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2. Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic 0 cells

Author

Szymczak, F., Alvelos, M.I., Marin-Canas, S., Castela, A., Demine, S., Colli, M.L., Beeck, A.O. de, Thomaidou, S., Marselli, L., Zaldumbide, A., Marchetti, P., and Eizirik, D.L.

Abstract

IFNa is a key regulator of the dialogue between pancreatic 0 cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human 0 cells, fostering autoantigen presentation to the immune system. We observed by bulk and single-cell RNA sequencing that exposure of human induced pluripotentderived islet-like cells to IFNa 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 insulinproducing EndoC-0H1 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 IFNa on alternative splicing, a generator of 0 cell neoantigens, suggesting that it is a central player of the effects of IFNa on 0 cells that contribute to trigger and amplify autoimmunity in T1D.

Published
2022

4. First world consensus conference on pancreas transplantation: Part I-Methods and results of literature search

Author

Boggi, U., Vistoli, F., Marchetti, P., Kandaswamy, R., Berney, T., Andres, A., Arbogast, H. P., Badet, L., Baronti, W., Bartlett, S. T., Benedetti, E., Branchereau, J., Burke, G. W. 3., Buron, F., Caldara, R., Cardillo, M., Casanova, D., Cipriani, F., Cooper, M., Cupisti, A., de Koning, E. J. P., Davide, J., Drachenberg, C., Ettorre, G. M., Fernandez Cruz, L., Fridell, J. A., Friend, P. J., Furian, L., Gaber, O. A., Gruessner, A. C., Gruessner, R. W. G., Gunton, J. E., Han, D. -J., Iacopi, S., Kauffmann, E. F., Kaufman, D., Kenmochi, T., Khambalia, H. A., Lai, Q., Langer, R. M., Maffi, P., Marselli, L., Menichetti, F., Miccoli, M., Mittal, S., Morelon, E., Napoli, N., Neri, F., Oberholzer, J., Odorico, J. S., Ollinger, R., Oniscu, G., Orlando, G., Ortenzi, M., Perosa, M., Perrone, V. G., Redfield, R. R., Ricci, C., Rigotti, P., Robertson, R. P., Ross, L. F., Rossi, M., Saudek, F., Scalea, J. R., Schenker, P., Secchi, A., Socci, C., Sousa Silva, D., Squifflet, J. P., Stock, P. G., Stratta, R. J., Terrenzio, C., Uva, P., Watson, C. C. E., White, S. A., Boggi U., Vistoli F., Marchetti P., Kandaswamy R., Berney T., Andres A., Arbogast H.P., Badet L., Baronti W., Bartlett S.T., Benedetti E., Branchereau J., Burke G.W., Buron F., Caldara R., Cardillo M., Casanova D., Cipriani F., Cooper M., Cupisti A., de Koning E.J.P., Davide J., Drachenberg C., Ettorre G.M., Fernandez Cruz L., Fridell J.A., Friend P.J., Furian L., Gaber O.A., Gruessner A.C., Gruessner R.W.G., Gunton J.E., Han D.-J., Iacopi S., Kauffmann E.F., Kaufman D., Kenmochi T., Khambalia H.A., Lai Q., Langer R.M., Maffi P., Marselli L., Menichetti F., Miccoli M., Mittal S., Morelon E., Napoli N., Neri F., Oberholzer J., Odorico J.S., Ollinger R., Oniscu G., Orlando G., Ortenzi M., Perosa M., Perrone V.G., Redfield R.R., Ricci C., Rigotti P., Robertson R.P., Ross L.F., Rossi M., Saudek F., Scalea J.R., Schenker P., Secchi A., Socci C., Sousa Silva D., Squifflet J.P., Stock P.G., Stratta R.J., Terrenzio C., Uva P., Watson C.C.E., and White S.A.

Subjects
clinical research / practice, diabetes, pancreas / simultaneous pancreas-kidney transplantation, survey, Consensus, Humans, Pancreas Transplantation, medicine.medical_treatment, media_common.quotation_subject, Delphi method, Consensu, Pancreas transplantation, Session (web analytics), Jury, Voting, medicine, Immunology and Allergy, Pharmacology (medical), Grading (education), media_common, Transplantation, Medical education, business.industry, pancreas / simultaneous pancreas‐kidney transplantation, Systematic review, diabete, Special Articles, Original Article, First World, business, Human
Abstract

Comprehensive evidence‐based guidelines for the practice of pancreas transplantation are yet to be established. The First World Consensus Conference on Pancreas Transplantation was convened for this purpose. A steering committee selected the participants and defined the questions to be addressed. A group of literature reviewers identified 597 studies to be included in summaries for guidelines production. Expert groups formulated the first draft of recommendations. Two rounds of discussion and voting occurred online, using the Delphi method (agreement rate ≥85%). After each round, critical responses of experts were reviewed, and recommendations were amended accordingly. Recommendations were finalized after live discussions. Each session was preceded by expert presentations and a summary of results of systematic literature review. Up to three voting rounds were allowed for each recommendation. To avoid potential conflicts of interest, deliberations on issues regarding the impact of pancreas transplantation on the management of diabetes were conducted by an independent jury. Recommendations on technical issues were determined by experts and validated using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Quality of evidence was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) methodology. Each recommendation received a GRADE rating (Grading of Recommendations, Assessment, Development and Evaluations)., This article presents the results of literature search and the methods used to provide evidence‐based guidelines for the practice of pancreas transplantation at the First World Consensus Conference on Pancreas Transplantation.

Published
2021

13. An integrated multi-omics approach identifies the landscape of interferon-alpha-mediated responses of human pancreatic beta cells

Author

Colli, ML, Ramos-Rodriguez, M, Nakayasu, ES, Alvelos, MI, Lopes, M, Hill, JLE, Turatsinze, JV, de Brachene, AC, Russell, MA, Raurell-Vila, H, Castela, A, Juan-Mateu, J, Webb-Robertson, BJM, Krogvold, L, Dahl-Jorgensen, K, Marselli, L, Marchetti, P, Richardson, SJ, Morgan, NG, Metz, TO, Pasquali, L, and Eizirik, DL

Abstract

Interferon-alpha (IFN alpha), a type I interferon, is expressed in the islets of type 1 diabetic individuals, and its expression and signaling are regulated by T1D genetic risk variants and viral infections associated with T1D. We presently characterize human beta cell responses to IFN alpha by combining ATAC-seq, RNA-seq and proteomics assays. The initial response to IFN alpha is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation. IFN alpha induces changes in alternative splicing (AS) and first exon usage, increasing the diversity of transcripts expressed by the beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may expand antigens presented by beta cells to the immune system. Beta cells also up-regulate the checkpoint proteins PDL1 and HLA-E that may exert a protective role against the autoimmune assault. Data mining of the present multi-omics analysis identifies two compound classes that antagonize IFN alpha effects on human beta cells. The cytokine IFN alpha is expressed in the islets of individuals with type 1 diabetes and contributes to local inflammation and destruction of beta cells. Here, the authors provide a global multiomics view of IFN alpha -induced changes in human beta cells at the level of chromatin, mRNA and protein expression.

Published
2020

14. Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPAR[[gamma].sub.2] in the modulation of insulin secretion

Author

Lupi, R., Del Guerra, S., Marselli, L., Bugliani, M., Boggi, U., Mosca, F., Marchetti, P., and Del Prato, S.

Subjects
Fatty acids -- Research, Biological sciences
Abstract

Lupi, R., S. Del Guerra, L. Marselli, M. Bugliani, U. Boggi, F. Mosca, P. Marchetti, and S. Del Prato. Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPA[R.sub.[gamma]2] in the modulation of insulin secretion. Am J Physiol Endocrinol Metab 286: E560--E567, 2004. First published November 18, 2003; 10.1152/ajpendo.00561.2002.--Peroxisome proliferator-activated receptors (PPARs) are a subgroup of the superfamily of nuclear receptors, with three distinct main types: [alpha], [beta] and [gamma] (subdivided into [[gamma].sub.1] and [[gamma].sub.2]). Recently, the presence of PPA[R.sub.[gamma]] has been reported in human islets. Whether other PPAR types can be found in human islets, how islet PPA[R.sub.[gamma]] mRNA expression is regulated by the metabolic milieu, their role in insulin secretion, and the effects of a PPA[R.sub.[gamma]] agonist are not known. In this study, human pancreatic islets were prepared by collagenase digestion and density gradient purification from nonobese adult donors. The presence of PPAR mRNAs was assessed by RT-PCR, and the effect was evaluated of exposure for up to 24 h to either 22.2 mmol/l glucose and/or 0.25, 0.5, or 1.0 mmol/l long-chain fatty acid mixture (oleate to palmitate, 2:1). PPAR[beta] and, to a greater extent, total PPA[R.sub.[gamma]] and PPAR[R.sub.[gamma]2] mRNAs were expressed in human islets, whereas PPA[alpha] mRNA was not detected. Compared with human adipose tissue, PPA[R.sub.[gamma]] mRNA was expressed at lower levels in the islets, and PPAR[beta] at similar levels. The expression of PPA[R.sub.[gamma]2] mRNA was not affected by exposure to 22.2 mmol/l glucose, whereas it decreased markedly and time dependently after exposure to progressively higher free fatty acids (FFA). This latter effect was not affected by the concomitant presence of high glucose. Exposure to FFA caused inhibition of insulin mRNA expression, glucose-stimulated insulin release, and reduction of islet insulin content. The PPA[R.sub.[gamma]] agonists rosiglitazone and 15-deoxy-[[DELTA]-.sup.12,14] prostaglandin [J.sub.2] prevented the cytostatic effect of FFA as well as the FFA-induced changes of PPAR and insulin mRNA expression. In conclusion, this study shows that PPAR[R.sub.[gamma]] mRNA is expressed in human pancreatic islets, with predominance of PPA[R.sub.[gamma]2]; exposure to FFA downregulates PPA[R.sub.[gamma]2] and insulin mRNA expression and inhibits glucose-stimulated insulin secretion; exposure to PPA[R.sub.[gamma]] agonists can prevent these effects. pancreatic islets; peroxisome proliferator-activated receptors; polymerase chain reaction; messenger ribonucleic acid; lipotoxicity; glucotoxicity; prostaglandin; free fatty acids

Published
2004

20. Gain of function mutations in Malate Dehydrogenase 2 (MDH2) cause familial diabetes of the adulthood

Author

Pezzilli, S, Jungtrakoon, P, Pannone, L, Marucci, A, Biagini, T, Buranasupkajorn, P, Di Paola, R, Ceron, J, Marselli, L, Marchetti, P, Mazza, T, Martinelli, S, Trischitta, V, Doria, A, and Prudente, S

Subjects
familial diabetes, familial diabetes, MODY, malate dehydrogenase 2, mitochondrial function, cell metabolism, mitochondrial function, cell metabolism, MODY, malate dehydrogenase 2
Published
2019

25. High resolution MALDI-FTICR-MSI analysis of intact proteins in mouse pancreas tissue

Author

Piga, I, Heijs, B, Nicolardi, S, Giusti, L, Marselli, L, Marchetti, P, Lucacchini, A, McDonnell, LA, Piga, I, Heijs, B, Nicolardi, S, Giusti, L, Marselli, L, Marchetti, P, Lucacchini, A, and Mcdonnell, L

Subjects
MALDI-MSI, MALDI-FTICR, Pancreas, Type 2 diabetes, Intact Proteins, MALDI-MSI, MALDI-FTICR, Pancreas, Intact proteins, proteomics
Published
2016

27. Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β cell are associated with glucose intolerance in humans and mice

Author

Mehta, Z, Fine, N, Pullen, T, Cane, M, Hu, M, Chabosseau, P, Meur, G, Velayos-Baeza, A, Monaco, A, Marselli, L, Marchetti, P, Rutter, G, Commission of the European Communities, The Royal Society, Medical Research Council (MRC), and Wellcome Trust

Subjects
Male, Physiology, Blotting, Western, Vesicular Transport Proteins, Nerve Tissue Proteins, C2CD4A, Real-Time Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Mice, Endocrinology & Metabolism, Sex Factors, Endocrinology, VPS13C, Insulin-Secreting Cells, Physiology (medical), Glucose Intolerance, Insulin Secretion, Animals, Insulin, GWAS, Pancreas, Mice, Knockout, Calcium-Binding Proteins, Proteins, Type 2 diabetes, 11 Medical And Health Sciences, 06 Biological Sciences, β-cell, Diabetes and Metabolism, Endocrinology, Diabetes and Metabolism, Diabetes Mellitus, Type 2, Glucagon-Secreting Cells, Call for Papers, Calcium, Female, Insulin Resistance
Abstract

Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female (n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13c(fl/fl):Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca(2+) were significantly increased in islets from female KO mice, suggesting impaired Ca(2+) sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved.

Published
2016

28. Salvage of an Octogenarian Liver Graft Using Normothermic Perfusion: A Case Report

Author

Pezzati, D., primary, Ghinolfi, D., additional, Balzano, E., additional, De Simone, P., additional, Coletti, L., additional, Roffi, N., additional, Rreka, E., additional, Meacci, L., additional, Campani, D., additional, Mazzoni, A., additional, Paolicchi, A., additional, Caponi, L., additional, Marchetti, P., additional, Marselli, L., additional, and Filipponi, F., additional

Published
2017
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