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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

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

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).

Published
2021

4. First World Consensus Conference on pancreas transplantation: Part II – recommendations

Author

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

Abstract

The First World Consensus Conference on Pancreas Transplantation provided 49 jury deliberations regarding the impact of pancreas transplantation on the treatment of diabetic patients, and 110 experts’ recommendations for the practice of pancreas transplantation. The main message from this consensus conference is that both simultaneous pancreas-kidney transplantation (SPK) and pancreas transplantation alone can improve long-term patient survival, and all types of pancreas transplantation dramatically improve the quality of life of recipients. Pancreas transplantation may also improve the course of chronic complications of diabetes, depending on their severity. Therefore, the advantages of pancreas transplantation appear to clearly surpass potential disadvantages. Pancreas after kidney transplantation increases the risk of mortality only in the early period after transplantation, but is associated with improved life expectancy thereafter. Additionally, preemptive SPK, when compared to SPK performed in patients undergoing dialysis, appears to be associated with improved outcomes. Time on dialysis has negative prognostic implications in SPK recipients. Increased long-term survival, improvement in the course of diabetic complications, and amelioration of quality of life justify preferential allocation of kidney grafts to SPK recipients. Audience discussions and live voting are available online at the following URL address: http://mediaeventi.unipi.it/category/1st-world-consensus-conference-of-pancreas-transplantation/246.

Published
2021

6. 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

9. Noradrenergic fibers are associated with beta-cell dedifferentiation and impaired beta-cell function in humans

Author

Cinti, Francesca, Mezza, Teresa, Severi, I., Suleiman, M., Cefalo, Chiara Maria Assunta, Sorice, G. P., Moffa, Simona, Impronta, Flavia, Quero, Giuseppe, Alfieri, Sergio, Mari, A., Pontecorvi, Alfredo, Marselli, L., Cinti, Saverio, Marchetti, P., Giaccari, Andrea, Cinti F. (ORCID:0000-0001-5170-7055), Mezza T. (ORCID:0000-0001-5407-9576), Cefalo C. M. A., Moffa S., Impronta F., Quero G. (ORCID:0000-0002-0001-9479), Alfieri S. (ORCID:0000-0002-0404-724X), Pontecorvi A. (ORCID:0000-0003-0570-6865), Cinti S., Giaccari A. (ORCID:0000-0002-7462-7792), Cinti, Francesca, Mezza, Teresa, Severi, I., Suleiman, M., Cefalo, Chiara Maria Assunta, Sorice, G. P., Moffa, Simona, Impronta, Flavia, Quero, Giuseppe, Alfieri, Sergio, Mari, A., Pontecorvi, Alfredo, Marselli, L., Cinti, Saverio, Marchetti, P., Giaccari, Andrea, Cinti F. (ORCID:0000-0001-5170-7055), Mezza T. (ORCID:0000-0001-5407-9576), Cefalo C. M. A., Moffa S., Impronta F., Quero G. (ORCID:0000-0002-0001-9479), Alfieri S. (ORCID:0000-0002-0404-724X), Pontecorvi A. (ORCID:0000-0003-0570-6865), Cinti S., and Giaccari A. (ORCID:0000-0002-7462-7792)

Abstract

Aims/hypothesis: Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the “disappearance” of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. Methods: Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. Results: The islets of diabetic subjects were 3 times more innervated than controls (0.91 ± 0.21 vs 0.32 ± 0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = −0.84; p = 0.01), incremental second-phase insulin secretion (r = −0.84, p = 0.03) and arginine-stimulated insulin secretion (r = −0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). Conclusions/interpretation: Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.

Published
2021

16. 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

17. 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

23. 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

24. Ultra-high resolution MALDI-FTICR-MSI analysis of intact proteins in mouse and human pancreas tissue

Author

Piga, I, Heijs, B, Nicolardi, S, Giusti, L, Marselli, L, Marchetti, P, Mazzoni, M, Lucacchini, A, Mcdonnell, L, Piga, Isabella, Heijs, Bram, Nicolardi, Simone, Giusti, Laura, Marselli, Lorella, Marchetti, Piero, Mazzoni, Maria Rosa, Lucacchini, Antonio, McDonnell, Liam A., Piga, I, Heijs, B, Nicolardi, S, Giusti, L, Marselli, L, Marchetti, P, Mazzoni, M, Lucacchini, A, Mcdonnell, L, Piga, Isabella, Heijs, Bram, Nicolardi, Simone, Giusti, Laura, Marselli, Lorella, Marchetti, Piero, Mazzoni, Maria Rosa, Lucacchini, Antonio, and McDonnell, Liam A.

Abstract

Matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) of intact proteins is mostly performed using time-of-flight (TOF) based mass spectrometers, operated in linear mode. Linear MALDI-TOF systems provide limited mass resolving power and mass accuracy, which complicates assigning identities to the peaks in the MSI datasets. In this work we report ultra-high mass resolution MALDI-MSI based on 15T Fourier transform ion cyclotron resonance (FTICR) mass spectrometry for the analysis of intact proteins directly from non-embedded and OCT-embedded mouse and human (control and type 2 diabetes) pancreas so that small endocrine compartments (islets of Langerhans) may be analyzed in control and pathological tissues. Sample preparation methods, in terms of increased sensitivity while limiting lateral diffusion of analytes, have been investigated. By combining protein localization, high mass accuracy, and the clearly resolved isotope patterns we were able to assign protein identities with additional confidence, including proteins of similar average mass and with interspersed isotopomers. These capabilities allowed us to ascertain the presence of many protein adducts that, with a low resolving power instrument, could be misinterpreted as distinct protein ions. (C) 2017 Published by Elsevier B.V

Published
2019

25. Modulation of Autophagy Influences the Function and Survival of Human Pancreatic Beta Cells Under Endoplasmic Reticulum Stress Conditions and in Type 2 Diabetes

Author

Bugliani, M., Mossuto, Sandra, Grano, Francesca, Suleiman, Mara, Marselli, L., Boggi, U., De Simone, Paolo, Eizirik, Decio L., Cnop, Miriam, Marchetti, P., De Tata, Vincenzo, Bugliani, M., Mossuto, Sandra, Grano, Francesca, Suleiman, Mara, Marselli, L., Boggi, U., De Simone, Paolo, Eizirik, Decio L., Cnop, Miriam, Marchetti, P., and De Tata, Vincenzo

Abstract

Autophagy is the major mechanism involved in degradation and recycling of intracellular components, and its alterations have been proposed to cause beta cell dysfunction. In this study, we explored the effects of autophagy modulation in human islets under conditions associated to endoplasmic reticulum (ER) stress. Human pancreatic islets were isolated by enzymatic digestion and density gradient purification from pancreatic samples of non-diabetic (ND; n, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

30. 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

32. Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes

Author

Solimena, Michele, Schulte, A., Marselli, L., Ehehalt, F., Richter, D., Kleeberg, M., Mziaut, H., Knoch, K., Parnis, J., Bugliani, M., Siddiq, A., Jörns, A., Burdet, F., Liechti, R., Suleiman, M., Margerie, D., Syed, F., Distler, M., Grützmann, R., Petretto, E., Moreno-Moral, A., Wegbrod, C., Sönmez, A., Pfriem, K., Friedrich, A., Meinel, J., Wollheim, C., Baretton, G., Scharfmann, R., Nogoceke, E., Bonifacio, E., Sturm, D., Meyer-Puttlitz, B., Boggi, U., Saeger, H., Filipponi, F., Lesche, M., Meda, P., Dahl, A., Wigger, L., Xenarios, I., Falchi, M., Thorens, B., Weitz, J., Bokvist, K., Lenzen, S., Rutter, G., Froguel, P., von Bülow, M., Ibberson, M., Marchetti, P., Solimena, Michele, Schulte, A., Marselli, L., Ehehalt, F., Richter, D., Kleeberg, M., Mziaut, H., Knoch, K., Parnis, J., Bugliani, M., Siddiq, A., Jörns, A., Burdet, F., Liechti, R., Suleiman, M., Margerie, D., Syed, F., Distler, M., Grützmann, R., Petretto, E., Moreno-Moral, A., Wegbrod, C., Sönmez, A., Pfriem, K., Friedrich, A., Meinel, J., Wollheim, C., Baretton, G., Scharfmann, R., Nogoceke, E., Bonifacio, E., Sturm, D., Meyer-Puttlitz, B., Boggi, U., Saeger, H., Filipponi, F., Lesche, M., Meda, P., Dahl, A., Wigger, L., Xenarios, I., Falchi, M., Thorens, B., Weitz, J., Bokvist, K., Lenzen, S., Rutter, G., Froguel, P., von Bülow, M., Ibberson, M., and Marchetti, P.

Abstract

© 2017, The Author(s). Aims/hypothesis: Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium (www.imidia.org) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP). Methods: Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells. Results: Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate =0.05, fold change =1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and RE

Published
2018

34. Palmitate-induced lipotoxicity alters acetylation of multiple proteins in clonal beta cells and human pancreatic islets

Author

Ciregia, F, Bugliani, M, Ronci, M, Giusti, L, Boldrini, C, Mazzoni, Mr, Mossuto, S, Grano, F, Cnop, M, Marselli, L, Giannaccini, G, Urbani, Andrea, Lucacchini, A, Marchetti, P, Urbani, A (ORCID:0000-0001-9168-3174), Ciregia, F, Bugliani, M, Ronci, M, Giusti, L, Boldrini, C, Mazzoni, Mr, Mossuto, S, Grano, F, Cnop, M, Marselli, L, Giannaccini, G, Urbani, Andrea, Lucacchini, A, Marchetti, P, and Urbani, A (ORCID:0000-0001-9168-3174)

Abstract

Type 2 diabetes is characterized by progressive beta cell dysfunction, with lipotoxicity playing a possible pathogenetic role. Palmitate is often used to examine the direct effects of lipotoxicity and it may cause mitochondrial alterations by activating protein acetylation. However, it is unknown whether palmitate influences protein acetylation in beta cells. We investigated lysine acetylation in mitochondrial proteins from INS-1E beta cells (INS-1E) and in proteins from human pancreatic islets (HPI) after 24 h palmitate exposure. First, we confirmed that palmitate damages beta cells and demonstrated that chemical inhibition of deacetylation also impairs INS-1E function and survival. Then, by 2-D gel electrophoresis, Western Blot and Liquid Chromatography-Mass Spectrometry we evaluated the effects of palmitate on protein acetylation. In mitochondrial preparations from palmitate-treated INS-1E, 32 acetylated spots were detected, with 13 proteins resulting over-acetylated. In HPI, 136 acetylated proteins were found, of which 11 were over-acetylated upon culture with palmitate. Interestingly, three proteins, glutamate dehydrogenase, mitochondrial superoxide dismutase, and SREBP-1, were over-acetylated in both INS-1E and HPI. Therefore, prolonged exposure to palmitate induces changes in beta cell protein lysine acetylation and this modification could play a role in causing beta cell damage. Dysregulated acetylation may be a target to counteract palmitate-induced beta cell lipotoxicity.

Published
2017

35. 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

36. 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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40. TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic Beta Cells.

Author

Marroquí, Laura, Dos Santos, Reinaldo Sousa, Floyel, T, Grieco, Fabio Arturo, Santin Gomez, Izortze, Op de Beek, A, Marselli, L, Marchetti, Piero, Pociot, Flemming, Eizirik, Decio L., Marroquí, Laura, Dos Santos, Reinaldo Sousa, Floyel, T, Grieco, Fabio Arturo, Santin Gomez, Izortze, Op de Beek, A, Marselli, L, Marchetti, Piero, Pociot, Flemming, and Eizirik, Decio L.

Abstract

info:eu-repo/semantics/published

Published
2015

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