Publications

@article{Yi2025,

title = {Transcriptomics of autoimmune diseases identifies FGFR1 as a target for pancreatic β-cell protection},

author = {Xiaoyan Yi and Priscila L. Zimath and Eugenia Martin-Vazquez and Junior Garcia Oliveira and Sayro Jawurek and Alexandra C. Title and Burcak Yesildag and Nizar I. Mourad and Antoine Buemi and François Pattou and Julie Kerr-Conte and Sabine Costagliola and Mírian Romitti and Decio L. Eizirik},

doi = {10.1016/j.jaut.2025.103469},

issn = {0896-8411},

year  = {2025},

date = {2025-09-00},

journal = {Journal of Autoimmunity},

volume = {156},

publisher = {Elsevier BV},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lytrivi2025,

title = {Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells},

author = {Maria Lytrivi and Yue Tong and Enrico Virgilio and Xiaoyan Yi and Miriam Cnop},

doi = {10.1038/s41574-025-01129-5},

issn = {1759-5037},

year  = {2025},

date = {2025-06-04},

journal = {Nat Rev Endocrinol},

publisher = {Springer Science and Business Media LLC},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Costa-Junior2025,

title = {Exercise-induced meteorin-like protein protects human pancreatic beta cells from cytokine-induced apoptosis},

author = {José Maria Costa-Junior and Alexandra Coomans de Brachène and Anyïshai E. Musuaya and Priscila L. Zimath and Eugenia Martin-Vazquez and Junior G. Oliveira and Julie Carpentier and Vitalie Faoro and Malgorzata Klass and Miriam Cnop and Decio L. Eizirik},

doi = {10.1007/s00125-025-06426-2},

issn = {1432-0428},

year  = {2025},

date = {2025-04-12},

journal = {Diabetologia},

publisher = {Springer Science and Business Media LLC},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40162226,

title = {The type 1 diabetes candidate genes PTPN2 and BACH2 regulate novel IFN-α-induced crosstalk between the JAK/STAT and MAPKs pathways in human beta cells},

author = {Arturo Roca Rivada and Junior Garcia de Oliveira and Maria Eugenia Martin-Vazquez Garcia and Alexandra Coomans de Brachene and Xiaoyan Yi and Jose Costa Junior and Priscila Zimath and Flore Van Goethem and François Pattou and Julie Kerr-Conte and Antoine Buemi and Nizar Mourad and Décio Eizirik},

doi = {10.21203/rs.3.rs-6079043/v1},

issn = {2693-5015},

year  = {2025},

date = {2025-03-01},

journal = {Res Sq},

abstract = {Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to the progressive loss of pancreatic beta cells. Interferons (IFNs) contribute to the initiation and amplification of beta cell autoimmunity. STAT1 is the main mediator of IFN signalling but little is known on its complex activation processes and role in the progression of beta cell failure. We presently show that two T1D candidate genes (i.e.  and  ) modulate STAT1 activation via two different pathways, namely the JAK/STAT, involved in the short-term phosphorylation of its tyrosine residue (Y701), and the MAPKs pathway, involved in the long-term phosphorylation of its serine residue (S727). Each STAT1 phosphorylation type can independently induce expression of the chemokine  , but both residues are necessary for the expression of MHC class I molecules. IFN-α-induced STAT1 activation is dynamic and residue-dependent, being STAT1-Y701 fast (detectable after 4h) but transitory (back to basal by 24h) while STAT1-S727 increases slowly (peak at 48h) and is associated with the long-term effects of IFN-α exposure. These pathways can be chemically dissociated in human beta cells by the use of JAK1/2, TYK2 or JNK1 inhibitors. The present findings provide a novel understanding of the dynamics of STAT1 activation and will be useful to develop novel and hopefully targeted (i.e. favouring individuals with particular polymorphisms) therapies for T1D and other autoimmune diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39824805,

title = {Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells},

author = {Alexia Carré and Fatoumata Samassa and Zhicheng Zhou and Javier Perez-Hernandez and Christiana Lekka and Anthony Manganaro and Masaya Oshima and Hanqing Liao and Robert Parker and Annalisa Nicastri and Barbara Brandao and Maikel L Colli and Decio L Eizirik and Jahnavi Aluri and Deep Patel and Marcus Göransson and Orlando Burgos Morales and Amanda Anderson and Laurie Landry and Farah Kobaisi and Raphael Scharfmann and Lorella Marselli and Piero Marchetti and Sylvaine You and Maki Nakayama and Sine R Hadrup and Sally C Kent and Sarah J Richardson and Nicola Ternette and Roberto Mallone},

doi = {10.1038/s41467-025-55908-9},

issn = {2041-1723},

year  = {2025},

date = {2025-01-01},

journal = {Nat Commun},

volume = {16},

number = {1},

pages = {765},

abstract = {Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8 T cells. Lastly, islets of patients with T1D show preferential HLA-B hyper-expression when compared with non-diabetic donors, and islet-infiltrating CD8 T cells reactive to HLA-B-restricted granule peptides are found in T1D donors. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward alternative epitopes presented by HLA-B, hence recruiting T cells with a distinct repertoire that may be relevant to T1D pathogenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{PIRON2025101004,

title = {Identification of novel type 1 and type 2 diabetes genes by co-localization of human islet eQTL and GWAS variants with colocRedRibbon},

author = {Anthony Piron and Florian Szymczak and Lise Folon and Daniel J. M. Crouch and Theodora Papadopoulou and Maria Lytrivi and Yue Tong and Maria Inês Alvelos and Maikel L. Colli and Xiaoyan Yi and Marcin L. Pekalski and Konstantinos Hatzikotoulas and Alicia Huerta-Chagoya and Henry J. Taylor and Matthieu Defrance and John A. Todd and Décio L. Eizirik and Josep M. Mercader and Miriam Cnop},

url = {https://www.sciencedirect.com/science/article/pii/S2666979X25002605},

doi = {https://doi.org/10.1016/j.xgen.2025.101004},

issn = {2666-979X},

year  = {2025},

date = {2025-01-01},

journal = {Cell Genomics},

pages = {101004},

abstract = {Summary 

Over 1,000 genetic variants have been associated with diabetes by genome-wide association studies (GWASs), but for most, their functional impact is unknown; only 7% alter gene expression in pancreatic islets in expression quantitative trait locus (eQTL) studies. To fill this gap, we developed a co-localization pipeline, colocRedRibbon, that prefilters eQTLs by the direction of effect on gene expression and shortlists overlapping eQTL and GWAS variants prior to co-localization. Applying colocRedRibbon to recent diabetes and glycemic trait GWASs, we identified 292 co-localizing gene regions, including 24 co-localizations for type 1 diabetes and 268 for type 2 diabetes and glycemic traits, representing a 4-fold increase. A low-frequency type 2 diabetes protective variant increases islet MYO5C expression, and a type 1 diabetes protective variant increases FUT2 expression. These novel co-localizations advance the understanding of diabetes genetics and its impact on human islet biology. colocRedRibbon has broad applicability to co-localize GWASs and various QTLs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ROCARIVADA2025105932,

title = {The type 1 diabetes candidate genes PTPN2 and BACH2 regulate the IFN-α-induced crosstalk between JAK/STAT and MAPKs pathways in human beta cells},

author = {Arturo Roca-Rivada and Junior Garcia Oliveira and Eugenia Martin-Vazquez and Alexandra Coomans Brachène and Xiaoyan Yi and Jose Maria Costa-Júnior and Priscila L. Zimath and Flore Van Goethem and François Pattou and Julie Kerr-Conte and Antoine Buemi and Nizar I. Mourad and Decio L. Eizirik},

url = {https://www.sciencedirect.com/science/article/pii/S2352396425003767},

doi = {https://doi.org/10.1016/j.ebiom.2025.105932},

issn = {2352-3964},

year  = {2025},

date = {2025-01-01},

journal = {eBioMedicine},

volume = {120},

pages = {105932},

abstract = {Summary 

Background 

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to the progressive loss of pancreatic beta cells. Interferons (IFNs) contribute to the initiation and amplification of beta cell autoimmunity. STAT1 is the main mediator of IFN signalling but little is known about its complex activation processes and role in the progression of beta cell failure. 

Methods 

We investigated the IFN-α-stimulated STAT1 pathway from three human beta cell models: EndoC-βH1 cells, iPSC-derived islet-like cells and human islets by directly targeting two T1D candidate genes, namely PTPN2 and BACH2. 

Findings 

We presently show that PTPN2 and BACH2 modulate STAT1 activation via two different pathways, namely the JAK/STAT, involved in the phosphorylation of its tyrosine residue (Y701), and the MAPKs pathway, involved in the phosphorylation of its serine residue (S727). Each STAT1 phosphorylation type can independently induce expression of CXCL10, but both residues are necessary for the expression of MHC class I molecules. IFN-α-induced STAT1 activation is dynamic and residue-dependent, being STAT1-Y701 fast but transitory, while STAT1-S727 increases slowly and is associated with the long-term effects of IFN-α exposure. 

Interpretation 

The present findings provide a better understanding of the dynamics of STAT1 activation in human beta cells and will be useful to develop new and targeted (i.e. favouring individuals with particular polymorphisms) therapies for T1D and other autoimmune diseases. 

Funding 

EFSD and Sanofi European Diabetes Research Programme on autoimmunity in type 1 diabetes; Breakthrough T1D, HIRN-CBDS, NIDDK, Fondation Saint-Luc, Programme d’Investissement d’Avenir’ to European Genomic Institute for Diabetes, and Fondation de la Recherche Médicale.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bonfim2024,

title = {The N6-methyladenosine RNA epigenetic modification modulates the amplification of coxsackievirus B1 in human pancreatic beta cells},

author = {Maressa Fernandes Bonfim and Camille Aitchedji and Flore Van Goethem and Lionel Sauvage and Thibault Poinsot and Emilie Calonne and Rachel Deplus and François Fuks and Decio L. Eizirik and Anne Op de Beeck},

doi = {10.3389/fmicb.2024.1501061},

issn = {1664-302X},

year  = {2024},

date = {2024-12-18},

journal = {Front. Microbiol.},

volume = {15},

publisher = {Frontiers Media SA},

abstract = {Type 1 diabetes (T1D) is characterized by a prolonged autoimmune attack resulting in the massive loss of insulin-producing beta cells. The initiation and progression of T1D depends on a complex interaction between genetic, immunological and environmental factors. Epidemiological, experimental and clinical evidence suggest a link between viral infections, particularly Coxsackievirus type B (CVB), and T1D development. Specifically, infections by the CVB serotype 1 (CVB1) contribute to the triggering of autoimmunity against beta cells in genetically predisposed individuals, and prolonged and probably non-lytic infections by CVB are associated with the development of T1D. However, the molecular mechanisms underlying CVB1 replication and establishing persistent infections in human pancreatic beta cells remain poorly understood. Here we show that the N6-methyladenosine (m6A) RNA epigenetic modification machinery regulates CVB1 amplification in the human beta cells. Using small interfering RNA (siRNA) targeting m6A writers and erasers, we observed that downregulation of m6A writers increases CVB1 amplification, while the downregulation of m6A erasers decreases it. Notably, the inhibition of Fat Mass and Obesity-associated protein (FTO), a key m6A eraser, reduced by 95% the production of infectious CVB1 in both human insulin-producing EndoC-βH1 cells and in induced pluripotent stem cell (iPSC)-derived islets. The FTO inhibitor reduced CVB1 expression within 6 h post-infection, suggesting a direct regulation of the CVB1 genome by m6A modification. Furthermore, in the absence of viral replication, FTO inhibition also decreased the translation of the incoming CVB1 genome, indicating that m6A plays a critical role in the initial stages of viral RNA translation. In addition, modulation of the m6A machinery affected the type I interferon response after poly-IC transfection, a mimic of RNA virus replication, but did not affect the cellular antiviral response in CVB1-infected cells. Altogether, these observations suggest that m6A directly affects CVB1 production. Our study provides the first evidence that the m6A epigenetic modification machinery controls CVB amplification in human pancreatic beta cells. This suggests that the m6A machinery is a potential target to control CVB infection in T1D and raises the possibility of an epigenetic control in the establishment of persistent CVB infections observed in the pancreas in individuals with type 1 diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39702941,

title = {LRH-1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype},

author = {Nadia Cobo-Vuilleumier and Silvia Rodríguez-Fernandez and Livia López-Noriega and Petra I Lorenzo and Jaime M Franco and Christian C Lachaud and Eugenia Martin Vazquez and Raquel Araujo Legido and Akaitz Dorronsoro and Raul López-Férnandez-Sobrino and Beatriz Fernández-Santos and Carmen Espejo Serrano and Daniel Salas-Lloret and Nila van Overbeek and Mireia Ramos-Rodriguez and Carmen Mateo-Rodríguez and Lucia Hidalgo and Sandra Marin-Canas and Rita Nano and Ana I Arroba and Antonio Campos Caro and Alfred Co Vertegaal and Alejandro Martin-Montalvo and Franz Martín and Manuel Aguilar-Diosdado and Lorenzo Piemonti and Lorenzo Pasquali and Roman González Prieto and Maria Isabel García Sánchez and Decio L Eizirik and Maria Asuncion Martínez-Brocca and Marta Vives-Pi and Benoit R Gauthier},

doi = {10.1002/ctm2.70134},

issn = {2001-1326},

year  = {2024},

date = {2024-12-01},

journal = {Clin Transl Med},

volume = {14},

number = {12},

pages = {e70134},

abstract = {BACKGROUND: The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross-talk between the immune system and insulin-producing beta cells, has hindered the development of effective disease-modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH-1/NR5A2 activation and improve islet survival.nnMETHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH-1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T-cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001-target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co-cultures of PBMCs and iPSCs-derived islet organoids were performed to assess the impact of BL001 on beta cell viability.nnRESULTS: LRH-1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro-inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro-inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro-inflammatory to an anti-inflammatory/tolerogenic state, resulting in the inhibition of CD4 and CD8 T-cell proliferation. BL001 treatment also increased CD4/CD25/FoxP3 regulatory T-cells and Th2 cells within PBMCs while decreasing CD8+ T-cell proliferation. Additionally, BL001 alleviated PBMC-induced apoptosis and maintained insulin expression in human iPSC-derived islet organoids.nnCONCLUSION: These findings demonstrate the potential of LRH-1/NR5A2 activation to modulate immune responses and support beta cell viability in T1D, suggesting a new therapeutic approach.nnKEY POINTS: LRH-1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro-inflammatory cell surface markers and cytokine release. LRH-1/NR5A2 promotes a mitohormesis-induced immuno-resistant phenotype to pro-inflammatory macrophages. Mature dendritic cells acquire a tolerogenic phenotype via LRH-1/NR5A2-stimulated mitochondria turnover. LRH-1/NR5A2 agonistic activation expands a CD4/CD25/FoxP3 T-cell subpopulation. Pharmacological activation of LRH-1/NR5A2 improves the survival iPSC-islets-like organoids co-cultured with PBMCs from individuals with T1D.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sarkar2024,

title = {Regulation of β-cell death by ADP-ribosylhydrolase ARH3 via lipid signaling in insulitis},

author = {Soumyadeep Sarkar and Cailin Deiter and Jennifer E. Kyle and Michelle A. Guney and Dylan Sarbaugh and Ruichuan Yin and Xiangtang Li and Yi Cui and Mireia Ramos-Rodriguez and Carrie D. Nicora and Farooq Syed and Jonas Juan-Mateu and Charanya Muralidharan and Lorenzo Pasquali and Carmella Evans-Molina and Decio L. Eizirik and Bobbie-Jo M. Webb-Robertson and Kristin Burnum-Johnson and Galya Orr and Julia Laskin and Thomas O. Metz and Raghavendra G. Mirmira and Lori Sussel and Charles Ansong and Ernesto S. Nakayasu},

doi = {10.1186/s12964-023-01437-1},

issn = {1478-811X},

year  = {2024},

date = {2024-12-00},

journal = {Cell Commun Signal},

volume = {22},

number = {1},

publisher = {Springer Science and Business Media LLC},

abstract = {Abstract

                Background

                Lipids are regulators of insulitis and β-cell death in type 1 diabetes development, but the underlying mechanisms are poorly understood. Here, we investigated how the islet lipid composition and downstream signaling regulate β-cell death.

              

                Methods

                We performed lipidomics using three models of insulitis: human islets and EndoC-βH1 β cells treated with the pro-inflammatory cytokines interlukine-1β and interferon-γ, and islets from pre-diabetic non-obese mice. We also performed mass spectrometry and fluorescence imaging to determine the localization of lipids and enzyme in islets. RNAi, apoptotic assay, and qPCR were performed to determine the role of a specific factor in lipid-mediated cytokine signaling.

              

                Results

                Across all three models, lipidomic analyses showed a consistent increase of lysophosphatidylcholine species and phosphatidylcholines with polyunsaturated fatty acids and a reduction of triacylglycerol species. Imaging assays showed that phosphatidylcholines with polyunsaturated fatty acids and their hydrolyzing enzyme phospholipase PLA2G6 are enriched in islets. In downstream signaling, omega-3 fatty acids reduce cytokine-induced β-cell death by improving the expression of ADP-ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-mediated reduction of the histone methylation polycomb complex PRC2 component Suz12, upregulating the expression of Arh3, which in turn decreases cell apoptosis.

              

                Conclusions

                Our data provide insights into the change of lipidomics landscape in β cells during insulitis and identify a protective mechanism by omega-3 fatty acids.

                

              },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39508879,

title = {Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8 T cell activity and biomarker during the evolution of type 1 diabetes},

author = {Chaitra Rao and Daniel T Cater and Saptarshi Roy and Jerry Xu and Andre G De Oliveira and Carmella Evans-Molina and Jon D Piganelli and Decio L Eizirik and Raghavendra G Mirmira and Emily K Sims},

doi = {10.1007/s00125-024-06313-2},

issn = {1432-0428},

year  = {2024},

date = {2024-11-01},

journal = {Diabetologia},

abstract = {AIMS/HYPOTHESIS: Surviving beta cells in type 1 diabetes respond to inflammation by upregulating programmed death-ligand 1 (PD-L1) to engage immune cell programmed death protein 1 (PD-1) and limit destruction by self-reactive immune cells. Extracellular vesicles (EVs) and their cargo can serve as biomarkers of beta cell health and contribute to islet intercellular communication. We hypothesised that the inflammatory milieu of type 1 diabetes increases PD-L1 in beta cell EV cargo and that EV PD-L1 may protect beta cells against immune-mediated cell death.nnMETHODS: Beta cell lines and human islets were treated with proinflammatory cytokines to model the proinflammatory type 1 diabetes microenvironment. EVs were isolated using ultracentrifugation or size exclusion chromatography and analysed via immunoblot, flow cytometry and ELISA. EV PD-L1 binding to PD-1 was assessed using a competitive binding assay and in vitro functional assays testing the ability of EV PD-L1 to inhibit NOD CD8 T cells. Plasma EV and soluble PD-L1 were assayed in the plasma of islet autoantibody-positive (Ab) individuals or individuals with recent-onset type 1 diabetes and compared with levels in non-diabetic control individuals.nnRESULTS: PD-L1 protein co-localised with tetraspanin-associated proteins intracellularly and was detected on the surface of beta cell EVs. Treatment with IFN-α or IFN-γ for 24 h induced a twofold increase in EV PD-L1 cargo without a corresponding increase in the number of EVs. IFN exposure predominantly increased PD-L1 expression on the surface of beta cell EVs and beta cell EV PD-L1 showed a dose-dependent capacity to bind PD-1. Functional experiments demonstrated specific effects of beta cell EV PD-L1 to suppress proliferation and cytotoxicity of murine CD8 T cells. Plasma EV PD-L1 levels were increased in Abindividuals, particularly in those positive for a single autoantibody. Additionally, in Ab individuals or those who had type 1 diabetes, but not in control individuals, plasma EV PD-L1 positively correlated with circulating C-peptide, suggesting that higher EV PD-L1 could be protective for residual beta cell function.nnCONCLUSIONS/INTERPRETATION: IFN exposure increases PD-L1 on the beta cell EV surface. Beta cell EV PD-L1 binds PD1 and inhibits CD8 T cell proliferation and cytotoxicity. Circulating EV PD-L1 is higher in Ab individuals than in control individuals. Circulating EV PD-L1 levels correlate with residual C-peptide at different stages in type 1 diabetes progression. These findings suggest that EV PD-L1 could contribute to heterogeneity in type 1 diabetes progression and residual beta cell function and raise the possibility that EV PD-L1 could be exploited as a means to inhibit immune-mediated beta cell death.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Yi2024,

title = {β‐Cell gene expression stress signatures in types 1 and 2 diabetes},

author = {Xiaoyan Yi and Decio L. Eizirik},

doi = {10.1111/1753-0407.70026},

issn = {1753-0407},

year  = {2024},

date = {2024-11-00},

journal = {Journal of Diabetes},

volume = {16},

number = {11},

publisher = {Wiley},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39103322,

title = {Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function},

author = {Sarah Meulebrouck and Judith Merrheim and Gurvan Queniat and Cyril Bourouh and Mehdi Derhourhi and Mathilde Boissel and Xiaoyan Yi and Alaa Badreddine and Raphaël Boutry and Audrey Leloire and Bénédicte Toussaint and Souhila Amanzougarene and Emmanuel Vaillant and Emmanuelle Durand and Hélène Loiselle and Marlène Huyvaert and Aurélie Dechaume and Victoria Scherrer and Piero Marchetti and Beverley Balkau and Guillaume Charpentier and Sylvia Franc and Michel Marre and Ronan Roussel and Raphaël Scharfmann and Miriam Cnop and Mickaël Canouil and Morgane Baron and Philippe Froguel and Amélie Bonnefond},

doi = {10.1038/s41467-024-51004-6},

issn = {2041-1723},

year  = {2024},

date = {2024-08-01},

journal = {Nat Commun},

volume = {15},

number = {1},

pages = {6627},

abstract = {Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38914291,

title = {Untangling the genetics of beta cell dysfunction and death in type 1 diabetes},

author = {Catherine C Robertson and Ruth M Elgamal and Belle A Henry-Kanarek and Peter Arvan and Shuibing Chen and Sangeeta Dhawan and Decio L Eizirik and John S Kaddis and Golnaz Vahedi and Stephen C J Parker and Kyle J Gaulton and Scott A Soleimanpour},

doi = {10.1016/j.molmet.2024.101973},

issn = {2212-8778},

year  = {2024},

date = {2024-08-01},

journal = {Mol Metab},

volume = {86},

pages = {101973},

abstract = {BACKGROUND: Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing pancreatic beta cells. Over the past two decades, human genetic studies have provided new insight into the etiology of T1D, including an appreciation for the role of beta cells in their own demise.nnSCOPE OF REVIEW: Here, we outline models supported by human genetic data for the role of beta cell dysfunction and death in T1D. We highlight the importance of strong evidence linking T1D genetic associations to bona fide candidate genes for mechanistic and therapeutic consideration. To guide rigorous interpretation of genetic associations, we describe molecular profiling approaches, genomic resources, and disease models that may be used to construct variant-to-gene links and to investigate candidate genes and their role in T1D.nnMAJOR CONCLUSIONS: We profile advances in understanding the genetic causes of beta cell dysfunction and death at individual T1D risk loci. We discuss how genetic risk prediction models can be used to address disease heterogeneity. Further, we present areas where investment will be critical for the future use of genetics to address open questions in the development of new treatment and prevention strategies for T1D.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39072045,

title = {Multi-omics characterization of type 2 diabetes associated genetic variation},

author = {Ravi Mandla and Kim Lorenz and Xianyong Yin and Ozvan Bocher and Alicia Huerta-Chagoya and Ana Luiza Arruda and Anthony Piron and Susanne Horn and Ken Suzuki and Konstantinos Hatzikotoulas and Lorraine Southam and Henry Taylor and Kaiyuan Yang and Karin Hrovatin and Yue Tong and Maria Lytrivi and Nigel W Rayner and James B Meigs and Mark I McCarthy and Anubha Mahajan and Miriam S Udler and Cassandra N Spracklen and Michael Boehnke and Marijana Vujkovic and Jerome I Rotter and Decio L Eizirik and Miriam Cnop and Heiko Lickert and Andrew P Morris and Eleftheria Zeggini and Benjamin F Voight and Josep M Mercader},

doi = {10.1101/2024.07.15.24310282},

year  = {2024},

date = {2024-07-01},

journal = {medRxiv},

abstract = {Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 -effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits. We identified 773 of these - and distal-effector genes using either expression QTL data from understudied ancestry groups or inclusion of T2D index variants enriched in underrepresented populations, emphasizing the value of increasing population diversity in functional mapping. Linking these variants, genes, metabolites, and traits into a network, we elucidated mechanisms through which T2D-associated variation may impact disease risk. Finally, we showed that drugs targeting effector proteins were enriched in those approved to treat T2D, highlighting the potential of these results to prioritize drug targets for T2D. These results represent a leap in the molecular characterization of T2D-associated genetic variation and will aid in translating genetic findings into novel therapeutic strategies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38833073,

title = {Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer's disease pathology progression},

author = {Kunie Ando and Fahri Küçükali and Emilie Doeraene and Siranjeevi Nagaraj and Eugenia Maria Antonelli and May Thazin Htut and Zehra Yilmaz and Andreea-Claudia Kosa and Lidia Lopez-Guitierrez and Carolina Quintanilla-Sánchez and Emmanuel Aydin and Ana Raquel Ramos and Salwa Mansour and Sabrina Turbant and Stéphane Schurmans and Kristel Sleegers and Christophe Erneux and Jean-Pierre Brion and Karelle Leroy and },

doi = {10.1007/s00401-024-02745-7},

issn = {1432-0533},

year  = {2024},

date = {2024-06-01},

journal = {Acta Neuropathol},

volume = {147},

number = {1},

pages = {94},

abstract = {A recent large genome-wide association study has identified EGFR (encoding the epidermal growth factor EGFR) as a new genetic risk factor for late-onset AD. SHIP2, encoded by INPPL1, is taking part in the signalling and interactome of several growth factor receptors, such as the EGFR. While INPPL1 has been identified as one of the most significant genes whose RNA expression correlates with cognitive decline, the potential alteration of SHIP2 expression and localization during the progression of AD remains largely unknown. Here we report that gene expression of both EGFR and INPPL1 was upregulated in AD brains. SHIP2 immunoreactivity was predominantly detected in plaque-associated astrocytes and dystrophic neurites and its increase was correlated with amyloid load in the brain of human AD and of 5xFAD transgenic mouse model of AD. While mRNA of INPPL1 was increased in AD, SHIP2 protein undergoes a significant solubility change being depleted from the soluble fraction of AD brain homogenates and co-enriched with EGFR in the insoluble fraction. Using FRET-based flow cytometry biosensor assay for tau-tau interaction, overexpression of SHIP2 significantly increased the FRET signal while siRNA-mediated downexpression of SHIP2 significantly decreased FRET signal. Genetic association analyses suggest that some variants in INPPL1 locus are associated with the level of CSF pTau. Our data support the hypothesis that SHIP2 is an intermediate key player of EGFR and AD pathology linking amyloid and tau pathologies in human AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38895427b,

title = {Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice},

author = {Charanya Muralidharan and Fei Huang and Jacob R Enriquez and Jiayi E Wang and Jennifer B Nelson and Titli Nargis and Sarah C May and Advaita Chakraborty and Kayla T Figatner and Svetlana Navitskaya and Cara M Anderson and Veronica Calvo and David Surguladze and Mark J Mulvihill and Xiaoyan Yi and Soumyadeep Sarkar and Scott A Oakes and Bobbie-Jo M Webb-Robertson and Emily K Sims and Kirk A Staschke and Decio L Eizirik and Ernesto S Nakayasu and Michael E Stokes and Sarah A Tersey and Raghavendra G Mirmira},

doi = {10.1101/2023.10.06.561126},

year  = {2024},

date = {2024-06-01},

journal = {bioRxiv},

abstract = {Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eIF2α. In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity. We show that inhibition of the eIF2α kinase PERK, a common component of the UPR and ISR, reverses the mRNA translation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves β cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the UPR and PERK signaling pathways and alterations in antigen processing and presentation pathways in β cells. Spatial proteomics of islets from these mice shows an increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following PERK inhibition in human islets and EndoC-βH1 human β cells, interacts with and stabilizes PD-L1. Collectively, our studies show that PERK activity enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38822524,

title = {PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2},

author = {Chun-Liang Yang and Fa-Xi Wang and Jia-Hui Luo and Shan-Jie Rong and Wan-Ying Lu and Qi-Jie Chen and Jun Xiao and Ting Wang and Dan-Ni Song and Jing Liu and Qian Mo and Shuo Li and Yu Chen and Ya-Nan Wang and Yan-Jun Liu and Tong Yan and Wei-Kuan Gu and Shu Zhang and Fei Xiong and Qi-Lin Yu and Zi-Yun Zhang and Ping Yang and Shi-Wei Liu and Decio Eizirik and Ling-Li Dong and Fei Sun and Cong-Yi Wang},

doi = {10.1016/j.ymthe.2024.05.038},

issn = {1525-0024},

year  = {2024},

date = {2024-05-01},

journal = {Mol Ther},

abstract = {Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide-isomerase A3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein (CRP) level and disease activity score 28 (DAS28). Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor (TCR) signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing Th1 and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Arunagiri2024,

title = {Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis},

author = {Anoop Arunagiri and Maroof Alam and Leena Haataja and Hassan Draz and Bashiyer Alasad and Praveen Samy and Nadeed Sadique and Yue Tong and Ying Cai and Hadis Shakeri and Federica Fantuzzi and Hazem Ibrahim and Insook Jang and Vaibhav Sidarala and Scott A. Soleimanpour and Leslie S. Satin and Timo Otonkoski and Miriam Cnop and Pamela Itkin‐Ansari and Randal J. Kaufman and Ming Liu and Peter Arvan},

doi = {10.1002/pro.4949},

issn = {1469-896X},

year  = {2024},

date = {2024-04-00},

journal = {Protein Science},

volume = {33},

number = {4},

publisher = {Wiley},

abstract = {AbstractPrimary defects in folding of mutant proinsulin can cause dominant‐negative proinsulin accumulation in the endoplasmic reticulum (ER), impaired anterograde proinsulin trafficking, perturbed ER homeostasis, diminished insulin production, and β‐cell dysfunction. Conversely, if primary impairment of ER‐to‐Golgi trafficking (which also perturbs ER homeostasis) drives misfolding of nonmutant proinsulin—this might suggest bi‐directional entry into a common pathological phenotype (proinsulin misfolding, perturbed ER homeostasis, and deficient ER export of proinsulin) that can culminate in diminished insulin storage and diabetes. Here, we've challenged β‐cells with conditions that impair ER‐to‐Golgi trafficking, and devised an accurate means to assess the relative abundance of distinct folded/misfolded forms of proinsulin using a novel nonreducing SDS‐PAGE/immunoblotting protocol. We confirm abundant proinsulin misfolding upon introduction of a diabetogenic INS mutation, or in the islets of db/db mice. Whereas blockade of proinsulin trafficking in Golgi/post‐Golgi compartments results in intracellular accumulation of properly‐folded proinsulin (bearing native disulfide bonds), impairment of ER‐to‐Golgi trafficking (regardless whether such impairment is achieved by genetic or pharmacologic means) results in decreased native proinsulin with more misfolded proinsulin. Remarkably, reversible ER‐to‐Golgi transport defects (such as treatment with brefeldin A or cellular energy depletion) upon reversal quickly restore the ER folding environment, resulting in the disappearance of pre‐existing misfolded proinsulin while preserving proinsulin bearing native disulfide bonds. Thus, proper homeostatic balance of ER‐to‐Golgi trafficking is linked to a more favorable proinsulin folding (as well as trafficking) outcome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38409439,

title = {Interferons are key cytokines acting on pancreatic islets in type 1 diabetes},

author = {Alexandra Coomans de Brachène and Maria Ines Alvelos and Florian Szymczak and Priscila L Zimath and Angela Castela and Bianca Marmontel de Souza and Arturo Roca Rivada and Sandra Marín-Cañas and Xiaoyan Yi and Anne Op de Beeck and Noel G Morgan and Sebastian Sonntag and Sayro Jawurek and Alexandra C Title and Burcak Yesildag and François Pattou and Julie Kerr-Conte and Eduard Montanya and Montserrat Nacher and Lorella Marselli and Piero Marchetti and Sarah J Richardson and Decio L Eizirik},

doi = {10.1007/s00125-024-06106-7},

issn = {1432-0428},

year  = {2024},

date = {2024-02-01},

journal = {Diabetologia},

abstract = {AIMS/HYPOTHESIS: The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown.nnMETHODS: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes.nnRESULTS: IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to 'danger signals' such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells.nnCONCLUSIONS/INTERPRETATION: These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38409327,

title = {Redox regulation of mA methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes},

author = {Dario F De Jesus and Zijie Zhang and Natalie K Brown and Xiaolu Li and Ling Xiao and Jiang Hu and Matthew J Gaffrey and Garrett Fogarty and Sevim Kahraman and Jiangbo Wei and Giorgio Basile and Tariq M Rana and Clayton Mathews and Alvin C Powers and Audrey V Parent and Mark A Atkinson and Sirano Dhe-Paganon and Decio L Eizirik and Wei-Jun Qian and Chuan He and Rohit N Kulkarni},

doi = {10.1038/s41556-024-01368-0},

issn = {1476-4679},

year  = {2024},

date = {2024-02-01},

journal = {Nat Cell Biol},

abstract = {Type 1 diabetes (T1D) is characterized by the destruction of pancreatic β-cells. Several observations have renewed the interest in β-cell RNA sensors and editors. Here, we report that N-methyladenosine (mA) is an adaptive β-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. mA writer methyltransferase 3 (METTL3) levels increase drastically in β-cells at T1D onset but rapidly decline with disease progression. mA sequencing revealed the mA hypermethylation of several key innate immune mediators, including OAS1, OAS2, OAS3 and ADAR1 in human islets and EndoC-βH1 cells at T1D onset. METTL3 silencing enhanced 2'-5'-oligoadenylate synthetase levels by increasing its mRNA stability. Consistently, in vivo gene therapy to prolong Mettl3 overexpression specifically in β-cells delayed diabetes progression in the non-obese diabetic mouse model of T1D. Mechanistically, the accumulation of reactive oxygen species blocked upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced METTL3 levels and activity. Furthermore, we report that the cysteines in position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation and are important to the METTL3-mediated regulation of oligoadenylate synthase mRNA stability in human β-cells. Collectively, we report that mA regulates the innate immune response at the β-cell level during the onset of T1D in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Pirone202302203,

title = {RedRibbon: A new rank–rank hypergeometric overlap for gene and transcript expression signatures},

author = {Anthony Piron and Florian Szymczak and Theodora Papadopoulou and Maria Inês Alvelos and Matthieu Defrance and Tom Lenaerts and Décio L Eizirik and Miriam Cnop},

url = {https://www.life-science-alliance.org/content/7/2/e202302203},

doi = {10.26508/lsa.202302203},

year  = {2024},

date = {2024-01-01},

journal = {Life Science Alliance},

volume = {7},

number = {2},

publisher = {Life Science Alliance},

abstract = {High-throughput omics technologies have generated a wealth of large protein, gene, and transcript datasets that have exacerbated the need for new methods to analyse and compare big datasets. Rank–rank hypergeometric overlap is an important threshold-free method to combine and visualize two ranked lists of P-values or fold-changes, usually from differential gene expression analyses. Here, we introduce a new rank–rank hypergeometric overlap-based method aimed at gene level and alternative splicing analyses at transcript or exon level, hitherto unreachable as transcript numbers are an order of magnitude larger than gene numbers. We tested the tool on synthetic and real datasets at gene and transcript levels to detect correlation and anticorrelation patterns and found it to be fast and accurate, even on very large datasets thanks to an evolutionary algorithm-based minimal P-value search. The tool comes with a ready-to-use permutation scheme allowing the computation of adjusted P-values at low time cost. The package compatibility mode is a drop-in replacement to previous packages. RedRibbon holds the promise to accurately extricate detailed information from large comparative analyses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37949065,

title = {Stress-induced β cell early senescence confers protection against type 1 diabetes},

author = {Hugo Lee and Gulcan Semra Sahin and Chien-Wen Chen and Shreyash Sonthalia and Sandra Marín Cañas and Hulya Zeynep Oktay and Alexander T Duckworth and Gabriel Brawerman and Peter J Thompson and Maria Hatzoglou and Decio L Eizirik and Feyza Engin},

doi = {10.1016/j.cmet.2023.10.014},

issn = {1932-7420},

year  = {2023},

date = {2023-12-01},

journal = {Cell Metab},

volume = {35},

number = {12},

pages = {2200--2215.e9},

abstract = {During the progression of type 1 diabetes (T1D), β cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve β cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in β cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the β cell secretome that significantly enhances the leukemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced β cells, the reduction of β cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual β cells of T1D patients. Our findings reveal a previously unrecognized link between β cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37897566,

title = {Impact of metformin and Dysosmobacter welbionis on diet-induced obesity and diabetes: from clinical observation to preclinical intervention},

author = {Emilie Moens de Hase and Audrey M Neyrinck and Julie Rodriguez and Miriam Cnop and Nicolas Paquot and Jean-Paul Thissen and Yining Xu and Ana Beloqui and Laure B Bindels and Nathalie M Delzenne and Matthias Van Hul and Patrice D Cani},

doi = {10.1007/s00125-023-06032-0},

issn = {1432-0428},

year  = {2023},

date = {2023-10-01},

journal = {Diabetologia},

abstract = {AIMS/HYPOTHESIS: We aimed to investigate the association between the abundance of Dysosmobacter welbionis, a commensal gut bacterium, and metabolic health in human participants with obesity and diabetes, and the influence of metformin treatment and prebiotic intervention.nnMETHODS: Metabolic variables were assessed and faecal samples were collected from 106 participants in a randomised controlled intervention with a prebiotic stratified by metformin treatment (Food4Gut trial). The abundance of D. welbionis was measured by quantitative PCR and correlated with metabolic markers. The in vitro effect of metformin on D. welbionis growth was evaluated and an in vivo study was performed in mice to investigate the effects of metformin and D. welbionis J115 supplementation, either alone or in combination, on metabolic variables.nnRESULTS: D. welbionis abundance was unaffected by prebiotic treatment but was significantly higher in metformin-treated participants. Responders to prebiotic treatment had higher baseline D. welbionis levels than non-responders. D. welbionis was negatively correlated with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and fasting blood glucose levels in humans with obesity and type 2 diabetes. In vitro, metformin had no direct effect on D. welbionis growth. In mice, D. welbionis J115 treatment reduced body weight gain and liver weight, and improved glucose tolerance to a better level than metformin, but did not have synergistic effects with metformin.nnCONCLUSIONS/INTERPRETATION: D. welbionis abundance is influenced by metformin treatment and associated with prebiotic response, liver health and glucose metabolism in humans with obesity and diabetes. This study suggests that D. welbionis may play a role in metabolic health and warrants further investigation.nnCLINICAL TRIAL: NCT03852069.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37493471,

title = {Islet cells in human type 1 diabetes: from recent advances to novel therapies - a symposium-based roadmap for future research},

author = {J Cantley and D L Eizirik and E Latres and C M Dayan},

doi = {10.1530/JOE-23-0082},

issn = {1479-6805},

year  = {2023},

date = {2023-09-01},

journal = {J Endocrinol},

volume = {259},

number = {1},

abstract = {There is a growing understanding that the early phases of type 1 diabetes (T1D) are characterised by a deleterious dialogue between the pancreatic beta cells and the immune system. This, combined with the urgent need to better translate this growing knowledge into novel therapies, provided the background for the JDRF-DiabetesUK-INNODIA-nPOD symposium entitled 'Islet cells in human T1D: from recent advances to novel therapies', which took place in Stockholm, Sweden, in September 2022. We provide in this article an overview of the main themes addressed in the symposium, pointing to both promising conclusions and key unmet needs that remain to be addressed in order to achieve better approaches to prevent or reverse T1D.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37749140,

title = {Myo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset},

author = {Jing Zhang and Yuan Zou and Longmin Chen and Fei Sun and Qianqian Xu and Qing Zhou and Yi Wang and Xi Luo and Na Wang and Yang Li and Shu Zhang and Fei Xiong and Ping Yang and Shiwei Liu and Tao Yang and Jianping Weng and Décio L Eizirik and Jinhua Yan and Zhiguang Zhou and Cong-Yi Wang},

doi = {10.1038/s41467-023-41534-w},

issn = {2041-1723},

year  = {2023},

date = {2023-09-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {5977},

abstract = {The regulation of autoimmunity against pancreatic islet β cells for type 1 diabetes (T1D) onset is still unclear. NOD/ShiLtJ (NOD) mice are prone to the onset of autoimmune diabetes, but its congenic strain, ALR/Lt (ALR), is not. Here we show that dendritic cells (DC) in ALR mice have impaired migratory and T-cell priming capability. Genomic comparative analysis maps a 33-bp deletion in the ALR Myosin IXb (Myo9b) gene when compared with NOD genome; meanwhile, data from knock-in models show that this ALR Myo9b allele impairs phenotypic and functional maturation of DCs, and prevents the development and progression of spontaneous autoimmune diabetes in NOD mice. In parallel, while the ALR 33-bp deletion of Myo9b is not conserved in human, we find a MYO9B R133Q polymorphism associating with increased risk of T1D and enhanced DC function in patients with T1D. Our results thus hint that alterations in Myo9b may contribute to altered DC function and autoimmune diabetes onset.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37442376,

title = {EndoC-βH5 cells are storable and ready-to-use human pancreatic beta cells with physiological insulin secretion},

author = {Bruno Blanchi and Marion Taurand and Claire Colace and Sofia Thomaidou and Charlotte Audeoud and Federica Fantuzzi and Toshiaki Sawatani and Sevda Gheibi and Joan Sabadell-Basallote and Fransje W J Boot and Thibault Chantier and Aline Piet and Charlotte Cavanihac and Marion Pilette and Adélie Balguerie and Hamza Olleik and Françoise Carlotti and Miriam Ejarque and Malin Fex and Hindrik Mulder and Miriam Cnop and Decio L Eizirik and Ouardane Jouannot and Anne-Lise Gaffuri and Paul Czernichow and Arnaud Zaldumbide and Raphaël Scharfmann and Philippe Ravassard},

doi = {10.1016/j.molmet.2023.101772},

issn = {2212-8778},

year  = {2023},

date = {2023-07-01},

journal = {Mol Metab},

pages = {101772},

abstract = {OBJECTIVES: Readily accessible human pancreatic beta cells that are functionally close to primary adult beta cells are a crucial model to better understand human beta cell physiology and develop new treatments for diabetes. We here report the characterization of EndoC-βH5 cells, the latest in the EndoC-βH cell family.nnMETHODS: EndoC-βH5 cells were generated by integrative gene transfer of immortalizing transgenes hTERT and SV40 large T along with Herpes Simplex Virus-1 thymidine kinase into human fetal pancreas. Immortalizing transgenes were removed after amplification using CRE activation and remaining non-excized cells eliminated using ganciclovir. Resulting cells were distributed as ready to use EndoC-βH5 cells. We performed transcriptome, immunological and extensive functional assays.nnRESULTS: Ready to use EndoC-βH5 cells display highly efficient glucose dependent insulin secretion. A robust 10-fold insulin secretion index was observed and reproduced in four independent laboratories across Europe. EndoC-βH5 cells secrete insulin in a dynamic manner in response to glucose and secretion is further potentiated by GIP and GLP-1 analogs. RNA-seq confirmed abundant expression of beta cell transcription factors and functional markers, including incretin receptors. Cytokines induce a gene expression signature of inflammatory pathways and antigen processing and presentation. Finally, modified HLA-A2 expressing EndoC-βH5 cells elicit specific A2-alloreactive CD8 T cell activation.nnCONCLUSIONS: EndoC-βH5 cells represent a unique storable and ready to use human pancreatic beta cell model with highly robust and reproducible features. Such cells are thus relevant for the study of beta cell function, screening and validation of new drugs, and development of disease models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37500058,

title = {Impact of saturated compared with unsaturated dietary fat on insulin sensitivity, pancreatic β-cell function and glucose tolerance: a systematic review and meta-analysis of randomized, controlled trials},

author = {Maria Lytrivi and Carolina Gomes Da Silveira Cauduro and Jésabelle Kibanda and Paulus Kristanto and Marianne Paesmans and Miriam Cnop},

doi = {10.1016/j.ajcnut.2023.07.018},

issn = {1938-3207},

year  = {2023},

date = {2023-07-01},

journal = {Am J Clin Nutr},

abstract = {BACKGROUND: The impact of the dietary fat type on type 2 diabetes (T2D) remains unclear.nnOBJECTIVES: We aimed to evaluate the effects of replacing dietary saturated fatty acids (SFA) with mono- or poly-unsaturated fatty acids (MUFA and PUFA, respectively) on insulin sensitivity, pancreatic β-cell function, and glucose tolerance, as surrogate endpoints for T2D.nnMETHODS: We conducted a systematic review and meta-analysis of randomized controlled trials that replaced ≥5% of total energy intake provided by SFA with MUFA or PUFA and reported indexes of insulin sensitivity, β-cell function, and/or glucose tolerance. We searched MEDLINE, Scopus, and the Cochrane Library (CENTRAL) up to 9 January, 2023. Eligible interventions had to be isocaloric, with no significant difference in other macronutrients. Data were synthesized using random-effects model meta-analysis.nnRESULTS: Of 6355 records identified, 10 parallel and 20 crossover trials with 1586 participants were included. The mean age of the participants was 42 years, 47% were male, mean body mass index (BMI; in kg/m) was 26.8, median baseline fasting glucose was 5.13 mmol/L, and the median duration of interventions was 5 weeks. Replacing SFA with MUFA or PUFA had no significant effects on insulin sensitivity [standardized mean difference (SMD) SFA compared with MUFA: 0.01, 95% confidence interval (CI): -0.06 to 0.09, I = 0% and SMD SFA compared with PUFA: 0, 95% CI: -0.15 to 0.14, I = 0%]. Replacing SFA with MUFA did not significantly impact the β-cell function, evaluated by the disposition index (mean difference: -12, 95% CI: -158 to 133, I=0%). Evidence on glucose tolerance (SFA compared with MUFA or PUFA) and on β-cell function when SFA were replaced with PUFA was scant.nnCONCLUSIONS: Short-term substitution of saturated with unsaturated fat does not significantly affect insulin sensitivity nor β-cell function (the latter in the SFA compared with MUFA comparison). Future studies are needed to elucidate longer term effects of dietary fat saturation on glucose homeostasis. This trial was registered at PROSPERO as CRD42020178382.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37250773,

title = {Adipose tissue plasticity in pheochromocytoma patients suggests a role of the splicing machinery in human adipose browning},

author = {Moisés Castellá and Albert Blasco-Roset and Marion Peyrou and Aleix Gavaldà-Navarro and Joan Villarroya and Tania Quesada-López and Leyre Lorente-Poch and Juan Sancho and Florian Szymczak and Anthony Piron and Sonia Rodríguez-Fernández and Stefania Carobbio and Albert Goday and Pere Domingo and Antonio Vidal-Puig and Marta Giralt and Décio L Eizirik and Francesc Villarroya and Rubén Cereijo},

doi = {10.1016/j.isci.2023.106847},

issn = {2589-0042},

year  = {2023},

date = {2023-06-01},

journal = {iScience},

volume = {26},

number = {6},

pages = {106847},

abstract = {Adipose tissue from pheochromocytoma patients acquires brown fat features, making it a valuable model for studying the mechanisms that control thermogenic adipose plasticity in humans. Transcriptomic analyses revealed a massive downregulation of splicing machinery components and splicing regulatory factors in browned adipose tissue from patients, with upregulation of a few genes encoding RNA-binding proteins potentially involved in splicing regulation. These changes were also observed in cell culture models of human brown adipocyte differentiation, confirming a potential involvement of splicing in the cell-autonomous control of adipose browning. The coordinated changes in splicing are associated with a profound modification in the expression levels of splicing-driven transcript isoforms for genes involved in the specialized metabolism of brown adipocytes and those encoding master transcriptional regulators of adipose browning. Splicing control appears to be a relevant component of the coordinated gene expression changes that allow human adipose tissue to acquire a brown phenotype.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37072614,

title = {Why does the immune system destroy pancreatic β-cells but not α-cells in type 1 diabetes?},

author = {Decio L Eizirik and Florian Szymczak and Roberto Mallone},

doi = {10.1038/s41574-023-00826-3},

issn = {1759-5037},

year  = {2023},

date = {2023-04-01},

journal = {Nat Rev Endocrinol},

abstract = {A perplexing feature of type 1 diabetes (T1D) is that the immune system destroys pancreatic β-cells but not neighbouring α-cells, even though both β-cells and α-cells are dysfunctional. Dysfunction, however, progresses to death only for β-cells. Recent findings indicate important differences between these two cell types. First, expression of BCL2L1, a key antiapoptotic gene, is higher in α-cells than in β-cells. Second, endoplasmic reticulum (ER) stress-related genes are differentially expressed, with higher expression levels of pro-apoptotic CHOP in β-cells than in α-cells and higher expression levels of HSPA5 (which encodes the protective chaperone BiP) in α-cells than in β-cells. Third, expression of viral recognition and innate immune response genes is higher in α-cells than in β-cells, contributing to the enhanced resistance of α-cells to coxsackievirus infection. Fourth, expression of the immune-inhibitory HLA-E molecule is higher in α-cells than in β-cells. Of note, α-cells are less immunogenic than β-cells, and the CD8 T cells invading the islets in T1D are reactive to pre-proinsulin but not to glucagon. We suggest that this finding is a result of the enhanced capacity of the α-cell to endure viral infections and ER stress, which enables them to better survive early stressors that can cause cell death and consequently amplify antigen presentation to the immune system. Moreover, the processing of the pre-proglucagon precursor in enteroendocrine cells might favour immune tolerance towards this potential self-antigen compared to pre-proinsulin.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36401627,

title = {Exercise as a non-pharmacological intervention to protect pancreatic beta cells in individuals with type 1 and type 2 diabetes},

author = {Alexandra Coomans de Brachène and Corentin Scoubeau and Anyïshai E Musuaya and Jose Maria Costa-Junior and Angela Castela and Julie Carpentier and Vitalie Faoro and Malgorzata Klass and Miriam Cnop and Decio L Eizirik},

doi = {10.1007/s00125-022-05837-9},

issn = {1432-0428},

year  = {2023},

date = {2023-03-01},

journal = {Diabetologia},

volume = {66},

number = {3},

pages = {450--460},

abstract = {AIMS/HYPOTHESIS: Diabetes is characterised by progressive loss of functional pancreatic beta cells. None of the therapeutic agents used to treat diabetes arrest this process; preventing beta cell loss remains a major unmet need. We have previously shown that serum from eight young healthy male participants who exercised for 8 weeks protected human islets and insulin-producing EndoC-βH1 cells from apoptosis induced by proinflammatory cytokines or the endoplasmic reticulum (ER) stressor thapsigargin. Whether this protective effect is influenced by sex, age, training modality, ancestry or diabetes is unknown.



METHODS: We enrolled 82 individuals, male or female, non-diabetic or diabetic, from different origins, in different supervised training protocols for 8-12 weeks (including training at home during the COVID-19 pandemic). EndoC-βH1 cells were treated with 'exercised' serum or with the exerkine clusterin to ascertain cytoprotection from ER stress.



RESULTS: The exercise interventions were effective and improved [Formula: see text] values in both younger and older, non-obese and obese, non-diabetic and diabetic participants. Serum obtained after training conferred significant beta cell protection (28% to 35% protection after 4 and 8 weeks of training, respectively) from severe ER stress-induced apoptosis. Cytoprotection was not affected by the type of exercise training or participant age, sex, BMI or ancestry, and persisted for up to 2 months after the end of the training programme. Serum from exercised participants with type 1 or type 2 diabetes was similarly protective. Clusterin reproduced the beneficial effects of exercised sera.



CONCLUSIONS/INTERPRETATION: These data uncover the unexpected potential to preserve beta cell health by exercise training, opening a new avenue to prevent or slow diabetes progression through humoral muscle-beta cell crosstalk.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36988639,

title = {Inhibition of the type 1 diabetes candidate gene PTPN2 aggravates TNF-α-induced human beta cell dysfunction and death},

author = {Arturo Roca-Rivada and Sandra Marín-Cañas and Maikel L Colli and Chiara Vinci and Toshiaki Sawatani and Lorella Marselli and Miriam Cnop and Piero Marchetti and Decio L Eizirik},

doi = {10.1007/s00125-023-05908-5},

issn = {1432-0428},

year  = {2023},

date = {2023-03-01},

journal = {Diabetologia},

abstract = {AIMS/HYPOTHESIS: TNF-α plays a role in pancreatic beta cell loss in type 1 diabetes mellitus. In clinical interventions, TNF-α inhibition preserves C-peptide levels in early type 1 diabetes. In this study we evaluated the crosstalk of TNF-α, as compared with type I IFNs, with the type 1 diabetes candidate gene PTPN2 (encoding protein tyrosine phosphatase non-receptor type 2 [PTPN2]) in human beta cells.



METHODS: EndoC-βH1 cells, dispersed human pancreatic islets or induced pluripotent stem cell (iPSC)-derived islet-like cells were transfected with siRNAs targeting various genes (siCTRL, siPTPN2, siJNK1, siJNK3 or siBIM). Cells were treated for 48 h with IFN-α (2000 U/ml) or TNF-α (1000 U/ml). Cell death was evaluated using Hoechst 33342 and propidium iodide staining. mRNA levels were assessed by quantitative reverse transcription PCR (qRT-PCR) and protein expression by immunoblot.



RESULTS: PTPN2 silencing sensitised beta cells to cytotoxicity induced by IFN-α and/or TNF-α by 20-50%, depending on the human cell model utilised; there was no potentiation between the cytokines. We silenced c-Jun N-terminal kinase (JNK)1 or Bcl-2-like protein 2 (BIM), and this abolished the proapoptotic effects of IFN-α, TNF-α or the combination of both after PTPN2 inhibition. We further observed that PTPN2 silencing increased TNF-α-induced JNK1 and BIM phosphorylation and that JNK3 is necessary for beta cell resistance to IFN-α cytotoxicity.



CONCLUSIONS/INTERPRETATION: We show that the type 1 diabetes candidate gene PTPN2 is a key regulator of the deleterious effects of TNF-α in human beta cells. It is conceivable that people with type 1 diabetes carrying risk-associated PTPN2 polymorphisms may particularly benefit from therapies inhibiting TNF-α.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{RN727,

title = {GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models},

author = {Vyron Gorgogietas and Bahareh Rajaei and Chae Heeyoung and Bruno J. Santacreu and Sandra Marín-Cañas and Paraskevi Salpea and Toshiaki Sawatani and Anyishai Musuaya and María N. Arroyo and Cristina Moreno-Castro and Khadija Benabdallah and Celine Demarez and Sanna Toivonen and Cristina Cosentino and Nathalie Pachera and Maria Lytrivi and Ying Cai and Lode Carnel and Cris Brown and Fumihiko Urano and Piero Marchetti and Patrick Gilon and Decio L. Eizirik and Miriam Cnop and Mariana Igoillo-Esteve},

doi = {10.1007/s00125-023-05905-8},

issn = {0012-186X 1432-0428},

year  = {2023},

date = {2023-01-30},

urldate = {2023-01-01},

journal = {Diabetologia},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36201618,

title = {Recognition of mRNA Splice Variant and Secretory Granule Epitopes by CD4+ T Cells in Type 1 Diabetes},

author = {Perrin Guyer and David Arribas-Layton and Anthony Manganaro and Cate Speake and Sandra Lord and Decio L Eizirik and Sally C Kent and Roberto Mallone and Eddie A James},

doi = {10.2337/db22-0191},

issn = {1939-327X},

year  = {2023},

date = {2023-01-01},

journal = {Diabetes},

volume = {72},

number = {1},

pages = {85--96},

abstract = {A recent discovery effort resulted in identification of novel splice variant and secretory granule antigens within the HLA class I peptidome of human islets and documentation of their recognition by CD8+ T cells from peripheral blood and human islets. In the current study, we applied a systematic discovery process to identify novel CD4+ T cell epitopes derived from these candidate antigens. We predicted 145 potential epitopes spanning unique splice junctions and within conventional secretory granule antigens and measured their in vitro binding to DRB1*04:01. We generated HLA class II tetramers for the 35 peptides with detectable binding and used these to assess immunogenicity and isolate T cell clones. Tetramers corresponding to peptides with verified immunogenicity were then used to label T cells specific for these putative epitopes in peripheral blood. T cells that recognize distinct epitopes derived from a cyclin I splice variant, neuroendocrine convertase 2, and urocortin-3 were detected at frequencies that were similar to those of an immunodominant proinsulin epitope. Cells specific for these novel epitopes predominantly exhibited a Th1-like surface phenotype. Among the three epitopes, responses to the cyclin I peptide exhibited a distinct memory profile. Responses to neuroendocrine convertase 2 were detected among pancreatic infiltrating T cells. These results further establish the contribution of unconventional antigens to the loss of tolerance in autoimmune diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36824360,

title = {A long non-coding RNA that harbors a SNP associated with type 2 diabetes regulates the expression of  gene in pancreatic beta cells},

author = {Itziar González-Moro and Henar Rojas-Márquez and Maialen Sebastian-delaCruz and Jon Mentxaka-Salgado and Ane Olazagoitia-Garmendia and Luis Manuel Mendoza and Aina Lluch and Federica Fantuzzi and Carmen Lambert and Jessica Ares Blanco and Lorella Marselli and Piero Marchetti and Miriam Cnop and Elías Delgado and José Manuel Fernández-Real and Francisco José Ortega and Ainara Castellanos-Rubio and Izortze Santin},

doi = {10.3389/fendo.2023.1101934},

issn = {1664-2392},

year  = {2023},

date = {2023-01-01},

journal = {Front Endocrinol (Lausanne)},

volume = {14},

pages = {1101934},

abstract = {INTRODUCTION: Most of the disease-associated single nucleotide polymorphisms (SNPs) lie in non- coding regions of the human genome. Many of these variants have been predicted to impact the expression and function of long non-coding RNAs (lncRNA), but the contribution of these molecules to the development of complex diseases remains to be clarified.



METHODS: Here, we performed a genetic association study between a SNP located in a lncRNA known as LncTGM2 and the risk of developing type 2 diabetes (T2D), and analyzed its implication in disease pathogenesis at pancreatic beta cell level. Genetic association study was performed on human samples linking the rs2076380 polymorphism with T2D and glycemic traits. The pancreatic beta cell line EndoC-bH1 was employed for functional studies based on LncTGM2 silencing and overexpression experiments. Human pancreatic islets were used for eQTL analysis.



RESULTS: We have identified a genetic association between LncTGM2 and T2D risk. Functional characterization of the LncTGM2 revealed its implication in the transcriptional regulation of TGM2, coding for a transglutaminase. The T2Dassociated risk allele in LncTGM2 disrupts the secondary structure of this lncRNA, affecting its stability and the expression of TGM2 in pancreatic beta cells. Diminished LncTGM2 in human beta cells impairs glucose-stimulated insulin release.



CONCLUSIONS: These findings provide novel information on the molecular mechanisms by which T2D-associated SNPs in lncRNAs may contribute to disease, paving the way for the development of new therapies based on the modulation of lncRNAs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36543979,

title = {Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis},

author = {Kerstin Griess and Michael Rieck and Nadine Müller and Gergely Karsai and Sonja Hartwig and Angela Pelligra and Robert Hardt and Caroline Schlegel and Jennifer Kuboth and Celina Uhlemeyer and Sandra Trenkamp and Kay Jeruschke and Jürgen Weiss and Leon Peifer-Weiss and Weiwei Xu and Sandra Cames and Xiaoyan Yi and Miriam Cnop and Mathias Beller and Holger Stark and Arun Kumar Kondadi and Andreas S Reichert and Daniel Markgraf and Marianne Wammers and Dieter Häussinger and Oliver Kuss and Stefan Lehr and Decio Eizirik and Heiko Lickert and Eckhard Lammert and Michael Roden and Dominic Winter and Hadi Al-Hasani and Doris Höglinger and Thorsten Hornemann and Jens C Brüning and Bengt-Frederik Belgardt},

doi = {10.1038/s41556-022-01027-2},

issn = {1476-4679},

year  = {2023},

date = {2023-01-01},

journal = {Nat Cell Biol},

volume = {25},

number = {1},

pages = {20--29},

abstract = {Impaired proinsulin-to-insulin processing in pancreatic β-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. ), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. ); nonetheless, the role of specific SL species in β-cell function and demise is unclear. Here we define the lipid signature of T2D-associated β-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. β-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL-protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum-Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in β-cell function and T2D-associated β-cell failure.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36415826,

title = {A single-cell human islet interactome atlas identifies disrupted autocrine and paracrine communications in type 2 diabetes},

author = {Emanuele Bosi and Lorella Marselli and Mara Suleiman and Marta Tesi and Carmela De Luca and Silvia Del Guerra and Miriam Cnop and Decio L Eizirik and Piero Marchetti},

doi = {10.1093/nargab/lqac084},

issn = {2631-9268},

year  = {2022},

date = {2022-12-01},

journal = {NAR Genom Bioinform},

volume = {4},

number = {4},

pages = {lqac084},

abstract = {A sensible control of hormone secretion from pancreatic islets requires concerted inter-cellular communications, but a comprehensive picture of the whole islet interactome is presently missing. Single-cell transcriptomics allows to overcome this and we used here a single-cell dataset from type 2 diabetic (T2D) and non-diabetic (ND) donors to leverage islet interaction networks. The single-cell dataset contains 3046 cells classified in 7 cell types. The interactions across cell types in T2D and ND were obtained and resulting networks analysed to identify high-centrality genes and altered interactions in T2D. The T2D interactome displayed a higher number of interactions (10 787) than ND (9707); 1289 interactions involved beta cells (1147 in ND). High-centrality genes included EGFR, FGFR1 and FGFR2, important for cell survival and proliferation. In conclusion, this analysis represents the first  model of the human islet interactome, enabling the identification of signatures potentially relevant for T2D pathophysiology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36345338,

title = {Mining the transcriptome of target tissues of autoimmune and degenerative pancreatic β-cell and brain diseases to discover therapies},

author = {Xiaoyan Yi and Bianca Marmontel de Souza and Toshiaki Sawatani and Florian Szymczak and Lorella Marselli and Piero Marchetti and Miriam Cnop and Decio L Eizirik},

doi = {10.1016/j.isci.2022.105376},

issn = {2589-0042},

year  = {2022},

date = {2022-11-01},

journal = {iScience},

volume = {25},

number = {11},

pages = {105376},

abstract = {Target tissues of autoimmune and degenerative diseases show signals of inflammation. We used publicly available RNA-seq data to study whether pancreatic β-cells in type 1 and type 2 diabetes and neuronal tissue in multiple sclerosis and Alzheimer's disease share inflammatory gene signatures. We observed concordantly upregulated genes in pairwise diseases, many of them related to signaling by interleukins and interferons. We next mined these signatures to identify therapies that could be re-purposed/shared among the diseases and identified the bromodomain inhibitors as potential perturbagens to revert the transcriptional signatures. We experimentally confirmed in human β-cells that bromodomain inhibitors I-BET151 and GSK046 prevent the deleterious effects of the pro-inflammatory cytokines interleukin-1β and interferon-γ and at least some of the effects of the metabolic stressor palmitate. These results demonstrate that key inflammation-induced molecular mechanisms are shared between β-cells and brain in autoimmune and degenerative diseases and that these signatures can be mined for drug discovery.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36289205,

title = {The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α},

author = {Vikash Chandra and Hazem Ibrahim and Clémentine Halliez and Rashmi B Prasad and Federica Vecchio and Om Prakash Dwivedi and Jouni Kvist and Diego Balboa and Jonna Saarimäki-Vire and Hossam Montaser and Tom Barsby and Väinö Lithovius and Isabella Artner and Swetha Gopalakrishnan and Leif Groop and Roberto Mallone and Decio L Eizirik and Timo Otonkoski},

doi = {10.1038/s41467-022-34069-z},

issn = {2041-1723},

year  = {2022},

date = {2022-10-01},

journal = {Nat Commun},

volume = {13},

number = {1},

pages = {6363},

abstract = {Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic β-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-Ι interferon (IFN-Ι) mediated intracellular signalling. To study the role of TYK2 in β-cell development and response to IFNα, we generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Here we show that loss of TYK2 compromises the emergence of endocrine precursors by regulating KRAS expression, while mature stem cell-islets (SC-islets) function is not affected. In the SC-islets, the loss or inhibition of TYK2 prevents IFNα-induced antigen processing and presentation, including MHC Class Ι and Class ΙΙ expression, enhancing their survival against CD8 T-cell cytotoxicity. These results identify an unsuspected role for TYK2 in β-cell development and support TYK2 inhibition in adult β-cells as a potent therapeutic target to halt T1D progression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36287121,

title = {Pro-Inflammatory Cytokines Promote the Transcription of Circular RNAs in Human Pancreatic β Cells},

author = {Simranjeet Kaur and Caroline Frørup and Aashiq H Mirza and Tina Fløyel and Reza Yarani and Maikel L Colli and Jesper Johannesen and Joachim Størling and Decio L Eizirik and Flemming Pociot},

doi = {10.3390/ncrna8050069},

issn = {2311-553X},

year  = {2022},

date = {2022-10-01},

journal = {Noncoding RNA},

volume = {8},

number = {5},

abstract = {Circular RNAs (circRNAs) have recently been implicated in impaired β-cell function in diabetes. Using microarray-based profiling of circRNAs in human EndoC-βH1 cells treated with pro-inflammatory cytokines, this study aimed to investigate the expression and possible regulatory roles of circRNAs in human β cells. We identified ~5000 β-cell-expressed circRNAs, of which 84 were differentially expressed (DE) after cytokine exposure. Pathway analysis of the host genes of the DE circRNAs revealed the enrichment of cytokine signaling pathways, indicative of circRNA transcription from inflammatory genes in response to cytokines. Multiple binding sites for β-cell-enriched microRNAs and RNA-binding proteins were observed for the highly upregulated circRNAs, supporting their function as 'sponges' or 'decoys'. We also present evidence for circRNA sequence conservation in multiple species, the presence of cytokine-induced regulatory elements, and putative protein-coding potential for the DE circRNAs. This study highlights the complex regulatory potential of circRNAs, which may play a crucial role during immune-mediated β-cell destruction in type 1 diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36134336,

title = {Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways},

author = {Emanuele Bosi and Piero Marchetti and Guy Allen Rutter and Decio Laks Eizirik},

doi = {10.1016/j.isci.2022.105056},

issn = {2589-0042},

year  = {2022},

date = {2022-10-01},

journal = {iScience},

volume = {25},

number = {10},

pages = {105056},

abstract = {Although glucagon secretion is perturbed in both T1D and T2D, the pathophysiological changes in individual pancreatic alpha cells are still obscure. Using recently curated single-cell RNASeq data from T1D or T2D donors and their controls, we identified alpha cell transcriptomic alterations consistent with both common and discrete pathways. Although alterations in alpha cell identity gene (ARX, MAFB) expression were conserved, cytokine-regulated genes and genes involved in glucagon biosynthesis and processing were up-regulated in T1D. Conversely, mitochondrial genes associated with ROS (COX7B, NQO2) were dysregulated in T2D. Additionally, T1D alpha cells displayed altered expression of autoimmune-induced ER stress genes (ERLEC1, HSP90), whilst those from T2D subjects showed modified glycolytic and citrate cycle gene (LDHA?, PDHB, PDK4) expression. Thus, despite conserved alterations related to loss of function, alpha cells display disease-specific gene signatures which may be secondary to the main pathogenic events in each disease, namely immune- or metabolism-mediated-stress, in T1D and T2D, respectively.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36103539,

title = {Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β cells},

author = {Florian Szymczak and Maria Inês Alvelos and Sandra Marín-Cañas and Ângela Castela and Stéphane Demine and Maikel Luis Colli and Anne Op de Beeck and Sofia Thomaidou and Lorella Marselli and Arnaud Zaldumbide and Piero Marchetti and Décio L Eizirik},

doi = {10.1126/sciadv.abn5732},

issn = {2375-2548},

year  = {2022},

date = {2022-09-01},

journal = {Sci Adv},

volume = {8},

number = {37},

pages = {eabn5732},

abstract = {IFNα is a key regulator of the dialogue between pancreatic β cells and the immune system in early type 1 diabetes (T1D). IFNα up-regulates HLA class I expression in human β cells, fostering autoantigen presentation to the immune system. We observed by bulk and single-cell RNA sequencing that exposure of human induced pluripotent-derived islet-like cells to IFNα induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulin-producing EndoC-βH1 and human islet cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I, antigen presentation-related genes, and chemokines. NLRC5 also mediates the effects of IFNα on alternative splicing, a generator of β cell neoantigens, suggesting that it is a central player of the effects of IFNα on β cells that contribute to trigger and amplify autoimmunity in T1D.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35954309,

title = {The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved},

author = {Laura Giusti and Marta Tesi and Federica Ciregia and Lorella Marselli and Lorenzo Zallocco and Mara Suleiman and Carmela De Luca and Silvia Del Guerra and Mariachiara Zuccarini and Marco Trerotola and Decio L Eizirik and Miriam Cnop and Maria R Mazzoni and Piero Marchetti and Antonio Lucacchini and Maurizio Ronci},

doi = {10.3390/cells11152465},

issn = {2073-4409},

year  = {2022},

date = {2022-08-01},

journal = {Cells},

volume = {11},

number = {15},

abstract = {Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}