{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:35:59Z","timestamp":1791520559612,"version":"4.3.4"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T00:00:00Z","timestamp":1717027200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T00:00:00Z","timestamp":1717027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Jonas & Christina af Jochnick Foundation"},{"name":"European Research Council","award":["ERC-2018-AdG 834860 EYELETS"],"award-info":[{"award-number":["ERC-2018-AdG 834860 EYELETS"]}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Berth von Kantzow\u2019s Foundation"},{"name":"Swedish Foundation for Strategic Research"},{"name":"Swedish Diabetes Association"},{"name":"Family Erling-Persson Foundation"},{"name":"Strategic Research Program in Diabetes at Karolinska Institutet"},{"DOI":"10.13039\/501100004047","name":"Karolinska Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Aims\/hypothesis<\/jats:title>\n                <jats:p>Prediabetic pancreatic beta cells can adapt their function to maintain normoglycaemia for a limited period of time, after which diabetes mellitus will manifest upon beta cell exhaustion. Understanding sex-specific beta cell compensatory mechanisms and their failure in prediabetes (impaired glucose tolerance) is crucial for early disease diagnosis and individualised treatment. Our aims were as follows: (1) to determine the key time points of the progression from beta cells\u2019 functional adaptations to their failure in vivo; and (2) to mechanistically explain in vivo sex-specific beta cell compensatory mechanisms and their failure in prediabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Islets from male and female transgenic <jats:italic>Ins1<\/jats:italic><jats:sup>CreERT2<\/jats:sup>-<jats:italic>GCaMP3<\/jats:italic> mice were transplanted into the anterior chamber of the eye of 10- to 12-week-old sex-matched C57BL\/6J mice. Recipient mice were fed either a control diet (CD) or western diet (WD) for a maximum of 4 months. Metabolic variables were evaluated monthly. Beta cell cytoplasmic free calcium concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) dynamics were monitored in vivo longitudinally by image fluorescence of the GCaMP3 reporter islets. Global islet beta cell [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> dynamics in line with single beta cell [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> analysis were used for beta cell coordination studies. The glucagon receptor antagonist L-168,049 (4 mmol\/l) was applied topically to the transplanted eyes to evaluate in vivo the effect of glucagon on beta cell [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>dynamics. Human islets from non-diabetic women and men were cultured for 24 h in either a control medium or high-fat\/high-glucose medium in the presence or absence of the glucagon receptor antagonist L-168,049. [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> dynamics of human islets were evaluated in vitro after 1 h exposure to Fura-10.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Mice fed a WD for 1 month displayed increased beta cell [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> dynamics linked to enhanced insulin secretion as a functional compensatory mechanism in prediabetes. Recruitment of inactive beta cells in WD-fed mice explained the improved beta cell function adaptation observed in vivo; this occurred in a sex-specific manner. Mechanistically, this was attributable to an intra-islet structural rearrangement involving alpha cells. These sex-dependent cytoarchitecture reorganisations, observed in both mice and humans, induced enhanced paracrine input from adjacent alpha cells, adjusting the glucose setpoint and amplifying the insulin secretion pathway. When WD feeding was prolonged, female mice maintained the adaptive mechanism due to their intrinsically high proportion of alpha cells. In males, [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> dynamics progressively declined subsequent to glucose stimulation while insulin secretion continue to increase, suggesting uncoordinated beta cell function as an early sign of diabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions\/interpretation<\/jats:title>\n                <jats:p>We identified increased coordination of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> dynamics as a beta cell functional adaptation mechanisms in prediabetes. Importantly, we uncovered the mechanisms by which sex-dependent beta cell [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> dynamics coordination is orchestrated by an intra-islet structure reorganisation increasing the paracrine input from alpha cells on beta cell function. Moreover, we identified reduced [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> dynamics coordination in response to glucose as an early sign of diabetes preceding beta cell secretory dysfunction, with males being more vulnerable. Alterations in coordination capacity of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> dynamics may thus serve as an early marker for beta cell failure in prediabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00125-024-06173-w","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T14:02:26Z","timestamp":1717077746000},"page":"1663-1682","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Sex-dependent intra-islet structural rearrangements affecting alpha-to-beta cell interactions lead to adaptive enhancements of Ca2+ dynamics in prediabetic beta cells"],"prefix":"10.1007","volume":"67","author":[{"given":"Montse","family":"Visa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per-Olof","family":"Berggren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"6173_CR1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.2337\/diabetes.53.suppl_3.S34","volume":"53","author":"GC Weir","year":"2004","unstructured":"Weir GC, Bonner-Weir S (2004) Progression to diabetes. Diabetes 53:34\u201341","journal-title":"Diabetes"},{"issue":"6","key":"6173_CR2","doi-asserted-by":"publisher","first-page":"353","DOI":"10.4161\/isl.2.6.13619","volume":"2","author":"J Ahr\u00e9n","year":"2010","unstructured":"Ahr\u00e9n J, Ahr\u00e9n B, Wierup N (2010) Increased \u03b2-cell volume in mice fed a high-fat diet: a dynamic study over 12 months. Islets 2(6):353\u2013356. https:\/\/doi.org\/10.4161\/isl.2.6.13619","journal-title":"Islets"},{"issue":"10","key":"6173_CR3","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"},{"issue":"7","key":"6173_CR4","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1007\/s00125-005-1772-9","volume":"48","author":"RL Hull","year":"2005","unstructured":"Hull RL, Kodama K, Utzschneider KM, Carr DB, Prigeon RL, Kahn SE (2005) Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation. Diabetologia 48(7):1350\u20131358. https:\/\/doi.org\/10.1007\/s00125-005-1772-9","journal-title":"Diabetologia"},{"issue":"9","key":"6173_CR5","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"},{"key":"6173_CR6","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":"6173_CR7","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/s00125-019-05040-3","volume":"63","author":"B Tramunt","year":"2020","unstructured":"Tramunt B, Smati S, Grandgeorge N et al (2020) Sex differences in metabolic regulation and diabetes susceptibility. Diabetologia 63:453\u2013461. https:\/\/doi.org\/10.1007\/s00125-019-05040-3","journal-title":"Diabetologia"},{"issue":"1464","key":"6173_CR8","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1098\/rstb.2005.1762","volume":"360","author":"PE MacDonald","year":"2005","unstructured":"MacDonald PE, Joseph JW, Rorsman P (2005) Glucose-sensing mechanisms in pancreatic \u03b2-cells. Philos Trans R Soc B: Biol Sci 360(1464):2211\u20132225. https:\/\/doi.org\/10.1098\/rstb.2005.1762","journal-title":"Philos Trans R Soc B: Biol Sci"},{"key":"6173_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep07845","volume":"5","author":"R Markovi\u010d","year":"2015","unstructured":"Markovi\u010d R, Sto\u017eer A, Gosak M, Dolen\u0161ek J, Marhl M, Rupnik MS (2015) Progressive glucose stimulation of islet beta cells reveals a transition from segregated to integrated modular functional connectivity patterns. Sci Rep 5:1\u201310. https:\/\/doi.org\/10.1038\/srep07845","journal-title":"Sci Rep"},{"issue":"6","key":"6173_CR10","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1038\/s42255-019-0075-2","volume":"1","author":"V Salem","year":"2019","unstructured":"Salem V, Silva LD, Suba K et al (2019) Leader \u03b2-cells coordinate Ca2+ dynamics across pancreatic islets in vivo. Nat Metab 1(6):615\u2013629. https:\/\/doi.org\/10.1038\/s42255-019-0075-2","journal-title":"Nat Metab"},{"issue":"5","key":"6173_CR11","doi-asserted-by":"publisher","first-page":"e126742","DOI":"10.1172\/jci.insight.126742","volume":"4","author":"ME Capozzi","year":"2019","unstructured":"Capozzi ME, Svendsen B, Encisco SE et al (2019) \u03b2 Cell tone is defined by proglucagon peptides through cAMP signaling. JCI Insight 4(5):e126742. https:\/\/doi.org\/10.1172\/jci.insight.126742","journal-title":"JCI Insight"},{"issue":"5","key":"6173_CR12","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/j.celrep.2018.10.018","volume":"25","author":"B Svendsen","year":"2018","unstructured":"Svendsen B, Larsen O, Gabe MBN et al (2018) Insulin secretion depends on intra-islet glucagon signaling. Cell Rep 25(5):1127-1134.e2. https:\/\/doi.org\/10.1016\/j.celrep.2018.10.018","journal-title":"Cell Rep"},{"issue":"3","key":"6173_CR13","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.cmet.2018.01.015","volume":"27","author":"R Rodriguez-Diaz","year":"2018","unstructured":"Rodriguez-Diaz R, Molano RD, Weitz JR et al (2018) Paracrine interactions within the pancreatic islet determine the glycemic set point. Cell Metab 27(3):549-558.e4. https:\/\/doi.org\/10.1016\/j.cmet.2018.01.015","journal-title":"Cell Metab"},{"issue":"5","key":"6173_CR14","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1016\/j.bpj.2017.07.021","volume":"113","author":"MJ Westacott","year":"2017","unstructured":"Westacott MJ, Ludin NWF, Benninger RKP (2017) Spatially organized \u03b2-cell subpopulations control electrical dynamics across islets of Langerhans. Biophys J 113(5):1093\u20131108. https:\/\/doi.org\/10.1016\/j.bpj.2017.07.021","journal-title":"Biophys J"},{"issue":"3","key":"6173_CR15","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1097\/01.mpa.0000175891.58918.c8","volume":"31","author":"N Gustavsson","year":"2005","unstructured":"Gustavsson N, Larsson-Nyr\u00e9n G, Lindstr\u00f6m P (2005) Pancreatic \u03b2 cells from db\/db mice show cell-specific [Ca 2+]i and NADH responses to glucose but not to \u03b1-ketoisocaproic acid. Pancreas 31(3):242\u2013250. https:\/\/doi.org\/10.1097\/01.mpa.0000175891.58918.c8","journal-title":"Pancreas"},{"issue":"3","key":"6173_CR16","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.cmet.2016.06.020","volume":"24","author":"NR Johnston","year":"2016","unstructured":"Johnston NR, Mitchell RK, Haythorne E et al (2016) Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab 24(3):389\u2013401. https:\/\/doi.org\/10.1016\/j.cmet.2016.06.020","journal-title":"Cell Metab"},{"issue":"3","key":"6173_CR17","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1007\/s00424-013-1389-7","volume":"466","author":"B Colsoul","year":"2014","unstructured":"Colsoul B, Jacobs G, Philippaert K et al (2014) Insulin downregulates the expression of the Ca2+-activated nonselective cation channel TRPM5 in pancreatic islets from leptin-deficient mouse models. Pflugers Arch 466(3):611\u2013621. https:\/\/doi.org\/10.1007\/s00424-013-1389-7","journal-title":"Pflugers Arch"},{"issue":"2","key":"6173_CR18","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1007\/s00125-012-2758-z","volume":"56","author":"TM Reinbothe","year":"2013","unstructured":"Reinbothe TM, Alkayyali S, Ahlqvist E et al (2013) The human L-type calcium channel Cav13 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes. Diabetologia 56(2):340\u2013349. https:\/\/doi.org\/10.1007\/s00125-012-2758-z","journal-title":"Diabetologia"},{"issue":"8","key":"6173_CR19","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.tem.2014.02.005","volume":"25","author":"RKP Benninger","year":"2014","unstructured":"Benninger RKP, Piston DW (2014) Cellular communication and heterogeneity in pancreatic islet insulin secretion dynamics. Trends Endocrinol Metab 25(8):399\u2013406. https:\/\/doi.org\/10.1016\/j.tem.2014.02.005","journal-title":"Trends Endocrinol Metab"},{"issue":"10","key":"6173_CR20","doi-asserted-by":"publisher","first-page":"4182","DOI":"10.1172\/JCI68459","volume":"123","author":"DJ Hodson","year":"2013","unstructured":"Hodson DJ, Mitchell RK, Bellomo EA et al (2013) Lipotoxicity disrupts incretin-regulated human \u03b2 cell connectivity. J Clin Investig 123(10):4182\u20134194. https:\/\/doi.org\/10.1172\/JCI68459","journal-title":"J Clin Investig"},{"issue":"8","key":"6173_CR21","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1007\/s00125-002-0883-9","volume":"45","author":"M Ravier","year":"2002","unstructured":"Ravier M, Sehlin J, Henquin J (2002) Disorganization of cytoplasmic Ca2+ oscillations and pulsatile insulin secretion in islets from ob\/ob mice. Diabetologia 45(8):1154\u20131163. https:\/\/doi.org\/10.1007\/s00125-002-0883-9","journal-title":"Diabetologia"},{"key":"6173_CR22","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.semcdb.2020.01.008","volume":"103","author":"O Idevall-Hagren","year":"2020","unstructured":"Idevall-Hagren O, Tengholm A (2020) Metabolic regulation of calcium signaling in beta cells. Semin Cell Dev Biol 103:20\u201330. https:\/\/doi.org\/10.1016\/j.semcdb.2020.01.008","journal-title":"Semin Cell Dev Biol"},{"issue":"10","key":"6173_CR23","doi-asserted-by":"publisher","first-page":"4676","DOI":"10.1529\/biophysj.107.125088","volume":"95","author":"M Zhang","year":"2008","unstructured":"Zhang M, Fendler B, Peercy B et al (2008) Long lasting synchronization of calcium oscillations by cholinergic stimulation in isolated pancreatic islets. Biophys J 95(10):4676\u20134688. https:\/\/doi.org\/10.1529\/biophysj.107.125088","journal-title":"Biophys J"},{"issue":"1","key":"6173_CR24","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1096\/fj.201901302RR","volume":"34","author":"S Jacob","year":"2020","unstructured":"Jacob S, K\u00f6hler M, Tr\u00f6ster P et al (2020) In vivo Ca2+ dynamics in single pancreatic \u03b2 cells. FASEB J 34(1):945\u2013959. https:\/\/doi.org\/10.1096\/fj.201901302RR","journal-title":"FASEB J"},{"issue":"3","key":"6173_CR25","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1007\/s00125-014-3468-5","volume":"58","author":"B Thorens","year":"2015","unstructured":"Thorens B, Tarussio D, Maestro MA, Rovira M, Heikkil\u00e4 E, Ferrer J (2015) Ins1 Cre knock-in mice for beta cell-specific gene recombination. Diabetologia 58(3):558\u2013565. https:\/\/doi.org\/10.1007\/s00125-014-3468-5","journal-title":"Diabetologia"},{"issue":"9","key":"6173_CR26","doi-asserted-by":"publisher","first-page":"3131","DOI":"10.1523\/JNEUROSCI.4469-11.2012","volume":"32","author":"HA Zariwala","year":"2012","unstructured":"Zariwala HA, Borghuis BG, Hoogland TM et al (2012) A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo. J Neurosci 32(9):3131\u20133141. https:\/\/doi.org\/10.1523\/JNEUROSCI.4469-11.2012","journal-title":"J Neurosci"},{"issue":"1","key":"6173_CR27","doi-asserted-by":"publisher","first-page":"3700","DOI":"10.1038\/s41467-019-11517-x","volume":"10","author":"R Arrojo e Drigo","year":"2019","unstructured":"Arrojo e Drigo R, Jacob S, Garc\u00eda-Prieto C et al (2019) Structural basis for delta cell paracrine regulation in pancreatic islets. Nat Commun 10(1):3700. https:\/\/doi.org\/10.1038\/s41467-019-11517-x","journal-title":"Nat Commun"},{"issue":"12","key":"6173_CR28","doi-asserted-by":"publisher","first-page":"4100","DOI":"10.2337\/db13-1855","volume":"63","author":"L Li","year":"2014","unstructured":"Li L, Trifunovic A, K\u00f6hler M et al (2014) Defects in \u03b2-cell Ca2+ dynamics in age-induced diabetes. Diabetes 63(12):4100\u20134114. https:\/\/doi.org\/10.2337\/db13-1855","journal-title":"Diabetes"},{"issue":"5","key":"6173_CR29","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.2337\/db09-1177","volume":"59","author":"D Bosco","year":"2010","unstructured":"Bosco D, Armanet M, Morel P et al (2010) Unique arrangement of \u03b1- and \u03b2-cells in human islets of Langerhans. Diabetes 59(5):1202\u20131210. https:\/\/doi.org\/10.2337\/db09-1177","journal-title":"Diabetes"},{"issue":"6","key":"6173_CR30","doi-asserted-by":"publisher","first-page":"603","DOI":"10.7150\/ijms.24492","volume":"15","author":"YS Lee","year":"2018","unstructured":"Lee YS, Jun HS (2018) Glucagon-like peptide-1 receptor agonist and glucagon increase glucose-stimulated insulin secretion in beta cells via distinct adenylyl cyclases. Int J Med Sci 15(6):603\u2013609. https:\/\/doi.org\/10.7150\/ijms.24492","journal-title":"Int J Med Sci"},{"issue":"35","key":"6173_CR31","doi-asserted-by":"publisher","first-page":"13163","DOI":"10.1073\/pnas.0801059105","volume":"105","author":"H Ellingsgaard","year":"2008","unstructured":"Ellingsgaard H, Ehses JA, Hammar EB et al (2008) Interleukin-6 regulates pancreatic \u03b1-cell mass expansion. Proc Natl Acad Sci U S A 105(35):13163\u201313168. https:\/\/doi.org\/10.1073\/pnas.0801059105","journal-title":"Proc Natl Acad Sci U S A"},{"key":"6173_CR32","doi-asserted-by":"publisher","first-page":"101021","DOI":"10.1016\/j.molmet.2020.101021","volume":"40","author":"JA Kellard","year":"2020","unstructured":"Kellard JA, Rorsman NJG, Hill TG et al (2020) Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet. Mol Metab 40:101021. https:\/\/doi.org\/10.1016\/j.molmet.2020.101021","journal-title":"Mol Metab"},{"issue":"4","key":"6173_CR33","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/0026-0495(80)90014-1","volume":"29","author":"V Bonnevie-Nielsen","year":"1980","unstructured":"Bonnevie-Nielsen V (1980) Experimental diets affect pancreatic insulin and glucagon differently in male and female mice. Metabolism 29(4):386\u201391. https:\/\/doi.org\/10.1016\/0026-0495(80)90014-1","journal-title":"Metabolism"},{"issue":"4","key":"6173_CR34","first-page":"271","volume":"8","author":"V Bonnevie-Nielsen","year":"1982","unstructured":"Bonnevie-Nielsen V (1982) Different effects of high glucose and high fat diet on pancreatic insulin and glucagon in female and male mice. Diabete Metab 8(4):271\u2013277","journal-title":"Diabete Metab"},{"issue":"1","key":"6173_CR35","doi-asserted-by":"publisher","first-page":"R281","DOI":"10.1152\/ajpregu.2002.282.1.R281","volume":"282","author":"S Karlsson","year":"2002","unstructured":"Karlsson S, Scheurink AJ, Ahr\u00e9n B (2002) Gender difference in the glucagon response to glucopenic stress in mice. Am J Physiol Regul Integr Comp Physiol 282(1):R281-8. https:\/\/doi.org\/10.1152\/ajpregu.2002.282.1.R281","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"6173_CR36","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/s00125-019-05040-3","volume":"63","author":"B Tramunt","year":"2020","unstructured":"Tramunt B, Smati S, Grandgeorge N et al (2020) Sex differences in metabolic regulation and diabetes susceptibility. Diabetologia 63:453\u2013461. https:\/\/doi.org\/10.1007\/s00125-019-05040-3","journal-title":"Diabetologia"},{"issue":"1","key":"6173_CR37","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/s00125-004-1605-2","volume":"48","author":"H Sone","year":"2005","unstructured":"Sone H, Kagawa Y (2005) Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48(1):58\u201367. https:\/\/doi.org\/10.1007\/s00125-004-1605-2","journal-title":"Diabetologia"},{"issue":"7","key":"6173_CR38","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1007\/s00394-011-0266-4","volume":"51","author":"RE Stubbins","year":"2012","unstructured":"Stubbins RE, Holcomb VB, Hong J, N\u00fa\u00f1ez NP (2012) Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur J Nutr 51(7):861\u2013870. https:\/\/doi.org\/10.1007\/s00394-011-0266-4","journal-title":"Eur J Nutr"},{"issue":"5","key":"6173_CR39","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1210\/en.2008-0971","volume":"150","author":"E Riant","year":"2009","unstructured":"Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P (2009) Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology 150(5):2109\u20132117. https:\/\/doi.org\/10.1210\/en.2008-0971","journal-title":"Endocrinology"},{"issue":"2","key":"6173_CR40","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1080\/10408398.2011.651177","volume":"55","author":"R Comitato","year":"2015","unstructured":"Comitato R, Saba A, Turrini A, Arganini C, Virgili F (2015) Sex hormones and macronutrient metabolism. Crit Rev Food Sci Nutr 55(2):227\u2013241. https:\/\/doi.org\/10.1080\/10408398.2011.651177","journal-title":"Crit Rev Food Sci Nutr"},{"key":"6173_CR41","first-page":"263","volume":"56","author":"S Nishikawa","year":"2007","unstructured":"Nishikawa S, Yasoshima A, Doi K, Nakayama H, Uetsuka K (2007) Diet-induced obesity in C57BL \/ 6J and BALB \/ cA mice. Obesity 56:263\u2013272","journal-title":"Obesity"},{"issue":"7","key":"6173_CR42","doi-asserted-by":"publisher","first-page":"11756","DOI":"10.1038\/ncomms11756","volume":"11","author":"C Dorrell","year":"2016","unstructured":"Dorrell C, Schug J, Canaday PS et al (2016) Human islets contain four distinct subtypes of \u03b2 cells. Nat Commun 11(7):11756. https:\/\/doi.org\/10.1038\/ncomms11756","journal-title":"Nat Commun"},{"key":"6173_CR43","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.mam.2015.01.003","volume":"42","author":"LS Satin","year":"2015","unstructured":"Satin LS, Butler PC, Ha J, Sherman AS (2015) Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes. Mol Aspects Med 42:61\u201377. https:\/\/doi.org\/10.1016\/j.mam.2015.01.003","journal-title":"Mol Aspects Med"},{"issue":"1","key":"6173_CR44","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1210\/er.2006-0007","volume":"28","author":"J Gromada","year":"2007","unstructured":"Gromada J, Franklin I, Wollheim CB (2007) \u0391-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28(1):84\u2013116. https:\/\/doi.org\/10.1210\/er.2006-0007","journal-title":"Endocr Rev"},{"issue":"4","key":"6173_CR45","doi-asserted-by":"publisher","first-page":"E671","DOI":"10.1152\/ajpendo.00492.2002","volume":"284","author":"G Jiang","year":"2003","unstructured":"Jiang G, Zhang BB (2003) Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 284(4):E671-8. https:\/\/doi.org\/10.1152\/ajpendo.00492.2002","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"16","key":"6173_CR46","doi-asserted-by":"publisher","first-page":"e129954","DOI":"10.1172\/jci.insight.129954","volume":"5","author":"ME Capozzi","year":"2019","unstructured":"Capozzi ME, Wait JB, Koech J et al (2019) Glucagon lowers glycemia when \u03b2 cells are active. JCI Insight 5(16):e129954. https:\/\/doi.org\/10.1172\/jci.insight.129954","journal-title":"JCI Insight"},{"issue":"6","key":"6173_CR47","doi-asserted-by":"publisher","first-page":"e16096","DOI":"10.1371\/journal.pone.0016096","volume":"25","author":"Z Liu","year":"2011","unstructured":"Liu Z, Kim W, Chen Z et al (2011) Insulin and glucagon regulate pancreatic \u03b1-cell proliferation. PLoS One 25(6):e16096. https:\/\/doi.org\/10.1371\/journal.pone.0016096","journal-title":"PLoS One"},{"issue":"1","key":"6173_CR48","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1530\/JOE-19-0451","volume":"245","author":"N Tanday","year":"2020","unstructured":"Tanday N, Flatt PR, Irwin N, Moffett RC (2020) Liraglutide and sitagliptin counter beta- to alpha-cell transdifferentiation in diabetes. J Endocrinol 245(1):53\u201364. https:\/\/doi.org\/10.1530\/JOE-19-0451","journal-title":"J Endocrinol"},{"issue":"7","key":"6173_CR49","doi-asserted-by":"publisher","first-page":"2471","DOI":"10.2337\/db12-1001","volume":"62","author":"HS Spijker","year":"2013","unstructured":"Spijker HS, Ravelli RB, Mommaas-Kienhuis AM et al (2013) Conversion of mature human \u03b2-cells into glucagon-producing \u03b1-cells. Diabetes 62(7):2471\u20132480. https:\/\/doi.org\/10.2337\/db12-1001","journal-title":"Diabetes"},{"issue":"7","key":"6173_CR50","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.3390\/cells10071658","volume":"10","author":"A Sto\u017eer","year":"2021","unstructured":"Sto\u017eer A, Paradi\u017e Leitgeb E, Pohorec V et al (2021) The role of cAMP in beta cell stimulus-secretion and intercellular coupling. Cells 10(7):1658. https:\/\/doi.org\/10.3390\/cells10071658","journal-title":"Cells"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-024-06173-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-024-06173-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-024-06173-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T22:47:25Z","timestamp":1724453245000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-024-06173-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,30]]},"references-count":50,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["6173"],"URL":"https:\/\/doi.org\/10.1007\/s00125-024-06173-w","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,30]]},"assertion":[{"value":"7 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors thank the staff from the Department of Comparative Medicine (AKM) at Karolinska Institutet for technical support. Figs , ,  and the graphical abstract contain modified images from Servier Medical Art () licenced under a Creative Commons Attribution 4.0 Unported License ().","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The data generated in this study are available from the corresponding authors on reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open access funding provided by Karolinska Institute. This work was supported by funds from the Swedish Research Council, the Family Erling-Persson Foundation, the Novo Nordisk Foundation, the Jonas & Christina af Jochnick Foundation, the Swedish Diabetes Association, the Berth von Kantzow\u2019s Foundation, the Strategic Research Program in Diabetes at Karolinska Institutet, the European Research Council grant ERC-2018-AdG 834860 EYELETS and the Swedish Foundation for Strategic Research. MV was supported by a Novo Nordisk post-doctoral fellowship grant run in partnership with Karolinska Institutet.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"P-OB is founder and CEO of the biotech company Biocrine AB, which holds patents for the technique of islet transplantation into the ACE as a research tool.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"MV designed the study, performed, analysed and interpreted the experiments and wrote the manuscript. P-OB was the originator of this project, contributed to the experimental design and writing of the article, supervised the study and acquired funding. Both authors read and approved the final version of the manuscript to be published. P-OB is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}