Diabetes最新文献

Reduced function of the adaptor SH2B3 promotes T1D via altered cytokine-regulated, T cell intrinsic immune tolerance

IF 7.7 1区医学

Diabetes Pub Date : 2025-03-06 DOI: 10.2337/db24-0655

Taylor K. Watson, Aaron B.I. Rosen, Travis Drow, Jacob A. Medjo, Matthew A. MacQuivey, Yan Ge, H. Denny Liggitt, Dane A. Grosvenor, Kimberly A. Dill-McFarland, Matthew C. Altman, Patrick J. Concannon, Jane H. Buckner, David J. Rawlings, Eric J. Allenspach

{"title":"Reduced function of the adaptor SH2B3 promotes T1D via altered cytokine-regulated, T cell intrinsic immune tolerance","authors":"Taylor K. Watson, Aaron B.I. Rosen, Travis Drow, Jacob A. Medjo, Matthew A. MacQuivey, Yan Ge, H. Denny Liggitt, Dane A. Grosvenor, Kimberly A. Dill-McFarland, Matthew C. Altman, Patrick J. Concannon, Jane H. Buckner, David J. Rawlings, Eric J. Allenspach","doi":"10.2337/db24-0655","DOIUrl":"https://doi.org/10.2337/db24-0655","url":null,"abstract":"Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D. Fine mapping has demonstrated the most credible causative variant is the single nucleotide rs3184504*T polymorphism in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T cellintrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling. SH2B3 deficient naïve CD8+ T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the RIP-mOVA model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival and reduced activation-induced cell death. Lastly, we created a spontaneous NOD.Sh2b3-/- mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T cell tolerance limiting the T cell response to self-antigens.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"30 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570350","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}

引用次数: 0

Regulation of Type 1 Diabetes via Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2

IF 7.7 1区医学

Diabetes Pub Date : 2025-03-03 DOI: 10.2337/db24-1003

Jeongmin Lee, Alessandro Ustione, Emily M Wilkerson, Rekha Balakrishnan, Debbie C. Thurmond, Dennis Goldfarb, David W. Piston

{"title":"Regulation of Type 1 Diabetes via Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2","authors":"Jeongmin Lee, Alessandro Ustione, Emily M Wilkerson, Rekha Balakrishnan, Debbie C. Thurmond, Dennis Goldfarb, David W. Piston","doi":"10.2337/db24-1003","DOIUrl":"https://doi.org/10.2337/db24-1003","url":null,"abstract":"Current treatments for type 1 diabetes (T1D) focus on insulin replacement. We demonstrate the therapeutic potential of a secreted protein fraction from embryonic brown adipose tissue (BAT) that mediates insulin receptor-dependent recovery of euglycemia in a T1D model, nonobese diabetic (NOD) mice, by suppressing glucagon secretion. This fraction promotes white adipocyte differentiation and browning, maintains healthy BAT, and enhances glucose uptake in adipose tissue, skeletal muscle, and liver. We identify nidogen-2 as a critical BAT-secreted protein that reverses hyperglycemia in NOD mice, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the entire secreted fraction. Secretions from a BAT cell line with siRNA knockdown of nidogen-2 fail to inhibit glucagon secretion and restore euglycemia. These findings demonstrate that BAT-secreted peptides represent a novel therapeutic approach to diabetes management. Furthermore, our research reveals a novel signaling role for nidogen-2, beyond its traditional classification as an extracellular matrix protein.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"40 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538392","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}

引用次数: 0

Intermittent Low-Magnitude Pressure Applied Across Macroencapsulation Devices Enables Physiological Insulin Delivery Dynamics

IF 7.7 1区医学

Diabetes Pub Date : 2025-03-03 DOI: 10.2337/db24-0818

Ella A. Thomson, Sooyeon Lee, Haixia Xu, Hannah Moeller, Joanna Sands, Rayhan A. Lal, Justin P. Annes, Ada S. Y. Poon

{"title":"Intermittent Low-Magnitude Pressure Applied Across Macroencapsulation Devices Enables Physiological Insulin Delivery Dynamics","authors":"Ella A. Thomson, Sooyeon Lee, Haixia Xu, Hannah Moeller, Joanna Sands, Rayhan A. Lal, Justin P. Annes, Ada S. Y. Poon","doi":"10.2337/db24-0818","DOIUrl":"https://doi.org/10.2337/db24-0818","url":null,"abstract":"Cadaveric islet and stem cell-derived transplantation hold promise as treatments for type 1 diabetes (T1D). To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques that utilize diffusion to transport insulin across an immunoisolating barrier have been developed. However, despite several devices progressing to human clinical trials, none have successfully attained physiologic glucose control or insulin independence. Based on empirical evidence, macroencapsulation methods with multilayered, high islet surface density are incompatible with on-demand insulin delivery and physiologic glucose regulation, when solely reliant on diffusion. An additional driving force is essential to overcome the distance limit of diffusion. In this study, we present both theoretical evidence and experimental validation that applying pressure, at levels comparable to physiological diastolic blood pressure, significantly enhances insulin flux across immunoisolation membranes—increasing it by nearly three orders of magnitude. This significant enhancement in transport rate allows for precise, sub-minute regulation of both bolus and basal insulin delivery. By incorporating this technique with a pumpbased extravascular system, we demonstrate the ability to rapidly reduce glucose levels in diabetic rodent models, replicating the timescale and therapeutic effect of subcutaneous insulin injection or infusion. This advance provides a potential path towards achieving insulin independence with islet macroencapsulation.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"34 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538391","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}

引用次数: 0

Antihypertensive drug amlodipine besylate shows potential in alleviating diabetic peripheral neuropathy

IF 7.7 1区医学

Diabetes Pub Date : 2025-02-28 DOI: 10.2337/db24-0403

Yuxi Wei, Yujie Huang, Runzhi Huang, Yuan Ruan, Tian Feng, Fan Zhou, Wei Zhang, Jianyu Lu, Sujie Xie, Yuntao Yao, Jiaying Wang, Shizhao Ji, Xu Shen

{"title":"Antihypertensive drug amlodipine besylate shows potential in alleviating diabetic peripheral neuropathy","authors":"Yuxi Wei, Yujie Huang, Runzhi Huang, Yuan Ruan, Tian Feng, Fan Zhou, Wei Zhang, Jianyu Lu, Sujie Xie, Yuntao Yao, Jiaying Wang, Shizhao Ji, Xu Shen","doi":"10.2337/db24-0403","DOIUrl":"https://doi.org/10.2337/db24-0403","url":null,"abstract":"Diabetic peripheral neuropathy (DPN) is a common diabetic complication with no currently available curative treatments. Here, we demonstrated that the protein level of G-protein-coupled receptor 40 (GPR40) is significantly repressed in the sciatic nerves (SN) of DPN patients, as well as in the peripheral nerves, including dorsal root ganglia (DRG) and SN, of streptozotocin (STZ)-induced type 1 diabetic mice and BKS Cg-m+/+Lepr db/J (db/db) type 2 diabetic mice. We identified that amlodipine besylate (AB), a first-line clinical antihypertensive drug, as a GPR40 agonist capable of alleviating DPN-like pathologies in mice. These pathologies include neurological damage, destruction of myelin sheath structures, vascular injury, loss of intraepidermal nerve fibers, and impaired neurite outgrowth in DRG neurons. To elucidate the underlying mechanisms, we generated the DPN mice with GPR40-specific knockdown in SN and DRG tissues using adeno associated virus 8-GPR40-RNAi. Mechanistically, AB attenuated inflammatory responses via the GPR40/β-arrestin2/NLRP3 pathway and ameliorated mitochondrial dysfunction through the GPR40/LKB1/AMPK/SIRT1/PGC-1α pathway in DPN mice, which were all further validated in primary human Schwann cells. Additionally, AB suppressed the crosstalk between Schwann cells and endothelial cells /DRG neurons in DPN mice. Collectively, our findings highlight the potential of AB for the treatment of DPN.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"26 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526430","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}

引用次数: 0

Development of the Insulin Radioimmunoassay, the Watershed Moment in Diabetes Research: Revisiting 1960 Diabetes Classics by Berson and Yalow

IF 7.7 1区医学

Diabetes Pub Date : 2025-02-20 DOI: 10.2337/dbi24-0055

David A. D’Alessio

引用次数: 0

Lrtm1 - A Novel Sensor of Insulin Signaling and Regulator of Metabolism and Activity Lrtm1 - 胰岛素信号的新型传感器以及代谢和活动的调节器

IF 7.7 1区医学

Diabetes Pub Date : 2025-02-07 DOI: 10.2337/db24-1031

Yingying Yu, Guoxiao Wang, Wenqiang Chen, Xiangyu Liu, Vitor Rosetto Munoz, Weikang Cai, Antonio S. Gomes, C. Ronald Kahn

引用次数: 0

Atf4 protects islet β-cell identity and function under acute glucose-induced stress but promotes β-cell failure in the presence of free fatty acid

IF 7.7 1区医学

Diabetes Pub Date : 2025-02-03 DOI: 10.2337/db24-0360

Mahircan Yagan, Sadia Najam, Ruiying Hu, Yu Wang, Mathew Dickerson, Prasanna Dadi, Yanwen Xu, Alan J. Simmons, Roland Stein, Christopher M. Adams, David A. Jacobson, Ken S. Lau, Qi Liu, Guoqiang Gu

{"title":"Atf4 protects islet β-cell identity and function under acute glucose-induced stress but promotes β-cell failure in the presence of free fatty acid","authors":"Mahircan Yagan, Sadia Najam, Ruiying Hu, Yu Wang, Mathew Dickerson, Prasanna Dadi, Yanwen Xu, Alan J. Simmons, Roland Stein, Christopher M. Adams, David A. Jacobson, Ken S. Lau, Qi Liu, Guoqiang Gu","doi":"10.2337/db24-0360","DOIUrl":"https://doi.org/10.2337/db24-0360","url":null,"abstract":"Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in β-cells is minimally required for glucose homeostasis in juvenile and adolescent mice but it is needed for β-cell function during aging and under obesity-related metabolic stress. Henceforth, Atf4-deficient β-cells older than 2 months after birth display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced dysfunction and reduced production of several factors essential for β-cell identity. Atf4-deficient β-cells down-regulate genes involved in protein translation. They also upregulate several lipid metabolism or signaling genes, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for β-cell identity and function under high glucose. But Atf4 activation paradoxically induces β-cell failure in high levels of free fatty acids. Different transcriptional targets of Atf4 could be manipulated to protect β-cells from metabolic stress-induced failure.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083440","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}

引用次数: 0

Deubiquitinating enzyme USP2 alleviates muscle atrophy by stabilizing PPARγ

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-28 DOI: 10.2337/db24-0375

Shu Yang, Lijiao Xiong, Tingfeng Liao, Lixing Li, Yanchun Li, Lin Kang, Guangyan Yang, Zhen Liang

{"title":"Deubiquitinating enzyme USP2 alleviates muscle atrophy by stabilizing PPARγ","authors":"Shu Yang, Lijiao Xiong, Tingfeng Liao, Lixing Li, Yanchun Li, Lin Kang, Guangyan Yang, Zhen Liang","doi":"10.2337/db24-0375","DOIUrl":"https://doi.org/10.2337/db24-0375","url":null,"abstract":"Insulin resistance, a hallmark of type 2 diabetes, accelerates muscle breakdown and impairs energy metabolism. However, the role of Ubiquitin Specific Peptidase 2 (USP2), a key regulator of insulin resistance, in sarcopenia remains unclear. Peroxisome proliferator activated receptor γ (PPARγ) plays a critical role in regulating muscle atrophy. This study investigates the role of deubiquitinase USP2 in mitigating muscle atrophy. Our findings revealed reduced USP2 expression in skeletal muscles of patients with type 2 diabetes. In mouse models of diabetes- and dexamethasone (DEX)-induced muscle atrophy, USP2 expression was downregulated in skeletal muscles. Usp2 knockout exacerbated muscle loss and functional impairment induced by diabetes or DEX. Moreover, skeletal muscle-specific Usp2 knockout further aggravated muscle loss and functional impairment induced by diabetes. Local injection of AAV-Usp2 into the gastrocnemius muscles of diabetic mice increased muscle mass, and improved skeletal muscle performance and endurance. It enhanced insulin sensitivity in diabetic mice, shown by lower fasting serum glucose and insulin levels and better glucose tolerance. Mechanistic analysis showed USP2 directly interacted with PPARγ by deubiquitinating it, stabilizing its protein levels, enhancing insulin signaling and sensitivity, and maintaining muscle mass. Loss of PPARγ abolishes the regulatory effects of USP2 on insulin sensitivity and muscle atrophy. MYOD1 activates USP2 transcription by binding to its promoter region. This study demonstrates the protective role of USP2 in mitigating muscle atrophy by stabilizing PPARγ through deubiquitination, particularly in models of diabetic and DEX-induced muscle atrophy. Targeting the USP2-PPARγ axis may offer promising therapeutic strategies for metabolic disorders and sarcopenia.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"24 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054960","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}

引用次数: 0

An alternatively translated isoform of PPARG proposes AF-1 domain inhibition as an insulin sensitization target

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-24 DOI: 10.2337/db24-0497

Xiaomi Du, Karen Mendez-Lara, Siqi Hu, Rachel Diao, Guru Bhavimani, Ruben Hernandez, Kimberly Glass, Camila De Arruda Saldanha, Jason Flannick, Sven Heinz, Amit R. Majithia

{"title":"An alternatively translated isoform of PPARG proposes AF-1 domain inhibition as an insulin sensitization target","authors":"Xiaomi Du, Karen Mendez-Lara, Siqi Hu, Rachel Diao, Guru Bhavimani, Ruben Hernandez, Kimberly Glass, Camila De Arruda Saldanha, Jason Flannick, Sven Heinz, Amit R. Majithia","doi":"10.2337/db24-0497","DOIUrl":"https://doi.org/10.2337/db24-0497","url":null,"abstract":"PPARγ is the pharmacological target of thiazolidinediones (TZDs), potent insulin sensitizers that prevent metabolic disease morbidity but are accompanied by side effects such as weight gain, in part due to non-physiological transcriptional agonism. Using high throughput genome engineering, we targeted nonsense mutations to every exon of PPARG, finding an ATG in Exon 2 (chr3:12381414, CCDS2609 c.A403) that functions as an alternative translational start site. This downstream translation initiation site gives rise to a PPARγ protein isoform (M135), preferentially generated from alleles containing nonsense mutations upstream of c.A403. PPARγ M135 retains the DNA and ligand binding domains of full-length PPARγ but lacks the N-terminal AF-1 domain. Despite being truncated, PPARγ M135 shows increased transactivation of target genes, but only in the presence of agonists. Accordingly, human missense mutations disrupting AF-1 domain function actually increase agonist-induced cellular PPARγ activity compared to wild-type (WT), and carriers of these AF-1 disrupting variants are protected from metabolic syndrome. Thus, we propose the existence of PPARγ M135 as a fully functional, alternatively translated isoform that may be therapeutically generated to treat insulin resistance-related disorders.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"36 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031085","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}

引用次数: 0

Homeobox C4 transcription factor promotes adipose tissue thermogenesis

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-24 DOI: 10.2337/db24-0675

Ting Yang, Yuxuan Wang, Hang Li, Fengshou Shi, Siqi Xu, Yingting Wu, Jiaqi Xin, Yi Liu, Mengxi Jiang

{"title":"Homeobox C4 transcription factor promotes adipose tissue thermogenesis","authors":"Ting Yang, Yuxuan Wang, Hang Li, Fengshou Shi, Siqi Xu, Yingting Wu, Jiaqi Xin, Yi Liu, Mengxi Jiang","doi":"10.2337/db24-0675","DOIUrl":"https://doi.org/10.2337/db24-0675","url":null,"abstract":"The homeobox (HOX) family has shown potential in adipose development and function, yet the specific HOX proteins fueling adipose thermogenesis remain elusive. In this study, we uncovered the novel function of HOXC4 in stimulating adipose thermogenesis. Our bioinformatic analysis indicated an enrichment of Hoxc4 co-expressed genes in metabolic pathways and linked HOXC4 polymorphisms to metabolic parameters, suggesting its involvement in metabolic regulation. In mouse brown adipose tissue, HOXC4 expression negatively correlated with body weight and positively correlated with Ucp1 expression. Through gain- and loss-of-function experiments in mice, we established that HOXC4 is both sufficient and necessary for adipose thermogenesis, leading to enhanced cold tolerance and protection against diet-induced obesity and insulin resistance. Human and mouse primary adipocyte models further confirmed that the thermogenic activation function of HOXC4 is cell-autonomous. Mechanistically, HOXC4 collaborates with cofactor NCOA1 via its hexapeptide motif to form a transcriptional complex at the Ucp1 promoter, thereby promoting Ucp1 transcription and adipose thermogenesis. These findings delineate a novel mechanism by which HOXC4 drives thermogenic transcription and adipose energy metabolism, offering potential therapeutic targets for obesity-related metabolic disorders.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"61 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031303","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}

引用次数: 0