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Investigaci\u00f3n Biom\u00e9dica en Red","award":["CB07\/08\/0002"],"award-info":[{"award-number":["CB07\/08\/0002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven \u03b2-cell loss or by the progressive loss of \u03b2-cell function, due to continued metabolic stresses. Although both \u03b1- and \u03b2-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only \u03b1-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the \u03b1-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect \u03b2-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two \u03b2-cell lines\u2014namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-\u03b2H1 cells\u2014using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-\u03b2H1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced \u03b2-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-\u03b2H1 cells against the apoptosis triggered by these insults (&gt;80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in \u03b2-cells, participating both in cellular processes related to \u03b2-cell physiology and in fostering survival against pro-apoptotic insults.<\/jats:p>","DOI":"10.3390\/ijms24065657","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T03:50:45Z","timestamp":1678938645000},"page":"5657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["BCL-XL Overexpression Protects Pancreatic \u03b2-Cells against Cytokine- and Palmitate-Induced Apoptosis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7594-6365","authenticated-orcid":false,"given":"Atenea A.","family":"Perez-Serna","sequence":"first","affiliation":[{"name":"Instituto de Investigaci\u00f3n, Desarrollo e Innovaci\u00f3n en Biotecnolog\u00eda Sanitaria de Elche (IDiBE), Universidad Miguel Hern\u00e1ndez de Elche, 03202 Elche, Alicante, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas, Instituto de Salud Carlos III, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3219-4730","authenticated-orcid":false,"given":"Reinaldo S.","family":"Dos Santos","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n, Desarrollo e Innovaci\u00f3n en Biotecnolog\u00eda Sanitaria de Elche (IDiBE), Universidad Miguel Hern\u00e1ndez de Elche, 03202 Elche, Alicante, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas, Instituto de Salud Carlos III, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Ripoll","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n, Desarrollo e Innovaci\u00f3n en Biotecnolog\u00eda Sanitaria de Elche (IDiBE), Universidad Miguel Hern\u00e1ndez de Elche, 03202 Elche, Alicante, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas, Instituto de Salud Carlos III, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4178-2152","authenticated-orcid":false,"given":"Angel","family":"Nadal","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n, Desarrollo e Innovaci\u00f3n en Biotecnolog\u00eda Sanitaria de Elche (IDiBE), Universidad Miguel Hern\u00e1ndez de Elche, 03202 Elche, Alicante, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas, Instituto de Salud Carlos III, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Decio L.","family":"Eizirik","sequence":"additional","affiliation":[{"name":"ULB Center for Diabetes Research, Medical Faculty, Universit\u00e9 Libre de Bruxelles, 1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2931-9317","authenticated-orcid":false,"given":"Laura","family":"Marroqui","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n, Desarrollo e Innovaci\u00f3n en Biotecnolog\u00eda Sanitaria de Elche (IDiBE), Universidad Miguel Hern\u00e1ndez de Elche, 03202 Elche, Alicante, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas, Instituto de Salud Carlos III, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S97","DOI":"10.2337\/diabetes.54.suppl_2.S97","article-title":"Mechanisms of Pancreatic \u03b2-Cell Death in Type 1 and Type 2 Diabetes: Many Differences, Few Similarities","volume":"54","author":"Cnop","year":"2005","journal-title":"Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41574-020-0355-7","article-title":"Pancreatic \u03b2-Cells in Type 1 and Type 2 Diabetes Mellitus: Different Pathways to Failure","volume":"26","author":"Eizirik","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.tcb.2011.03.001","article-title":"Bcl-2 Proteins in Diabetes: Mitochondrial Pathways of \u03b2-Cell Death and Dysfunction","volume":"21","author":"Gurzov","year":"2011","journal-title":"Trends Cell Biol."},{"key":"ref_4","first-page":"a008714","article-title":"Mechanisms of Action of Bcl-2 Family Proteins","volume":"5","author":"Kale","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cell.2011.02.034","article-title":"Bcl-XL Retrotranslocates Bax from the Mitochondria into the Cytosol","volume":"145","author":"Edlich","year":"2011","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"39632","DOI":"10.1074\/jbc.M111.253591","article-title":"Cytokines Tumor Necrosis Factor-\u03b1 and Interferon-\u03b3 Induce Pancreatic \u03b2-Cell Apoptosis through STAT1-Mediated Bim Protein Activation","volume":"286","author":"Barthson","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1038\/cdd.2009.99","article-title":"Signaling by IL-1\u03b2+IFN-\u03b3 and ER Stress Converge on DP5\/Hrk Activation: A Novel Mechanism for Pancreatic \u03b2-Cell Apoptosis","volume":"16","author":"Gurzov","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.2337\/db12-0123","article-title":"Death Protein 5 and P53-Upregulated Modulator of Apoptosis Mediate the Endoplasmic Reticulum Stress\u2013Mitochondrial Dialog Triggering Lipotoxic Rodent and Human \u03b2-Cell Apoptosis","volume":"61","author":"Cunha","year":"2012","journal-title":"Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/s41419-020-2589-7","article-title":"BCL-XL\/BCL2L1 Is a Critical Anti-Apoptotic Protein That Promotes the Survival of Differentiating Pancreatic Cells from Human Pluripotent Stem Cells","volume":"11","author":"Loo","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/j.1582-4934.2007.00191.x","article-title":"Cytokine-Induced \u03b2-Cell Apoptosis Is NO-Dependent, Mitochondria-Mediated and Inhibited by BCL-XL","volume":"12","author":"Holohan","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.2337\/db08-1602","article-title":"Islet \u03b2-Cells Deficient in Bcl-XL Develop but Are Abnormally Sensitive to Apoptotic Stimuli","volume":"58","author":"Carrington","year":"2009","journal-title":"Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"19910","DOI":"10.1074\/jbc.M110.122374","article-title":"P53 Up-Regulated Modulator of Apoptosis (PUMA) Activation Contributes to Pancreatic \u03b2-Cell Apoptosis Induced by Proinflammatory Cytokines and Endoplasmic Reticulum Stress","volume":"285","author":"Gurzov","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e701","DOI":"10.1038\/cddis.2013.236","article-title":"Endoplasmic Reticulum Stress Sensitizes Pancreatic Beta Cells to Interleukin-1\u03b2-Induced Apoptosis via Bim\/A1 Imbalance","volume":"4","author":"Miani","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E340","DOI":"10.1152\/ajpendo.2000.278.2.E340","article-title":"Overexpression of Bcl-x(L) in \u03b2-Cells Prevents Cell Death but Impairs Mitochondrial Signal for Insulin Secretion","volume":"278","author":"Zhou","year":"2000","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.ebiom.2015.03.012","article-title":"Pancreatic \u03b1 Cells Are Resistant to Metabolic Stress-Induced Apoptosis in Type 2 Diabetes","volume":"2","author":"Marroqui","year":"2015","journal-title":"EBioMedicine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1172\/JCI117188","article-title":"Cytokines Suppress Human Islet Function Irrespective of Their Effects on Nitric Oxide Generation","volume":"93","author":"Eizirik","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9253","DOI":"10.1073\/pnas.91.20.9253","article-title":"Major Species Differences between Humans and Rodents in the Susceptibility to Pancreatic Beta-Cell Injury","volume":"91","author":"Eizirik","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1007\/s00125-015-3669-6","article-title":"Cytokines Induce Endoplasmic Reticulum Stress in Human, Rat and Mouse Beta Cells via Different Mechanisms","volume":"58","author":"Brozzi","year":"2015","journal-title":"Diabetologia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1006\/jsre.1997.4995","article-title":"Adenoviral Transfection of Isolated Pancreatic Islets: A Study of Programmed Cell Death (Apoptosis) and Islet Function","volume":"69","author":"Weber","year":"1997","journal-title":"J. Surg. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/ncb1302","article-title":"The Endoplasmic Reticulum Gateway to Apoptosis by Bcl-XL Modulation of the InsP3R","volume":"7","author":"White","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"170","DOI":"10.2337\/db11-1464","article-title":"Bcl-2 and Bcl-XL Suppress Glucose Signaling in Pancreatic \u03b2-Cells","volume":"62","author":"Luciani","year":"2013","journal-title":"Diabetes"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.ceca.2014.09.001","article-title":"Calcium Signaling in Pancreatic \u03b2-Cells in Health and in Type 2 Diabetes","volume":"56","author":"Gilon","year":"2014","journal-title":"Cell Calcium"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Klec, C., Ziomek, G., Pichler, M., Malli, R., and Graier, W.F. (2019). Calcium Signaling in SS-Cell Physiology and Pathology: A Revisit. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246110"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1242\/jcs.026062","article-title":"Initiation and Execution of Lipotoxic ER Stress in Pancreatic \u03b2-Cells","volume":"121","author":"Cunha","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1210\/er.2007-0015","article-title":"The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus","volume":"29","author":"Eizirik","year":"2008","journal-title":"Endocr. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5459","DOI":"10.1093\/emboj\/cdg533","article-title":"Bcl-XL\/Bcl-2 Coordinately Regulates Apoptosis, Cell Cycle Arrest and Cell Cycle Entry","volume":"22","author":"Janumyan","year":"2003","journal-title":"EMBO J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Borr\u00e1s, C., Mas-Bargues, C., Rom\u00e1n-Dom\u00ednguez, A., Sanz-Ros, J., Gimeno-Mallench, L., Ingl\u00e9s, M., Gambini, J., and Vi\u00f1a, J. (2020). BCL-XL, a Mitochondrial Protein Involved in Successful Aging: From C. Elegans to Human Centenarians. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020418"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1038\/ncb2330","article-title":"Bcl-XL Regulates Metabolic Efficiency of Neurons through Interaction with the Mitochondrial F1FO ATP Synthase","volume":"13","author":"Alavian","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"18","DOI":"10.2337\/db12-1023","article-title":"Dual Trade of Bcl-2 and Bcl-XL in Islet Physiology: Balancing Life and Death With Metabolism Secretion Coupling","volume":"62","author":"Soria","year":"2012","journal-title":"Diabetes"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Morris, J.L., Gillet, G., Prudent, J., and Popgeorgiev, N. (2021). Bcl-2 Family of Proteins in the Control of Mitochondrial Calcium Signalling: An Old Chap with New Roles. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073730"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1038\/sj.emboj.7601689","article-title":"Functional and Physical Interaction between Bcl-XL and a BH3-like Domain in Beclin-1","volume":"26","author":"Maiuri","year":"2007","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/j.1742-4658.2010.07965.x","article-title":"Bcl-2 and Bcl-XL Play Important Roles in the Crosstalk between Autophagy and Apoptosis","volume":"278","author":"Zhou","year":"2011","journal-title":"FEBS J."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pasula, D.J., Shi, R., Vanderkruk, B., Shih, A.Z.L., Zou, Y., Chaudhry, A., Hoffman, B.G., and Luciani, D.S. (2021). Bcl-XL Restricts Transcriptional, Morphological and Functional Decompensation of \u03b2-Cell Mitochondria under Chronic Glucose Excess. bioRxiv.","DOI":"10.1101\/2021.10.25.465491"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1083\/jcb.200405148","article-title":"The Diabetes-Linked Transcription Factor PAX4 Promotes \u03b2-Cell Proliferation and Survival in Rat and Human Islets","volume":"167","author":"Brun","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"50375","DOI":"10.1074\/jbc.M408493200","article-title":"Translocation of Bim to the Endoplasmic Reticulum (ER) Mediates ER Stress Signaling for Activation of Caspase-12 during ER Stress-Induced Apoptosis","volume":"279","author":"Morishima","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23629","DOI":"10.1074\/jbc.M114.569376","article-title":"Bcl-XL Protein Protects from C\/EBP Homologous Protein (CHOP)-Dependent Apoptosis during Plasma Cell Differentiation","volume":"289","author":"Gaudette","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/cdd.2010.68","article-title":"Bcl-2 Proteins Regulate ER Membrane Permeability to Luminal Proteins during ER Stress-Induced Apoptosis","volume":"18","author":"Wang","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Jabbour, L., Nguyen, T., Gadet, R., Lohez, O., Mikaelian, I., Gonzalo, P., Luyten, T., Chalabi-Dcha, M., Bultynck, G., and Rimokh, R. (2021). The Endoplasmic Reticulum Pool of Bcl-XL Dampens the Unfolded Protein Response through IP3R-Dependent Calcium Release. bioRxiv.","DOI":"10.1101\/2021.01.27.428229"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Wy\u017cewski, Z., \u015awitlik, W., Mielcarska, M.B., and Gregorczyk-Zboroch, K.P. (2021). The Role of Bcl-XL Protein in Viral Infections. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041956"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"22149","DOI":"10.3390\/ijms141122149","article-title":"The Protective Effect of Bcl-Xl Overexpression against Oxidative Stress-Induced Vascular Endothelial Cell Injury and the Role of the Akt\/ENOS Pathway","volume":"14","author":"Ni","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1073\/pnas.0333594100","article-title":"Bcl-XL Overexpression Blocks Bax-Mediated Mitochondrial Contact Site Formation and Apoptosis in Rod Photoreceptors of Lead-Exposed Mice","volume":"100","author":"He","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1007\/s00125-011-2070-3","article-title":"In Vivo Genetic Engineering of Murine Pancreatic Beta Cells Mediated by Single-Stranded Adeno-Associated Viral Vectors of Serotypes 6, 8 and 9","volume":"54","author":"Jimenez","year":"2011","journal-title":"Diabetologia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.molmet.2017.05.007","article-title":"AAV-Mediated Pancreatic Overexpression of Igf1 Counteracts Progression to Autoimmune Diabetes in Mice","volume":"6","author":"Mallol","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10518","DOI":"10.1038\/s41598-020-67136-w","article-title":"AAV8 Ins1-Cre Can Produce Efficient \u03b2-Cell Recombination but Requires Consideration of off-Target Effects","volume":"10","author":"Ramzy","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Singh, K., Bricard, O., Haughton, J., Bj\u00f6rkqvist, M., Thorstensson, M., Luo, Z., Mascali, L., Pasciuto, E., Mathieu, C., and Dooley, J. (2022). Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development. Biomolecules, 12.","DOI":"10.3390\/biom12101493"},{"key":"ref_46","first-page":"2111","article-title":"A Bcl-XL Transgene Promotes Malignant Conversion of Chemically Initiated Skin Papillomas","volume":"58","author":"Pena","year":"1998","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e355","DOI":"10.1038\/oncsis.2017.55","article-title":"Spontaneous Loss of B Lineage Transcription Factors Leads to Pre-B Leukemia in Ebf1+\/\u2013Bcl-XLTg Mice","volume":"6","author":"Delaney","year":"2017","journal-title":"Oncogenesis"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/s41419-021-04068-x","article-title":"BCLXL Gene Therapy Moderates Neuropathology in the DBA\/2J Mouse Model of Inherited Glaucoma","volume":"12","author":"Donahue","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.1172\/JCI58447","article-title":"A Genetically Engineered Human Pancreatic \u03b2 Cell Line Exhibiting Glucose-Inducible Insulin Secretion","volume":"121","author":"Ravassard","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/7651_2015_291","article-title":"Pancreatic Beta Cell Survival and Signaling Pathways: Effects of Type 1 Diabetes-Associated Genetic Variants","volume":"Volume 1433","author":"Santin","year":"2016","journal-title":"Methods in Molecular Biology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1210\/en.2017-00104","article-title":"Protective Role of Complement C3 against Cytokine-Mediated \u03b2-Cell Apoptosis","volume":"158","author":"Marroqui","year":"2017","journal-title":"Endocrinology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.2337\/db13-1443","article-title":"BACH2, a Candidate Risk Gene for Type 1 Diabetes, Regulates Apoptosis in Pancreatic \u03b2-Cells via JNK1 Modulation and Crosstalk with the Candidate Gene PTPN2","volume":"63","author":"Marroqui","year":"2014","journal-title":"Diabetes"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1007\/s001250100021","article-title":"A Choice of Death\u2014The Signal-Transduction of Immune-Mediated Beta-Cell Apoptosis","volume":"44","author":"Eizirik","year":"2001","journal-title":"Diabetologia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.2337\/diabetes.52.11.2701","article-title":"Discovery of Gene Networks Regulating Cytokine-Induced Dysfunction and Apoptosis in Insulin-Producing INS-1 Cells","volume":"52","author":"Kutlu","year":"2003","journal-title":"Diabetes"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1210\/me.2005-0268","article-title":"Cytokine-Induced Proapoptotic Gene Expression in Insulin-Producing Cells Is Related to Rapid, Sustained, and Nonoscillatory Nuclear Factor-\u039aB Activation","volume":"20","author":"Ortis","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"228","DOI":"10.2144\/000114285","article-title":"In Vitro Use of Free Fatty Acids Bound to Albumin: A Comparison of Protocols","volume":"58","author":"Oliveira","year":"2015","journal-title":"BioTechniques"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e1296995","DOI":"10.1080\/19382014.2017.1296995","article-title":"EndoC-\u0392H1 Cells Display Increased Sensitivity to Sodium Palmitate When Cultured in DMEM\/F12 Medium","volume":"9","author":"Krizhanovskii","year":"2017","journal-title":"Islets"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"107250","DOI":"10.1016\/j.envint.2022.107250","article-title":"G Protein-Coupled Estrogen Receptor Activation by Bisphenol-A Disrupts the Protection from Apoptosis Conferred by the Estrogen Receptors ER\u03b1 and ER\u03b2 in Pancreatic Beta Cells","volume":"164","author":"Encinar","year":"2022","journal-title":"Environ. Int."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3808","DOI":"10.2337\/db15-0362","article-title":"TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic \u03b2-Cells","volume":"64","author":"Marroqui","year":"2015","journal-title":"Diabetes"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1007\/s00125-016-4201-3","article-title":"Interferon-\u03b1 Mediates Human Beta Cell HLA Class I Overexpression, Endoplasmic Reticulum Stress and Apoptosis, Three Hallmarks of Early Human Type 1 Diabetes","volume":"60","author":"Marroqui","year":"2017","journal-title":"Diabetologia"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11770","DOI":"10.1038\/s41598-017-11995-3","article-title":"Molecular Mechanisms Involved in the Non-Monotonic Effect of Bisphenol-A on Ca2+ Entry in Mouse Pancreatic \u03b2-Cells","volume":"7","author":"Marroqui","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1210\/en.2013-1424","article-title":"Insulin Hypersecretion in Islets from Diet-Induced Hyperinsulinemic Obese Female Mice Is Associated with Several Functional Adaptations in Individual \u03b2-Cells","volume":"154","author":"Gonzalez","year":"2013","journal-title":"Endocrinology"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Dos Santos, R.S., Medina-Gali, R.M., Babiloni-Chust, I., Marroqui, L., and Nadal, A. (2022). In Vitro Assays to Identify Metabolism-Disrupting Chemicals with Diabetogenic Activity in a Human Pancreatic \u03b2-Cell Model. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095040"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.2337\/db16-0839","article-title":"DUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome with Diabetes and Bone Marrow Failure","volume":"66","author":"Daures","year":"2017","journal-title":"Diabetes"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1172\/JCI118950","article-title":"Glucose Promotes Survival of Rat Pancreatic \u03b2 Cells by Activating Synthesis of Proteins Which Suppress a Constitutive Apoptotic Program","volume":"98","author":"Hoorens","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.2337\/db08-1510","article-title":"PTPN2, a Candidate Gene for Type 1 Diabetes, Modulates Interferon-\u03b3- Induced Pancreatic \u03b2-Cell Apoptosis","volume":"58","author":"Moore","year":"2009","journal-title":"Diabetes"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1038\/cdd.2012.67","article-title":"C\/EBP Homologous Protein Contributes to Cytokine-Induced pro-Inflammatory Responses and Apoptosis in \u03b2-Cells","volume":"19","author":"Allagnat","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00125-018-4782-0","article-title":"DEXI, a Candidate Gene for Type 1 Diabetes, Modulates Rat and Human Pancreatic Beta Cell Inflammation via Regulation of the Type I IFN\/STAT Signalling Pathway","volume":"62","author":"Marroqui","year":"2019","journal-title":"Diabetologia"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Moore, F., Santin, I., Nogueira, T.C., Gurzov, E.N., Marselli, L., Marchetti, P., and Eizirik, D.L. 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