with high glucose (HG) or HG + palmitic acid (PA). Adeno-associated virus transfection, adenovirus infection, and a transgenic mouse model were used to modulate Yap expression both in vivo and in vitro. RNA sequencing and miRNA sequencing were used to identify Yap's downstream targets and related mechanisms. Functional assays, including assessment of molecular markers, cell morphology, and echocardiography, were conducted to evaluate cardiomyocyte hypertrophy and fibrosis. Results showed that Yap expression was elevated in HG or HG+PA-treated NRCMs and hearts of T2DM mice, promoting myocardial hypertrophy and fibrosis. Inhibition of Yap reduced cardiomyocyte cross-sectional area, collagen deposition, and levels of hypertrophy markers atrial natriuretic peptide and β-myosin heavy chain. RNA sequencing identified Sirt1 as a downstream target of Yap. Bioinformatics analysis indicated that Yap positively regulated miR-22-3p, which in turn inhibited Sirt1. Yap inhibition increased Sirt1 expression, alleviating myocardial remodeling. Conversely, Sirt1 knockdown reversed the protective effects of Yap inhibition, exacerbating hypertrophy and fibrosis. In conclusion, Yap promotes the progression of DCM by upregulating miR-22-3p expression and suppressing Sirt1 expression. Therapeutically targeting the newly identified Yap-miR-22-3p-Sirt1 axis could mitigate multiple aspects of diabetic cardiac remodeling.</p><p><strong>Article highlights: </strong>Diabetic cardiomyopathy (DCM) describes the abnormality of myocardial structure and function caused by diabetes, and Yes-associated protein (Yap) is linked to various cardiovascular diseases, modulating remodeling and cardiac function in hearts, but its role in DCM is unclear. How Yap affects myocardial structure and function in mice with type 2 diabetes mellitus and the underlying pathways were investigated. High glucose or high glucose plus palmitic acid levels enhance Yap activity, thereby promoting miR-22-3p expression and inhibiting sirtuin 1 (Sirt1) expression. The Yap-miR-22-3p-Sirt1 axis plays critical roles in the cause of DCM. The molecular pathways investigated offer promising targets for therapeutic intervention against DCM and provide new insights into the development of innovative treatment strategies to combat cardiac dysfunction in patients with diabetes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"974-990"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147328791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ketogenic Diet and Exercise Improve Peripheral Neuropathy in a Mouse Model of Metabolic Syndrome.","authors":"Stéphanie A Eid, Pongrat Jaisil, Kai Guo, John M Hayes, Crystal Pacut, Diana M Rigan, Andrew Carter, Samuel J Teener, Bhumsoo Kim, Chloe Kiriluk, William Lentz, Cameron M Miller, Ian Webber-Davis, Haley McQuown, Dae-Gyu Jang, Adam Patterson, Emily J Koubek, Dave Bridges, Junguk Hur, Jacob D Meyer, Eva L Feldman","doi":"10.2337/db25-1015","DOIUrl":"10.2337/db25-1015","url":null,"abstract":"<p><p>Metabolic syndrome (MetS) is a growing health concern that increases risk for peripheral neuropathy (PN), defined by nerve degeneration and sensory dysfunction. Although lifestyle strategies, like ketogenic diet (KD) and exercise, are known to mitigate MetS, their efficacy in maintaining nerve health or reversing established PN is less clear. First, in a maintenance paradigm, we tested whether long-term KD could maintain nerve health in mice, as opposed to a Western-style high-fat diet (HFD) that induces MetS PN. Second, in an intervention paradigm of mice with established MetS PN, we compared the efficacy of low-fat standard diet, KD, exercise, and combined KD-exercise interventions in reversing MetS PN. Long-term KD maintained body composition, nerve function, and neuromuscular innervation. In mice with established MetS PN, all interventions improved metabolic parameters and nerve function, albeit to varying extents. Transcriptomic profiling revealed that HFD dysregulated genes related to cytoskeletal dynamics and inflammation in sciatic nerve, with interventions partially reversing these changes. In muscle, dietary interventions modulated fatty acid and amino acid metabolism. Notably, exercise generated a unique gene expression signature in nerve and muscle. These findings support KD and exercise as promising approaches for treating MetS PN and offer mechanistic insights into their therapeutic benefits.</p><p><strong>Article highlights: </strong>Metabolic syndrome (MetS) increases risk for peripheral neuropathy (PN), a progressive nerve disorder with limited treatment options. We examined whether long-term ketogenic diet (KD) could maintain nerve health, and whether KD, exercise, or both could reverse established MetS PN. Maintenance KD preserved body composition, liver health, and nerve function, while all interventions improved metabolic and nerve outcomes to varying degrees. Transcriptomic profiling of sciatic nerve and gastrocnemius muscle revealed partial reversal of MetS-induced inflammatory, cytoskeletal, and metabolic gene alterations. These findings highlight KD and exercise for treating MetS PN.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"991-1006"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147492373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on Shah and Ayala. Interpreting Stage-Dependent Changes in Semaglutide Response: From Patterns to Mechanisms.","authors":"Giovanni Ragozzino, Maria Teresa Cantelli, Elisabetta Fulgione, Edi Mattera","doi":"10.2337/db26-0171","DOIUrl":"10.2337/db26-0171","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 6","pages":"e11-e12"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Downregulation of Type 1 Diabetes Susceptibility Gene PGM1 Induces Metabolic Imbalance and Stress in Pancreatic β-Cells.","authors":"Jody Ye, Yunping Qiu, Jennifer T Aguilan, Yan Sun, Rucha Kulkarni, Stanislovas S Jankauskas, Gaetano Santulli, Simone Sidoli, Irwin J Kurland, Yaron Tomer","doi":"10.2337/db25-0191","DOIUrl":"10.2337/db25-0191","url":null,"abstract":"<p><p>Phosphoglucomutase 1 (PGM1) is a type 1 diabetes susceptibility gene that potentially plays a key role in regulating central carbon metabolism in β-cells. Previous work suggested that β-cell PGM1 transcription is lowered after coxsackievirus B4 infection. Thus, we hypothesized that decreased PGM1 levels disrupt β-cell metabolic homeostasis and result in β-cell fragility and type 1 diabetes. First, we showed that the synthetic double-stranded RNA polyinosinic:polycytidylic acid, or Poly(I:C) attenuated PGM1 transcription both in human islets and EndoC-βH1 cell line. At 5.5 mmol/L glucose, PGM1 deficiency enhanced the rate of glycolysis, tricarboxylic acid cycle, hexosamine, and pentose phosphate pathway. However, at 20 mmol/L glucose, PGM1-deficient cells showed impaired mitochondrial respiration. Moreover, truncated N-glycans were enriched in PGM1-deficient cells, suggesting aberrant protein glycosylation. Autophagic flux, which was dependent on the lysosomal glycosylated protein function, was impaired in PGM1-deficient cells. Increased endoplasmic reticulum stress was evident in PGM1-deficient cells. Our results suggest that PGM1 is a metabolic regulator of pancreatic β-cells. Its deficiency leads to metabolic imbalance and cellular stress, potentially augmenting type 1 diabetes development.</p><p><strong>Article highlights: </strong>In the β-cell, the expression of phosphoglucomutase 1 (PGM1), a type 1 diabetes risk gene, is reduced by double-stranded RNA exposure, modeled by polyinosinic:polycytidylic acid transfection. Deficient PGM1 expression disrupts central carbon metabolism, protein glycosylation, and autophagic flux. These changes precipitate endoplasmic reticulum stress and mitochondrial dysfunction, potentially augmenting type 1 diabetes development.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"888-900"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the Timing of the Metabolic Inflection Point in Type 1 Diabetes Progression Using Machine Learning and Survival Analysis Models.","authors":"Eslam Montaser, Jay M Sosenko, Heba M Ismail","doi":"10.2337/db25-0961","DOIUrl":"10.2337/db25-0961","url":null,"abstract":"<p><p>An inflection point (IP) marking accelerated β-cell decline occurs ∼1-2 years before type 1 diabetes diagnosis. Precisely determining this timing could optimize clinical intervention. We developed machine learning models to predict proximity to the inferred metabolic IP using oral glucose tolerance test (OGTT) data from islet autoantibody-positive individuals in the TrialNet Pathway to Prevention study. OGTTs were retrospectively labeled by estimating time to the IP using thresholds from 1.2 to 1.6 years. Models were trained on engineered glucose and C-peptide dynamics, slopes, and composite indices, with feature selection by recursive feature elimination (RFE). Classifiers included support vector machines (SVM), random forests, and gradient boosting; a Cox proportional hazards model was also applied to estimate visit-level time to diagnosis and derive time-to-IP predictions. External validation was performed in the independent Diabetes Prevention Trial-Type 1 cohort. The best-performing model-SVM with RFE at the 1.4-year threshold-achieved an area under the curve of 0.77 (95% CI 0.72-0.82). The Cox model provided complementary numeric estimates of time to diagnosis and time to IP, sensitive to the cohort-level lead time offset (Δ). These findings show that machine learning and survival analysis can support early metabolic shift detection, enabling timely risk stratification and personalized monitoring in at-risk individuals.</p><p><strong>Article highlights: </strong>We undertook this study to improve early identification of the metabolic inflection point (IP) preceding clinical type 1 diabetes in autoantibody-positive individuals. We aimed to develop and validate machine learning models using oral glucose tolerance test-derived dynamic features to detect proximity to the IP. A support vector machine trained on TrialNet Pathway to Prevention and tested on Diabetes Prevention Trial-Type 1 achieved an area under the curve of 0.77 at 1.4 years prior to diagnosis, with strong calibration and interpretability. Additionally, a Cox proportional hazards model provided numeric estimates of time to IP, offering complementary predictions. These results can support earlier intervention and timely monitoring through personalized oral glucose tolerance test-based risk stratification.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"901-910"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human iPSC-Based Modeling Identifies Epigenetic Regulation at the KCNQ1 Locus During Early Islet Development That Contributes to Lower β-Cell Mass.","authors":"Anup K Nair, Michael Traurig, Yunhua L Muller, Divya Anup, Jeffrey R Sutherland, Emma Grellinger, Nizhoni Henry, Kim Weidrich, Koushik Ponnanna Cheranda, Clifton Bogardus, Leslie J Baier","doi":"10.2337/db25-0721","DOIUrl":"10.2337/db25-0721","url":null,"abstract":"<p><p>The strongest type 2 diabetes signal in Indigenous Americans from Arizona is in intron 15 of KCNQ1. We previously identified a functional region in this intron that contained four type 2 diabetes-associated single nucleotide polymorphisms (SNPs) (rs2299620, rs2237896, rs2237897, and rs74046911) and demonstrated functionality of this fragment using Indigenous American induced pluripotent stem cell (iPSC)-derived pancreatic islets (SC-islets). In the current study, we used isogenic iPSCs with targeted edits at these four SNPs, and three additional SNPs (rs2237895, rs60808706, and rs234864), to generate SC-islets and study the effect of these variants during different developmental stages. We identify an 11% reduction in stem cell-derived β-cells (SC-β-cells) in SC-islets with the risk alleles, suggesting an effect of these variants on β-cell mass. We further show premature endocrine commitment in cells with the risk allele and lower rate of β-cell commitment during the endocrine progenitor stages, likely due to differences in H19 and INS gene expression dynamics. We also show that the differential expression may be attributable to lower CpG methylation and higher chromatin accessibility in cells with the risk alleles. In summary, the type 2 diabetes SNPs at KCNQ1 affect SC-β-cell generation, and this effect is manifested early during development, likely via an epigenomic effect on gene regulation.</p><p><strong>Article highlights: </strong>We previously developed an induced pluripotent stem cell-based model to study an intronic region of KCNQ1 that represents the strongest association signal with type 2 diabetes in Indigenous Americans from Arizona. The current study builds on this model by using CRISPR/Cas9-edited isogenic cells that differ only by targeted type 2 diabetes single nucleotide polymorphisms in this intronic region. The effect of KCNQ1 type 2 diabetes single nucleotide polymorphisms on pancreatic β-cell development and the probable mechanism of this effect were previously unknown. The current study shows an effect on INS and H19 gene expression dynamics specifically during the endocrine progenitor stage of pancreatic islet development likely via an epigenomic effect on gene regulation resulting in generation of lower β-like cells. Individuals carrying KCNQ1 risk alleles for type 2 diabetes will likely benefit from therapeutics that increase pancreatic β-cell mass.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1038-1049"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Blood Sugar: Exploring the Contribution of Metabolic Syndrome to Peripheral Neuropathy.","authors":"Brett M Morrison","doi":"10.2337/dbi26-0009","DOIUrl":"10.2337/dbi26-0009","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 6","pages":"885-887"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippo-YAP Signaling Drives Epigenetic Vulnerability in the Diabetic Heart via the miR-22-3p-SIRT1 Axis: Linking Metabolic Stress to Chromatin Control.","authors":"Stanislovas S Jankauskas, Fahimeh Varzideh, Gaetano Santulli","doi":"10.2337/dbi26-0011","DOIUrl":"10.2337/dbi26-0011","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 6","pages":"882-884"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Comment on Uddin et al. Interpreting Retinal Hypoxia in Early Diabetes.","authors":"Md Imam Uddin","doi":"10.2337/dbi26-0015","DOIUrl":"10.2337/dbi26-0015","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 6","pages":"e17-e18"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD8+ Memory T Cells Encode Obesogenic Memory in White Adipose Tissue.","authors":"Sang Mun Han, Jae Bum Kim","doi":"10.2337/dbi26-0008","DOIUrl":"10.2337/dbi26-0008","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 6","pages":"879-881"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}