{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T17:31:28Z","timestamp":1755797488972,"version":"3.44.0"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100011570","name":"Stichting Diabetes Onderzoek Nederland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011570","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003092","name":"Diabetes Fonds","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003092","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Aims\/hypothesis<\/jats:title>\n            <jats:p>Identifying signalling pathways that are important in pancreatic beta cell stress and failure can give insight into possible treatment options to prevent the loss of functional beta cell mass in diabetes. The bone morphogenetic protein (BMP)\/SMAD family member <jats:italic>BMP5<\/jats:italic> has been reported to be specifically expressed in human beta cells, but its function is unknown. Here we hypothesised that BMP5 plays a role in the maintenance of beta cell function.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We assessed the expression of <jats:italic>BMP5<\/jats:italic> in publicly available single-cell RNA sequencing (scRNA-seq) datasets of primary human pancreatic islet cells from donors with or without type 2 diabetes, or islets exposed to stress conditions. Human islets and EndoC-\u03b2H1 cells were exposed to recombinant BMP5 and used for gene analysis, mitochondrial respiration and glucose-stimulated insulin secretion tests. In addition, we performed lentivirus\u2010mediated knockdown using short hairpin RNAs targeting <jats:italic>BMP5<\/jats:italic> in human islets and EndoC-\u03b2H1 cells for gene expression and glucose-stimulated insulin secretion analyses.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>scRNA-seq data revealed that <jats:italic>BMP5<\/jats:italic> is the most predominantly expressed BMP ligand in beta cells. <jats:italic>BMP5<\/jats:italic> and its target genes are upregulated in beta cells from donors with type 2 diabetes. Enhanced BMP5 signalling triggered an upregulation of stress-related genes, and a reduction in glucose-stimulated mitochondrial oxygen consumption and insulin secretion. In contrast, downregulation of <jats:italic>BMP5<\/jats:italic> in primary human islets enhanced beta cell function, which was associated with increased expression of key beta cell genes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>Altogether, these findings point toward a role for BMP5 in the regulation of beta cell function.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-025-06457-9","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T10:31:15Z","timestamp":1749119475000},"page":"1983-1996","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BMP5 signalling in beta cells and the impact on insulin secretion in the context of type 2 diabetes"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5404-1225","authenticated-orcid":false,"given":"Esm\u00e9e","family":"Dekker","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7230-3674","authenticated-orcid":false,"given":"Twan J. J.","family":"de Winter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8634-3244","authenticated-orcid":false,"given":"Amadeo","family":"Mu\u00f1oz Garcia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0924-7346","authenticated-orcid":false,"given":"Natascha","family":"de Graaf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9714-9735","authenticated-orcid":false,"given":"Maaike J.","family":"Roodzant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1232-7022","authenticated-orcid":false,"given":"Eelco J. P.","family":"de Koning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7929-8468","authenticated-orcid":false,"given":"Fran\u00e7oise","family":"Carlotti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"issue":"7","key":"6457_CR1","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/s41574-020-0355-7","volume":"16","author":"DL Eizirik","year":"2020","unstructured":"Eizirik DL, Pasquali L, Cnop M (2020) Pancreatic \u03b2-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol 16(7):349\u2013362. https:\/\/doi.org\/10.1038\/s41574-020-0355-7","journal-title":"Nat Rev Endocrinol"},{"issue":"10","key":"6457_CR2","doi-asserted-by":"publisher","first-page":"4974","DOI":"10.1210\/jcem.86.10.7938","volume":"86","author":"L Marselli","year":"2001","unstructured":"Marselli L, Dotta F, Piro S et al (2001) Th2 cytokines have a partial, direct protective effect on the function and survival of isolated human islets exposed to combined proinflammatory and Th1 cytokines. J Clin Endocrinol Metab 86(10):4974\u20134978. https:\/\/doi.org\/10.1210\/jcem.86.10.7938","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"6457_CR3","doi-asserted-by":"publisher","first-page":"2115","DOI":"10.1007\/s001250100021","volume":"44","author":"DL Eizirik","year":"2001","unstructured":"Eizirik DL, Mandrup-Poulsen T (2001) A choice of death \u2013 the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 44(12):2115\u20132133. https:\/\/doi.org\/10.1007\/s001250100021","journal-title":"Diabetologia"},{"issue":"2","key":"6457_CR4","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1007\/s00125-012-2762-3","volume":"56","author":"DL Eizirik","year":"2013","unstructured":"Eizirik DL, Miani M, Cardozo AK (2013) Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia 56(2):234\u2013241. https:\/\/doi.org\/10.1007\/s00125-012-2762-3","journal-title":"Diabetologia"},{"issue":"1","key":"6457_CR5","doi-asserted-by":"publisher","first-page":"6285","DOI":"10.1038\/s41598-017-06731-w","volume":"7","author":"TM Nordmann","year":"2017","unstructured":"Nordmann TM, Dror E, Schulze F et al (2017) The role of inflammation in \u03b2-cell dedifferentiation. Sci Rep 7(1):6285. https:\/\/doi.org\/10.1038\/s41598-017-06731-w","journal-title":"Sci Rep"},{"key":"6457_CR6","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jaut.2018.08.003","volume":"94","author":"A Lombardi","year":"2018","unstructured":"Lombardi A, Tsomos E, Hammerstad SS, Tomer Y (2018) Interferon alpha: the key trigger of type 1 diabetes. J Autoimmun 94:7\u201315. https:\/\/doi.org\/10.1016\/j.jaut.2018.08.003","journal-title":"J Autoimmun"},{"issue":"4","key":"6457_CR7","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/s0896-8411(03)00039-8","volume":"20","author":"G Wachlin","year":"2003","unstructured":"Wachlin G, Augstein P, Schr\u00f6der D et al (2003) IL-1\u03b2, IFN-\u03b3 and TNF-\u03b1 increase vulnerability of pancreatic beta cells to autoimmune destruction. J Autoimmun 20(4):303\u2013312. https:\/\/doi.org\/10.1016\/s0896-8411(03)00039-8","journal-title":"J Autoimmun"},{"issue":"8","key":"6457_CR8","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.2337\/db08-0178","volume":"58","author":"LG Grunnet","year":"2009","unstructured":"Grunnet LG, Aikin R, Tonnesen MF et al (2009) Proinflammatory cytokines activate the intrinsic apoptotic pathway in \u03b2-cells. Diabetes 58(8):1807\u20131815. https:\/\/doi.org\/10.2337\/db08-0178","journal-title":"Diabetes"},{"issue":"8","key":"6457_CR9","doi-asserted-by":"publisher","first-page":"E715","DOI":"10.1152\/ajpendo.00153.2015","volume":"309","author":"SJ Burke","year":"2015","unstructured":"Burke SJ, Stadler K, Lu D et al (2015) IL-1\u03b2 reciprocally regulates chemokine and insulin secretion in pancreatic \u03b2-cells via NF-\u03baB. Am J Physiol Endocrinol Metab 309(8):E715\u2013E726. https:\/\/doi.org\/10.1152\/ajpendo.00153.2015","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"10","key":"6457_CR10","doi-asserted-by":"publisher","first-page":"4065","DOI":"10.1210\/jc.2008-0396","volume":"93","author":"M B\u00f6ni-Schnetzler","year":"2008","unstructured":"B\u00f6ni-Schnetzler M, Thorne J, Parnaud G et al (2008) Increased interleukin (IL)-1\u03b2 messenger ribonucleic acid expression in \u03b2-cells of individuals with type 2 diabetes and regulation of IL-1\u03b2 in human islets by glucose and autostimulation. J Clin Endocrinol Metab 93(10):4065\u20134074. https:\/\/doi.org\/10.1210\/jc.2008-0396","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"6457_CR11","doi-asserted-by":"publisher","first-page":"2356","DOI":"10.2337\/db06-1650","volume":"56","author":"JA Ehses","year":"2007","unstructured":"Ehses JA, Perren A, Eppler E et al (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56(9):2356\u20132370. https:\/\/doi.org\/10.2337\/db06-1650","journal-title":"Diabetes"},{"issue":"2","key":"6457_CR12","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1038\/nri2925","volume":"11","author":"MY Donath","year":"2011","unstructured":"Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98\u2013107. https:\/\/doi.org\/10.1038\/nri2925","journal-title":"Nat Rev Immunol"},{"key":"6457_CR13","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1152\/physiol.00032.2009","volume":"24","author":"MY Donath","year":"2009","unstructured":"Donath MY, B\u00f6ni-Schnetzler M, Ellingsgaard H, Ehses JA (2009) Islet inflammation impairs the pancreatic \u03b2-cell in type 2 diabetes. Physiology (Bethesda) 24:325\u2013331. https:\/\/doi.org\/10.1152\/physiol.00032.2009","journal-title":"Physiology (Bethesda)"},{"issue":"3","key":"6457_CR14","doi-asserted-by":"publisher","first-page":"812","DOI":"10.2337\/diabetes.52.3.812","volume":"52","author":"J Spranger","year":"2003","unstructured":"Spranger J, Kroke A, M\u00f6hlig M et al (2003) Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 52(3):812\u2013817. https:\/\/doi.org\/10.2337\/diabetes.52.3.812","journal-title":"Diabetes"},{"issue":"10","key":"6457_CR15","doi-asserted-by":"publisher","first-page":"2307","DOI":"10.1007\/s00125-015-3669-6","volume":"58","author":"F Brozzi","year":"2015","unstructured":"Brozzi F, Nardelli TR, Lopes M et al (2015) Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms. Diabetologia 58(10):2307\u20132316. https:\/\/doi.org\/10.1007\/s00125-015-3669-6","journal-title":"Diabetologia"},{"issue":"2","key":"6457_CR16","doi-asserted-by":"publisher","first-page":"452","DOI":"10.2337\/diabetes.54.2.452","volume":"54","author":"AK Cardozo","year":"2005","unstructured":"Cardozo AK, Ortis F, Storling J et al (2005) Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic \u03b2-cells. Diabetes 54(2):452\u2013461. https:\/\/doi.org\/10.2337\/diabetes.54.2.452","journal-title":"Diabetes"},{"issue":"Suppl 3","key":"6457_CR17","doi-asserted-by":"publisher","first-page":"S16","DOI":"10.2337\/diabetes.53.suppl_3.s16","volume":"53","author":"GC Weir","year":"2004","unstructured":"Weir GC, Bonner-Weir S (2004) Five stages of evolving \u03b2-cell dysfunction during progression to diabetes. Diabetes 53(Suppl 3):S16\u2013S21. https:\/\/doi.org\/10.2337\/diabetes.53.suppl_3.s16","journal-title":"Diabetes"},{"issue":"9","key":"6457_CR18","doi-asserted-by":"publisher","first-page":"2676","DOI":"10.2337\/db15-1718","volume":"65","author":"C Chen","year":"2016","unstructured":"Chen C, Chmelova H, Cohrs CM et al (2016) Alterations in \u03b2-cell calcium dynamics and efficacy outweigh islet mass adaptation in compensation of insulin resistance and prediabetes onset. Diabetes 65(9):2676\u20132685. https:\/\/doi.org\/10.2337\/db15-1718","journal-title":"Diabetes"},{"issue":"10","key":"6457_CR19","doi-asserted-by":"publisher","first-page":"3515","DOI":"10.1210\/en.2013-1424","volume":"154","author":"A Gonzalez","year":"2013","unstructured":"Gonzalez A, Merino B, Marroqu\u00ed L et al (2013) Insulin hypersecretion in islets from diet-induced hyperinsulinemic obese female mice is associated with several functional adaptations in individual \u03b2-cells. Endocrinology 154(10):3515\u20133524. https:\/\/doi.org\/10.1210\/en.2013-1424","journal-title":"Endocrinology"},{"key":"6457_CR20","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.mce.2015.01.033","volume":"404","author":"E Irles","year":"2015","unstructured":"Irles E, \u00d1eco P, Lluesma M et al (2015) Enhanced glucose-induced intracellular signaling promotes insulin hypersecretion: pancreatic beta-cell functional adaptations in a model of genetic obesity and prediabetes. Mol Cell Endocrinol 404:46\u201355. https:\/\/doi.org\/10.1016\/j.mce.2015.01.033","journal-title":"Mol Cell Endocrinol"},{"key":"6457_CR21","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3389\/fncel.2013.00087","volume":"7","author":"B G\u00e1mez","year":"2013","unstructured":"G\u00e1mez B, Rodriguez-Carballo E, Ventura F (2013) BMP signaling in telencephalic neural cell specification and maturation. Front Cell Neurosci 7:87. https:\/\/doi.org\/10.3389\/fncel.2013.00087","journal-title":"Front Cell Neurosci"},{"issue":"4","key":"6457_CR22","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.cels.2016.09.002","volume":"3","author":"MJ Muraro","year":"2016","unstructured":"Muraro MJ, Dharmadhikari G, Gr\u00fcn D et al (2016) A single-cell transcriptome atlas of the human pancreas. Cell Syst 3(4):385-394.e383. https:\/\/doi.org\/10.1016\/j.cels.2016.09.002","journal-title":"Cell Syst"},{"issue":"5","key":"6457_CR23","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.cmet.2016.04.002","volume":"23","author":"HE Arda","year":"2016","unstructured":"Arda HE, Li L, Tsai J et al (2016) Age-dependent pancreatic gene regulation reveals mechanisms governing human \u03b2 cell function. Cell Metab 23(5):909\u2013920. https:\/\/doi.org\/10.1016\/j.cmet.2016.04.002","journal-title":"Cell Metab"},{"issue":"9","key":"6457_CR24","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.1101\/gr.150706.112","volume":"23","author":"AC Nica","year":"2013","unstructured":"Nica AC, Ongen H, Irminger JC et al (2013) Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome. Genome Res 23(9):1554\u20131562. https:\/\/doi.org\/10.1101\/gr.150706.112","journal-title":"Genome Res"},{"issue":"18","key":"6457_CR25","doi-asserted-by":"publisher","first-page":"e151621","DOI":"10.1172\/jci.insight.151621","volume":"6","author":"S Shrestha","year":"2021","unstructured":"Shrestha S, Saunders DC, Walker JT et al (2021) Combinatorial transcription factor profiles predict mature and functional human islet \u03b1 and \u03b2 cells. JCI Insight 6(18):e151621. https:\/\/doi.org\/10.1172\/jci.insight.151621","journal-title":"JCI Insight"},{"issue":"Pt 4","key":"6457_CR26","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1242\/jcs.115.4.753","volume":"115","author":"FX Jiang","year":"2002","unstructured":"Jiang FX, Stanley EG, Gonez LJ, Harrison LC (2002) Bone morphogenetic proteins promote development of fetal pancreas epithelial colonies containing insulin-positive cells. J Cell Sci 115(Pt 4):753\u2013760. https:\/\/doi.org\/10.1242\/jcs.115.4.753","journal-title":"J Cell Sci"},{"issue":"5","key":"6457_CR27","doi-asserted-by":"publisher","first-page":"418","DOI":"10.21037\/atm-21-831","volume":"9","author":"YY Qiu","year":"2021","unstructured":"Qiu YY, Zhang HS, Tang Y et al (2021) Mitochondrial dysfunction resulting from the down-regulation of bone morphogenetic protein\u00a05 may cause microtia. Ann Transl Med 9(5):418. https:\/\/doi.org\/10.21037\/atm-21-831","journal-title":"Ann Transl Med"},{"key":"6457_CR28","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.bbrc.2022.12.071","volume":"643","author":"B Pang","year":"2023","unstructured":"Pang B, Zhang LL, Li B, Sun FX, Wang ZD (2023) BMP5 ameliorates diabetic peripheral neuropathy by augmenting mitochondrial function and inhibiting apoptosis in Schwann cells. Biochem Biophys Res Commun 643:69\u201376. https:\/\/doi.org\/10.1016\/j.bbrc.2022.12.071","journal-title":"Biochem Biophys Res Commun"},{"issue":"11","key":"6457_CR29","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.2337\/db23-0130","volume":"72","author":"RM Elgamal","year":"2023","unstructured":"Elgamal RM, Kudtarkar P, Melton RL et al (2023) An integrated map of cell type-specific gene expression in pancreatic islets. Diabetes 72(11):1719\u20131728. https:\/\/doi.org\/10.2337\/db23-0130","journal-title":"Diabetes"},{"issue":"12","key":"6457_CR30","doi-asserted-by":"publisher","first-page":"e1002585","DOI":"10.1371\/journal.pbio.1002585","volume":"14","author":"A Richard","year":"2016","unstructured":"Richard A, Boullu L, Herbach U et al (2016) Single-cell-based analysis highlights a surge in cell-to-cell molecular variability preceding irreversible commitment in a differentiation process. PLoS Biol 14(12):e1002585. https:\/\/doi.org\/10.1371\/journal.pbio.1002585","journal-title":"PLoS Biol"},{"issue":"1","key":"6457_CR31","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.1038\/s41467-022-29588-8","volume":"13","author":"L van Gurp","year":"2022","unstructured":"van Gurp L, Fodoulian L, Oropeza D et al (2022) Generation of human islet cell type-specific identity genesets. Nat Commun 13(1):2020. https:\/\/doi.org\/10.1038\/s41467-022-29588-8","journal-title":"Nat Commun"},{"issue":"43","key":"6457_CR32","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545\u201315550. https:\/\/doi.org\/10.1073\/pnas.0506580102","journal-title":"Proc Natl Acad Sci USA"},{"issue":"3","key":"6457_CR33","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/ng1180","volume":"34","author":"VK Mootha","year":"2003","unstructured":"Mootha VK, Lindgren CM, Eriksson KF et al (2003) PGC-1\u03b1-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):267\u2013273. https:\/\/doi.org\/10.1038\/ng1180","journal-title":"Nat Genet"},{"key":"6457_CR34","doi-asserted-by":"publisher","first-page":"1381319","DOI":"10.3389\/fimmu.2024.1381319","volume":"15","author":"A Mu\u00f1oz Garc\u00eda","year":"2024","unstructured":"Mu\u00f1oz Garc\u00eda A, Juksar J, Groen N, Zaldumbide A, de Koning E, Carlotti F (2024) Single-cell transcriptomics reveals a role for pancreatic duct cells as potential mediators of inflammation in diabetes mellitus. Front Immunol 15:1381319. https:\/\/doi.org\/10.3389\/fimmu.2024.1381319","journal-title":"Front Immunol"},{"issue":"1","key":"6457_CR35","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1111\/ajt.13425","volume":"16","author":"MF Nijhoff","year":"2016","unstructured":"Nijhoff MF, Engelse MA, Dubbeld J et al (2016) Glycemic stability through islet-after-kidney transplantation using an alemtuzumab-based induction regimen and long-term triple-maintenance immunosuppression. Am J Transplant 16(1):246\u2013253. https:\/\/doi.org\/10.1111\/ajt.13425","journal-title":"Am J Transplant"},{"issue":"9","key":"6457_CR36","doi-asserted-by":"publisher","first-page":"3589","DOI":"10.1172\/JCI58447","volume":"121","author":"P Ravassard","year":"2011","unstructured":"Ravassard P, Hazhouz Y, Pechberty S et al (2011) A genetically engineered human pancreatic \u03b2 cell line exhibiting glucose-inducible insulin secretion. J Clin Investig 121(9):3589\u20133597. https:\/\/doi.org\/10.1172\/JCI58447","journal-title":"J Clin Investig"},{"issue":"2","key":"6457_CR37","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.ymthe.2003.11.021","volume":"9","author":"F Carlotti","year":"2004","unstructured":"Carlotti F, Bazuine M, Kekarainen T et al (2004) Lentiviral vectors efficiently transduce quiescent mature 3T3-L1 adipocytes. Mol Ther 9(2):209\u2013217. https:\/\/doi.org\/10.1016\/j.ymthe.2003.11.021","journal-title":"Mol Ther"},{"issue":"5","key":"6457_CR38","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1172\/JCI72674","volume":"124","author":"R Scharfmann","year":"2014","unstructured":"Scharfmann R, Pechberty S, Hazhouz Y et al (2014) Development of a conditionally immortalized human pancreatic beta cell line. J Clin Invest 124(5):2087\u20132098. https:\/\/doi.org\/10.1172\/JCI72674","journal-title":"J Clin Invest"},{"issue":"4","key":"6457_CR39","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1210\/jcem.84.4.5612","volume":"84","author":"RJ Mahler","year":"1999","unstructured":"Mahler RJ, Adler ML (1999) Clinical review 102: Type 2 diabetes mellitus: update on diagnosis, pathophysiology, and treatment. J Clin Endocrinol Metab 84(4):1165\u20131171. https:\/\/doi.org\/10.1210\/jcem.84.4.5612","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"6457_CR40","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/nrendo.2016.105","volume":"12","author":"P Zimmet","year":"2016","unstructured":"Zimmet P, Alberti KG, Magliano DJ, Bennett PH (2016) Diabetes mellitus statistics on prevalence and mortality: facts and fallacies. Nat Rev Endocrinol 12(10):616\u2013622. https:\/\/doi.org\/10.1038\/nrendo.2016.105","journal-title":"Nat Rev Endocrinol"},{"issue":"2","key":"6457_CR41","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/s41556-018-0271-4","volume":"21","author":"GG Nair","year":"2019","unstructured":"Nair GG, Liu JS, Russ HA et al (2019) Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived \u03b2 cells. Nat Cell Biol 21(2):263\u2013274. https:\/\/doi.org\/10.1038\/s41556-018-0271-4","journal-title":"Nat Cell Biol"},{"issue":"5","key":"6457_CR42","doi-asserted-by":"publisher","first-page":"e33023","DOI":"10.1371\/journal.pone.0033023","volume":"7","author":"JD Wikstrom","year":"2012","unstructured":"Wikstrom JD, Sereda SB, Stiles L et al (2012) A novel high-throughput assay for islet respiration reveals uncoupling of rodent and human islets. PLoS One 7(5):e33023. https:\/\/doi.org\/10.1371\/journal.pone.0033023","journal-title":"PLoS One"},{"issue":"4","key":"6457_CR43","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1152\/physrev.00009.2016","volume":"96","author":"DG Nicholls","year":"2016","unstructured":"Nicholls DG (2016) The pancreatic \u03b2-cell: a bioenergetic perspective. Physiol Rev 96(4):1385\u20131447. https:\/\/doi.org\/10.1152\/physrev.00009.2016","journal-title":"Physiol Rev"},{"issue":"3","key":"6457_CR44","doi-asserted-by":"publisher","first-page":"e0120879","DOI":"10.1371\/journal.pone.0120879","volume":"10","author":"LE Andersson","year":"2015","unstructured":"Andersson LE, Valtat B, Bagge A et al (2015) Characterization of stimulus-secretion coupling in the human pancreatic EndoC-\u03b2H1 beta cell line. PLoS One 10(3):e0120879. https:\/\/doi.org\/10.1371\/journal.pone.0120879","journal-title":"PLoS One"},{"issue":"2","key":"6457_CR45","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1007\/s00125-006-0490-2","volume":"50","author":"H Wang","year":"2007","unstructured":"Wang H, Brun T, Kataoka K, Sharma AJ, Wollheim CB (2007) MAFA controls genes implicated in insulin biosynthesis and secretion. Diabetologia 50(2):348\u2013358. https:\/\/doi.org\/10.1007\/s00125-006-0490-2","journal-title":"Diabetologia"},{"issue":"12","key":"6457_CR46","doi-asserted-by":"publisher","first-page":"4969","DOI":"10.1128\/mcb.25.12.4969-4976.2005","volume":"25","author":"C Zhang","year":"2005","unstructured":"Zhang C, Moriguchi T, Kajihara M et al (2005) MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol 25(12):4969\u20134976. https:\/\/doi.org\/10.1128\/mcb.25.12.4969-4976.2005","journal-title":"Mol Cell Biol"},{"issue":"2","key":"6457_CR47","doi-asserted-by":"publisher","first-page":"e13761","DOI":"10.1111\/apha.13761","volume":"234","author":"LR Cataldo","year":"2022","unstructured":"Cataldo LR, Singh T, Achanta K et al (2022) MAFA and MAFB regulate exocytosis-related genes in human \u03b2-cells. Acta Physiol (Oxf) 234(2):e13761. https:\/\/doi.org\/10.1111\/apha.13761","journal-title":"Acta Physiol (Oxf)"},{"issue":"8","key":"6457_CR48","doi-asserted-by":"publisher","first-page":"3305","DOI":"10.1172\/jci65390","volume":"123","author":"S Guo","year":"2013","unstructured":"Guo S, Dai C, Guo M et al (2013) Inactivation of specific \u03b2 cell transcription factors in type 2 diabetes. J Clin Invest 123(8):3305\u20133316. https:\/\/doi.org\/10.1172\/jci65390","journal-title":"J Clin Invest"},{"issue":"8","key":"6457_CR49","doi-asserted-by":"publisher","first-page":"2928","DOI":"10.2337\/db14-1752","volume":"64","author":"HS Spijker","year":"2015","unstructured":"Spijker HS, Song H, Ellenbroek JH et al (2015) Loss of \u03b2-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits. Diabetes 64(8):2928\u20132938. https:\/\/doi.org\/10.2337\/db14-1752","journal-title":"Diabetes"},{"issue":"1","key":"6457_CR50","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1186\/s13287-020-01977-0","volume":"11","author":"II Aigha","year":"2020","unstructured":"Aigha II, Abdelalim EM (2020) NKX6.1 transcription factor: a crucial regulator of pancreatic \u03b2 cell development, identity, and proliferation. Stem Cell Res Ther 11(1):459. https:\/\/doi.org\/10.1186\/s13287-020-01977-0","journal-title":"Stem Cell Res Ther"},{"issue":"6","key":"6457_CR51","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1016\/j.celrep.2013.08.010","volume":"4","author":"BL Taylor","year":"2013","unstructured":"Taylor BL, Liu FF, Sander M (2013) Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Rep 4(6):1262\u20131275. https:\/\/doi.org\/10.1016\/j.celrep.2013.08.010","journal-title":"Cell Rep"},{"issue":"1","key":"6457_CR52","doi-asserted-by":"publisher","first-page":"e1003274","DOI":"10.1371\/journal.pgen.1003274","volume":"9","author":"AE Schaffer","year":"2013","unstructured":"Schaffer AE, Taylor BL, Benthuysen JR et al (2013) Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic beta cell identity. PLoS Genet 9(1):e1003274. https:\/\/doi.org\/10.1371\/journal.pgen.1003274","journal-title":"PLoS Genet"},{"issue":"1","key":"6457_CR53","doi-asserted-by":"publisher","first-page":"e2400470","DOI":"10.1002\/adbi.202400470","volume":"9","author":"E Dekker","year":"2024","unstructured":"Dekker E, Tri\u00f1anes J, Mu\u00f1oz Garcia A, de Graaf N, de Koning E, Carlotti F (2024) Enhanced BMP signaling alters human \u03b2-cell identity and function. Adv Biol (Weinh) 9(1):e2400470. https:\/\/doi.org\/10.1002\/adbi.202400470","journal-title":"Adv Biol (Weinh)"},{"issue":"7","key":"6457_CR54","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41419-023-05906-w","volume":"14","author":"AI Urizar","year":"2023","unstructured":"Urizar AI, Prause M, Ingerslev LR et al (2023) Beta cell dysfunction induced by bone morphogenetic protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding. Cell Death Dis 14(7):399. https:\/\/doi.org\/10.1038\/s41419-023-05906-w","journal-title":"Cell Death Dis"},{"issue":"12","key":"6457_CR55","doi-asserted-by":"publisher","first-page":"2546","DOI":"10.1007\/s00125-014-3384-8","volume":"57","author":"C Bruun","year":"2014","unstructured":"Bruun C, Christensen GL, Jacobsen ML et al (2014) Inhibition of beta cell growth and function by bone morphogenetic proteins. Diabetologia 57(12):2546\u20132554. https:\/\/doi.org\/10.1007\/s00125-014-3384-8","journal-title":"Diabetologia"},{"issue":"6","key":"6457_CR56","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1007\/s00125-015-3568-x","volume":"58","author":"GL Christensen","year":"2015","unstructured":"Christensen GL, Jacobsen ML, Wendt A et al (2015) Bone morphogenetic protein 4 inhibits insulin secretion from rodent beta cells through regulation of calbindin1 expression and reduced voltage-dependent calcium currents. Diabetologia 58(6):1282\u20131290. https:\/\/doi.org\/10.1007\/s00125-015-3568-x","journal-title":"Diabetologia"},{"issue":"18","key":"6457_CR57","doi-asserted-by":"publisher","first-page":"2364","DOI":"10.1161\/01.Cir.0000164201.40634.1d","volume":"111","author":"A Csiszar","year":"2005","unstructured":"Csiszar A, Smith KE, Koller A, Kaley G, Edwards JG, Ungvari Z (2005) Regulation of bone morphogenetic protein-2 expression in endothelial cells: role of nuclear factor-\u03baB activation by tumor necrosis factor-\u03b1, H2O2, and high intravascular pressure. Circulation 111(18):2364\u20132372. https:\/\/doi.org\/10.1161\/01.Cir.0000164201.40634.1d","journal-title":"Circulation"},{"issue":"33","key":"6457_CR58","doi-asserted-by":"publisher","first-page":"31128","DOI":"10.1074\/jbc.M300703200","volume":"278","author":"GP Sorescu","year":"2003","unstructured":"Sorescu GP, Sykes M, Weiss D et al (2003) Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response. J Biol Chem 278(33):31128\u201331135. https:\/\/doi.org\/10.1074\/jbc.M300703200","journal-title":"J Biol Chem"},{"issue":"1","key":"6457_CR59","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1186\/s13075-015-0710-6","volume":"17","author":"A Varas","year":"2015","unstructured":"Varas A, Valencia J, Lavocat F et al (2015) Blockade of bone morphogenetic protein signaling potentiates the pro-inflammatory phenotype induced by interleukin-17 and tumor necrosis factor-\u03b1 combination in rheumatoid synoviocytes. Arthritis Res Ther 17(1):192. https:\/\/doi.org\/10.1186\/s13075-015-0710-6","journal-title":"Arthritis Res Ther"},{"issue":"10","key":"6457_CR60","doi-asserted-by":"publisher","first-page":"2807","DOI":"10.1002\/art.11389","volume":"48","author":"RJ Lories","year":"2003","unstructured":"Lories RJ, Derese I, Ceuppens JL, Luyten FP (2003) Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis. Arthritis Rheum 48(10):2807\u20132818. https:\/\/doi.org\/10.1002\/art.11389","journal-title":"Arthritis Rheum"},{"issue":"1","key":"6457_CR61","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1089\/jir.2014.0199","volume":"36","author":"A Ibarra Urizar","year":"2016","unstructured":"Ibarra Urizar A, Friberg J, Christensen DP, Lund Christensen G, Billestrup N (2016) Inflammatory cytokines stimulate bone morphogenetic protein-2 expression and release from pancreatic beta cells. J Interferon Cytokine Res 36(1):20\u201329. https:\/\/doi.org\/10.1089\/jir.2014.0199","journal-title":"J Interferon Cytokine Res"},{"issue":"2","key":"6457_CR62","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/s42255-022-00531-x","volume":"4","author":"M Fasolino","year":"2022","unstructured":"Fasolino M, Schwartz GW, Patil AR et al (2022) Single-cell multi-omics analysis of human pancreatic islets reveals novel cellular states in type 1 diabetes. Nat Metab 4(2):284\u2013299. https:\/\/doi.org\/10.1038\/s42255-022-00531-x","journal-title":"Nat Metab"},{"key":"6457_CR63","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/s41467-021-27622-9","volume":"13","author":"S Vukicevic","year":"2022","unstructured":"Vukicevic S, Colliva A, Kufner V et al (2022) Bone morphogenetic protein 1.3 inhibition decreases scar formation and supports cardiomyocyte survival after myocardial infarction. Nat Commun 13:81. https:\/\/doi.org\/10.1038\/s41467-021-27622-9","journal-title":"Nat Commun"},{"issue":"4","key":"6457_CR64","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1002\/stem.2533","volume":"35","author":"HY Shih","year":"2017","unstructured":"Shih HY, Hsu SY, Ouyang P et al (2017) Bmp5 regulates neural crest cell survival and proliferation via two different signaling pathways. Stem Cells 35(4):1003\u20131014. https:\/\/doi.org\/10.1002\/stem.2533","journal-title":"Stem Cells"},{"issue":"7","key":"6457_CR65","doi-asserted-by":"publisher","first-page":"9646","DOI":"10.18632\/aging.202708","volume":"13","author":"Y Shao","year":"2021","unstructured":"Shao Y, Zhao C, Pan J et al (2021) BMP5 silencing inhibits chondrocyte senescence and apoptosis as well as osteoarthritis progression in mice. Aging (Albany NY) 13(7):9646\u20139664. https:\/\/doi.org\/10.18632\/aging.202708","journal-title":"Aging (Albany NY)"},{"issue":"7","key":"6457_CR66","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1038\/s12276-023-01019-8","volume":"55","author":"E-H Choi","year":"2023","unstructured":"Choi E-H, Park S-J (2023) TXNIP: A key protein in the cellular stress response pathway and a potential therapeutic target. Exp Mol Med 55(7):1348\u20131356. https:\/\/doi.org\/10.1038\/s12276-023-01019-8","journal-title":"Exp Mol Med"},{"issue":"10","key":"6457_CR67","doi-asserted-by":"publisher","first-page":"3581","DOI":"10.1096\/fj.08-111690","volume":"22","author":"J Chen","year":"2008","unstructured":"Chen J, Hui ST, Couto FM et al (2008) Thioredoxin-interacting protein deficiency induces Akt\/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes. FASEB J 22(10):3581\u20133594. https:\/\/doi.org\/10.1096\/fj.08-111690","journal-title":"FASEB J"},{"issue":"13\u201315","key":"6457_CR68","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1089\/ars.2021.0038","volume":"36","author":"H Masutani","year":"2022","unstructured":"Masutani H (2022) Thioredoxin-interacting protein in cancer and diabetes. Antioxid Redox Signal 36(13\u201315):1001\u20131022. https:\/\/doi.org\/10.1089\/ars.2021.0038","journal-title":"Antioxid Redox Signal"},{"key":"6457_CR69","doi-asserted-by":"publisher","first-page":"115472","DOI":"10.1016\/j.bone.2020.115472","volume":"138","author":"G Sanchez-Duffhues","year":"2020","unstructured":"Sanchez-Duffhues G, Williams E, Goumans MJ, Heldin CH, Ten Dijke P (2020) Bone morphogenetic protein receptors: structure, function and targeting by selective small molecule kinase inhibitors. Bone 138:115472. https:\/\/doi.org\/10.1016\/j.bone.2020.115472","journal-title":"Bone"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-025-06457-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-025-06457-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-025-06457-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T20:02:28Z","timestamp":1755547348000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-025-06457-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,5]]},"references-count":69,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["6457"],"URL":"https:\/\/doi.org\/10.1007\/s00125-025-06457-9","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"type":"print","value":"0012-186X"},{"type":"electronic","value":"1432-0428"}],"subject":[],"published":{"date-parts":[[2025,6,5]]},"assertion":[{"value":"9 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We thank the pancreas donors and their families, the pancreatic islet isolation team of the LUMC, M. Zuurmond (LUMC) for creating the graphical abstract, and R. C. Hoeben and M. Rabelink (viral vector facility, LUMC) for production of the lentiviral vectors. We also thank N. de Jong and F. Lambregtse for their technical support. Parts of the data were presented at the Annual Dutch Diabetes Research Meeting in 2023.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The data that support the findings of this study are available from the corresponding author upon reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"FC and EJPdK have received funding from the DON Foundation, the Dutch Diabetes Research Foundation, Breakthrough T1D (formerly known as JDRF), the Bontius Foundation and the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) (NNF21CC0073729).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"ED designed and performed the experiments and wrote the manuscript. TJJdW performed differential gene expression analysis on type 2 diabetes donor datasets. AMG performed the scRNA-seq data analysis. NdG and MJR provided technical support. FC and EJPdK supervised the project, assisted in the design and interpretation of the data, and acquired the funding for the project. FC wrote the manuscript. All authors contributed to the article and approved the final version. FC is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}