{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:45:36Z","timestamp":1791765936522,"version":"4.3.4"},"reference-count":77,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":111,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["bilateral grants I3562-B27 and I4319-B30"],"award-info":[{"award-number":["bilateral grants I3562-B27 and I4319-B30"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001821","name":"Vienna Science and Technology Fund","doi-asserted-by":"publisher","award":["LS23-026"],"award-info":[{"award-number":["LS23-026"]}],"id":[{"id":"10.13039\/501100001821","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"The Slovenian Research and Innovation Agency","doi-asserted-by":"publisher","award":["P3-0396"],"award-info":[{"award-number":["P3-0396"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK127236"],"award-info":[{"award-number":["R01DK127236"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000361","name":"Diabetes UK","doi-asserted-by":"publisher","award":["BDA 16\/0005485"],"award-info":[{"award-number":["BDA 16\/0005485"]}],"id":[{"id":"10.13039\/501100000361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT212625\/Z\/18\/Z"],"award-info":[{"award-number":["WT212625\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R022259\/1"],"award-info":[{"award-number":["MR\/R022259\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["CIHR-IRSC TDP-186358 and JDRF 4-SRA-2023-1182-S-N"],"award-info":[{"award-number":["CIHR-IRSC TDP-186358 and JDRF 4-SRA-2023-1182-S-N"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CRCHUM start-up funds, and Innovation Canada John R. Evans Leader Awards"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Glucose and paracrine regulation of \u03b1-cells, particularly with respect to sex differences, is still poorly understood. Here, we imaged islets from GluCre:GCaMP6f mice in pancreatic slices, additionally loaded with a red Ca\u00b2\u207a indicator, to precisely interrogate Ca\u00b2\u207a dynamics in \u03b1-cells and the adjacent \u03b2- and \u03b4-cells. During a glucose ramp (1.8-10.8\u2009mM), \u03b1-cell Ca\u00b2\u207a oscillations were heterogeneous, antiphasic to \u03b2-cells, and inversely correlated with \u03b4-cells. Selective inhibition of insulin receptor (InsR) and somatostatin receptor subtypes-2 and 3 (SSTR2\/3) shifted the majority of \u03b1-cells to hyperactivity, delayed the decline of \u03b1-cell activity and onset of \u03b2-cell Ca\u00b2\u207a oscillations during the ramp. While female \u03b1-cells exhibited greater sensitivity to SSTR2\/3 inhibition, male \u03b1-cells were more responsive to InsR blockade. Under complete SSTR2\/3 and InsR antagonism, \u03b1-cells exhibited elevated Ca\u00b2\u207a oscillations but remained glucose-dependent. We conclude that intra-islet coordination fine-tunes \u03b1-cell glucose responses, with sex-specific paracrine signaling potentially shaping glucagon profiles in metabolic disease.<\/jats:p>","DOI":"10.1038\/s42003-026-10163-6","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T11:25:09Z","timestamp":1782213909000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pancreatic \u03b1-cells are functionally heterogeneous and sex-dependently regulated by neighboring endocrine cells"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5168-1174","authenticated-orcid":false,"given":"Ya-Chi","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3744-4882","authenticated-orcid":false,"given":"Marjan","family":"Slak Rupnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6360-0343","authenticated-orcid":false,"given":"Guy A.","family":"Rutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"10163_CR1","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1007\/s00125-006-0511-1","volume":"50","author":"E Vieira","year":"2007","unstructured":"Vieira, E., Salehi, A. & Gylfe, E. Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia 50, 370\u2013379 (2007).","journal-title":"Diabetologia"},{"key":"10163_CR2","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1677\/JOE-08-0290","volume":"199","author":"I Quesada","year":"2008","unstructured":"Quesada, I., Tuduri, E., Ripoll, C. & Nadal, A. Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes. J. Endocrinol. 199, 5\u201319 (2008).","journal-title":"J. Endocrinol."},{"key":"10163_CR3","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/j.cmet.2013.10.014","volume":"18","author":"Q Zhang","year":"2013","unstructured":"Zhang, Q. et al. Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab. 18, 871\u2013882 (2013).","journal-title":"Cell Metab."},{"key":"10163_CR4","doi-asserted-by":"publisher","first-page":"e143","DOI":"10.1371\/journal.pbio.0050143","volume":"5","author":"PE MacDonald","year":"2007","unstructured":"MacDonald, P. E. et al. A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol. 5, e143 (2007).","journal-title":"PLoS Biol."},{"key":"10163_CR5","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1113\/jphysiol.2010.200345","volume":"589","author":"YC Huang","year":"2011","unstructured":"Huang, Y. C., Rupnik, M. & Gaisano, H. Y. Unperturbed islet alpha-cell function examined in mouse pancreas tissue slices. J. Physiol. 589, 395\u2013408 (2011).","journal-title":"J. Physiol."},{"key":"10163_CR6","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.ceca.2003.10.002","volume":"35","author":"YJ Liu","year":"2004","unstructured":"Liu, Y. J., Vieira, E. & Gylfe, E. A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic alpha-cell. Cell Calcium 35, 357\u2013365 (2004).","journal-title":"Cell Calcium"},{"key":"10163_CR7","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13464","volume":"229","author":"SFS Xu","year":"2020","unstructured":"Xu, S. F. S., Andersen, D. B., Izarzugaza, J. M. G., Kuhre, R. E. & Holst, J. J. In the rat pancreas, somatostatin tonically inhibits glucagon secretion and is required for glucose-induced inhibition of glucagon secretion. Acta Physiol. 229, e13464 (2020).","journal-title":"Acta Physiol."},{"key":"10163_CR8","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1113\/JP274581","volume":"596","author":"LJB Briant","year":"2018","unstructured":"Briant, L. J. B. et al. Delta-cells and beta-cells are electrically coupled and regulate alpha-cell activity via somatostatin. J. Physiol. 596, 197\u2013215 (2018).","journal-title":"J. Physiol."},{"key":"10163_CR9","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.1038\/s42255-024-01139-z","volume":"6","author":"TG Hill","year":"2024","unstructured":"Hill, T. G. et al. Loss of electrical beta-cell to delta-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes. Nat. Metab. 6, 2070\u20132081 (2024).","journal-title":"Nat. Metab."},{"key":"10163_CR10","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1111\/j.1469-7793.2001.00519.x","volume":"535","author":"J Gromada","year":"2001","unstructured":"Gromada, J., Hoy, M., Buschard, K., Salehi, A. & Rorsman, P. Somatostatin inhibits exocytosis in rat pancreatic alpha-cells by G(i2)-dependent activation of calcineurin and depriming of secretory granules. J. Physiol. 535, 519\u2013532 (2001).","journal-title":"J. Physiol."},{"key":"10163_CR11","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.cmet.2005.11.015","volume":"3","author":"E Xu","year":"2006","unstructured":"Xu, E. et al. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab. 3, 47\u201358 (2006).","journal-title":"Cell Metab."},{"key":"10163_CR12","doi-asserted-by":"publisher","first-page":"E1107","DOI":"10.1152\/ajpendo.00207.2012","volume":"303","author":"B Kailey","year":"2012","unstructured":"Kailey, B. et al. SSTR2 is the functionally dominant somatostatin receptor in human pancreatic beta- and alpha-cells. Am. J. Physiol. Endocrinol. Metab. 303, E1107\u2013E1116 (2012).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"10163_CR13","doi-asserted-by":"publisher","first-page":"E130","DOI":"10.1152\/ajpendo.00344.2014","volume":"308","author":"AD Elliott","year":"2015","unstructured":"Elliott, A. D., Ustione, A. & Piston, D. W. Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic alpha-cell by lowering cAMP. Am. J. Physiol. Endocrinol. Metab. 308, E130\u2013E143 (2015).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"10163_CR14","doi-asserted-by":"publisher","first-page":"4861","DOI":"10.1210\/en.2005-0800","volume":"146","author":"HL Olsen","year":"2005","unstructured":"Olsen, H. L. et al. Glucose stimulates glucagon release in single rat alpha-cells by mechanisms that mirror the stimulus-secretion coupling in beta-cells. Endocrinology 146, 4861\u20134870 (2005).","journal-title":"Endocrinology"},{"key":"10163_CR15","doi-asserted-by":"publisher","first-page":"1500","DOI":"10.2337\/diabetes.49.9.1500","volume":"49","author":"S Barg","year":"2000","unstructured":"Barg, S., Galvanovskis, J., Gopel, S. O., Rorsman, P. & Eliasson, L. Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells. Diabetes 49, 1500\u20131510 (2000).","journal-title":"Diabetes"},{"key":"10163_CR16","doi-asserted-by":"publisher","first-page":"412","DOI":"10.2337\/db07-1298","volume":"58","author":"N Quoix","year":"2009","unstructured":"Quoix, N. et al. Glucose and pharmacological modulators of ATP-sensitive K+ channels control [Ca2+]c by different mechanisms in isolated mouse alpha-cells. Diabetes 58, 412\u2013421 (2009).","journal-title":"Diabetes"},{"key":"10163_CR17","doi-asserted-by":"publisher","first-page":"14389","DOI":"10.1074\/jbc.M109.069195","volume":"285","author":"SJ Le Marchand","year":"2010","unstructured":"Le Marchand, S. J. & Piston, D. W. Glucose suppression of glucagon secretion: metabolic and calcium responses from alpha-cells in intact mouse pancreatic islets. J. Biol. Chem. 285, 14389\u201314398 (2010).","journal-title":"J. Biol. Chem."},{"key":"10163_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2022.101495","volume":"61","author":"B Singh","year":"2022","unstructured":"Singh, B., Khattab, F. & Gilon, P. Glucose inhibits glucagon secretion by decreasing [Ca(2+)](c) and by reducing the efficacy of Ca(2+) on exocytosis via somatostatin-dependent and independent mechanisms. Mol. Metab. 61, 101495 (2022).","journal-title":"Mol. Metab."},{"key":"10163_CR19","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1016\/j.cmet.2020.04.005","volume":"31","author":"J Camunas-Soler","year":"2020","unstructured":"Camunas-Soler, J. et al. Patch-seq links single-cell transcriptomes to human islet dysfunction in diabetes. Cell Metab. 31, 1017\u20131031.e1014 (2020).","journal-title":"Cell Metab."},{"key":"10163_CR20","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1007\/s00424-016-1864-z","volume":"468","author":"H Shuai","year":"2016","unstructured":"Shuai, H., Xu, Y., Yu, Q., Gylfe, E. & Tengholm, A. Fluorescent protein vectors for pancreatic islet cell identification in live-cell imaging. Pflug. Arch. 468, 1765\u20131777 (2016).","journal-title":"Pflug. Arch."},{"key":"10163_CR21","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.cmet.2016.08.020","volume":"24","author":"A Segerstolpe","year":"2016","unstructured":"Segerstolpe, A. et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab. 24, 593\u2013607 (2016).","journal-title":"Cell Metab."},{"key":"10163_CR22","doi-asserted-by":"publisher","first-page":"135","DOI":"10.4161\/isl.2.3.11815","volume":"2","author":"DJ Steiner","year":"2010","unstructured":"Steiner, D. J., Kim, A., Miller, K. & Hara, M. Pancreatic islet plasticity: interspecies comparison of islet architecture and composition. Islets 2, 135\u2013145 (2010).","journal-title":"Islets"},{"key":"10163_CR23","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1002\/j.2040-4603.2021.tb00177.x","volume":"11","author":"XW Ng","year":"2021","unstructured":"Ng, X. W., Chung, Y. H. & Piston, D. W. Intercellular communication in the islet of langerhans in health and disease. Compr. Physiol. 11, 2191\u20132225 (2021).","journal-title":"Compr. Physiol."},{"key":"10163_CR24","doi-asserted-by":"publisher","first-page":"2155","DOI":"10.1210\/en.2005-1249","volume":"147","author":"YM Leung","year":"2006","unstructured":"Leung, Y. M. et al. Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 5\u2019-triphosphate inhibition. Endocrinology 147, 2155\u20132162 (2006).","journal-title":"Endocrinology"},{"key":"10163_CR25","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/nm.3872","volume":"21","author":"T van der Meulen","year":"2015","unstructured":"van der Meulen, T. et al. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. Nat. Med 21, 769\u2013776 (2015).","journal-title":"Nat. Med"},{"key":"10163_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08193-8","volume":"10","author":"E Vergari","year":"2019","unstructured":"Vergari, E. et al. Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion. Nat. Commun. 10, 139 (2019).","journal-title":"Nat. Commun."},{"key":"10163_CR27","doi-asserted-by":"publisher","first-page":"519","DOI":"10.2337\/db11-0786","volume":"62","author":"YC Huang","year":"2013","unstructured":"Huang, Y. C. et al. In situ electrophysiological examination of pancreatic alpha cells in the streptozotocin-induced diabetes model, revealing the cellular basis of glucagon hypersecretion. Diabetes 62, 519\u2013530 (2013).","journal-title":"Diabetes"},{"key":"10163_CR28","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s42255-019-0158-0","volume":"2","author":"E Vergari","year":"2020","unstructured":"Vergari, E. et al. Somatostatin secretion by Na(+)-dependent Ca(2+)-induced Ca(2+) release in pancreatic delta-cells. Nat. Metab. 2, 32\u201340 (2020).","journal-title":"Nat. Metab."},{"key":"10163_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-015-1591-y","volume":"15","author":"PA Diaz-Valencia","year":"2015","unstructured":"Diaz-Valencia, P. A., Bougneres, P. & Valleron, A. J. Global epidemiology of type 1 diabetes in young adults and adults: a systematic review. BMC Public Health 15, 255 (2015).","journal-title":"BMC Public Health"},{"key":"10163_CR30","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1007\/s00125-023-05891-x","volume":"66","author":"A Kautzky-Willer","year":"2023","unstructured":"Kautzky-Willer, A., Leutner, M. & Harreiter, J. Sex differences in type 2 diabetes. Diabetologia 66, 986\u20131002 (2023).","journal-title":"Diabetologia"},{"key":"10163_CR31","doi-asserted-by":"publisher","unstructured":"Jacobo-Piqueras, N., Theiner, T., Geisler, S. M. & Tuluc, P. Molecular mechanism responsible for sex differences in electrical activity of mouse pancreatic beta cells. JCI Insight 9, https:\/\/doi.org\/10.1172\/jci.insight.171609 (2024).","DOI":"10.1172\/jci.insight.171609"},{"key":"10163_CR32","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.molmet.2018.05.017","volume":"15","author":"M Gannon","year":"2018","unstructured":"Gannon, M., Kulkarni, R. N., Tse, H. M. & Mauvais-Jarvis, F. Sex differences underlying pancreatic islet biology and its dysfunction. Mol. Metab. 15, 82\u201391 (2018).","journal-title":"Mol. Metab."},{"key":"10163_CR33","doi-asserted-by":"publisher","unstructured":"Mauvais-Jarvis, F. & Lindsey, S. H. Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations. J Clin. Invest. 134, https:\/\/doi.org\/10.1172\/JCI180073 (2024).","DOI":"10.1172\/JCI180073"},{"key":"10163_CR34","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/nature12354","volume":"499","author":"TW Chen","year":"2013","unstructured":"Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295\u2013300 (2013).","journal-title":"Nature"},{"key":"10163_CR35","doi-asserted-by":"publisher","first-page":"E1030","DOI":"10.1152\/ajpendo.00022.2013","volume":"305","author":"C Shiota","year":"2013","unstructured":"Shiota, C. et al. alpha-cells are dispensable in postnatal morphogenesis and maturation of mouse pancreatic islets. Am. J. Physiol. Endocrinol. Metab. 305, E1030\u2013E1040 (2013).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"10163_CR36","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.2337\/db22-0952","volume":"72","author":"S Postic","year":"2023","unstructured":"Postic, S. et al. Tracking Ca2+ dynamics in NOD mouse islets during spontaneous diabetes development. Diabetes 72, 1251\u20131261 (2023).","journal-title":"Diabetes"},{"key":"10163_CR37","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1038\/s42255-024-01097-6","volume":"6","author":"GA Rutter","year":"2024","unstructured":"Rutter, G. A., Gresch, A., Delgadillo Silva, L. & Benninger, R. K. P. Exploring pancreatic beta-cell subgroups and their connectivity. Nat. Metab. 6, 2039\u20132053 (2024).","journal-title":"Nat. Metab."},{"key":"10163_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31373-6","volume":"13","author":"H Ren","year":"2022","unstructured":"Ren, H. et al. Pancreatic alpha and beta cells are globally phase-locked. Nat. Commun. 13, 3721 (2022).","journal-title":"Nat. Commun."},{"key":"10163_CR39","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1038\/s41574-018-0097-y","volume":"14","author":"J Gromada","year":"2018","unstructured":"Gromada, J., Chabosseau, P. & Rutter, G. A. The alpha-cell in diabetes mellitus. Nat. Rev. Endocrinol. 14, 694\u2013704 (2018).","journal-title":"Nat. Rev. Endocrinol."},{"key":"10163_CR40","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.molmet.2016.04.007","volume":"5","author":"MR DiGruccio","year":"2016","unstructured":"DiGruccio, M. R. et al. Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Mol. Metab. 5, 449\u2013458 (2016).","journal-title":"Mol. Metab."},{"key":"10163_CR41","doi-asserted-by":"publisher","first-page":"2239","DOI":"10.2337\/db17-0880","volume":"67","author":"BK Lai","year":"2018","unstructured":"Lai, B. K. et al. Somatostatin is only partly required for the glucagonostatic effect of glucose but is necessary for the glucagonostatic effect of K(ATP) channel blockers. Diabetes 67, 2239\u20132253 (2018).","journal-title":"Diabetes"},{"key":"10163_CR42","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.bbrc.2008.08.151","volume":"376","author":"L Schaffer","year":"2008","unstructured":"Schaffer, L. et al. A novel high-affinity peptide antagonist to the insulin receptor. Biochem. Biophys. Res. Commun. 376, 380\u2013383 (2008).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10163_CR43","doi-asserted-by":"publisher","first-page":"4765","DOI":"10.1113\/JP279775","volume":"598","author":"Q Zhang","year":"2020","unstructured":"Zhang, Q., Dou, H. & Rorsman, P. Resistance is futile?\u2019 - paradoxical inhibitory effects of K(ATP) channel closure in glucagon-secreting alpha-cells. J. Physiol. 598, 4765\u20134780 (2020).","journal-title":"J. Physiol."},{"key":"10163_CR44","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03034-0","volume":"9","author":"D Basco","year":"2018","unstructured":"Basco, D. et al. alpha-cell glucokinase suppresses glucose-regulated glucagon secretion. Nat. Commun. 9, 546 (2018).","journal-title":"Nat. Commun."},{"key":"10163_CR45","doi-asserted-by":"publisher","first-page":"2272","DOI":"10.1210\/endo.139.5.5990","volume":"139","author":"D Djordjijevic","year":"1998","unstructured":"Djordjijevic, D. et al. Effect of 17beta-estradiol on somatostatin receptor expression and inhibitory effects on growth hormone and prolactin release in rat pituitary cell cultures. Endocrinology 139, 2272\u20132277 (1998).","journal-title":"Endocrinology"},{"key":"10163_CR46","doi-asserted-by":"publisher","first-page":"28","DOI":"10.3389\/fphar.2019.00028","volume":"10","author":"V Rossi","year":"2019","unstructured":"Rossi, V. et al. Estrogens modulate somatostatin receptors expression and synergize with the somatostatin analog pasireotide in prostate cells. Front Pharm. 10, 28 (2019).","journal-title":"Front Pharm."},{"key":"10163_CR47","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1477-3163-4-10","volume":"4","author":"JA Rivera","year":"2005","unstructured":"Rivera, J. A., Alturaihi, H. & Kumar, U. Differential regulation of somatostatin receptors 1 and 2 mRNA and protein expression by tamoxifen and estradiol in breast cancer cells. J. Carcinog. 4, 10 (2005).","journal-title":"J. Carcinog."},{"key":"10163_CR48","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1161\/CIRCRESAHA.108.190041","volume":"105","author":"T Saito","year":"2009","unstructured":"Saito, T. et al. Estrogen contributes to gender differences in mouse ventricular repolarization. Circ. Res 105, 343\u2013352 (2009).","journal-title":"Circ. Res"},{"key":"10163_CR49","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2023.171003","volume":"165","author":"A Novikoff","year":"2023","unstructured":"Novikoff, A. & Muller, T. D. The molecular pharmacology of glucagon agonists in diabetes and obesity. Peptides 165, 171003 (2023).","journal-title":"Peptides"},{"key":"10163_CR50","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1007\/s00125-017-4354-8","volume":"60","author":"MA Sanchez-Garrido","year":"2017","unstructured":"Sanchez-Garrido, M. A. et al. GLP-1\/glucagon receptor co-agonism for treatment of obesity. Diabetologia 60, 1851\u20131861 (2017).","journal-title":"Diabetologia"},{"key":"10163_CR51","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1038\/nm.3115","volume":"19","author":"PI Mighiu","year":"2013","unstructured":"Mighiu, P. I. et al. Hypothalamic glucagon signaling inhibits hepatic glucose production. Nat. Med. 19, 766\u2013772 (2013).","journal-title":"Nat. Med."},{"key":"10163_CR52","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/0361-9230(85)90153-4","volume":"15","author":"WA Banks","year":"1985","unstructured":"Banks, W. A. & Kastin, A. J. Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res Bull. 15, 287\u2013292 (1985).","journal-title":"Brain Res Bull."},{"key":"10163_CR53","doi-asserted-by":"publisher","first-page":"4368","DOI":"10.1073\/pnas.81.14.4368","volume":"81","author":"NM Hoosein","year":"1984","unstructured":"Hoosein, N. M. & Gurd, R. S. Identification of glucagon receptors in rat brain. Proc. Natl. Acad. Sci. USA 81, 4368\u20134372 (1984).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10163_CR54","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1507\/endocrj1954.27.Supplement_135","volume":"27","author":"H Sasaki","year":"1980","unstructured":"Sasaki, H. et al. Glucagon-like substance in the canine brain. Endocrinol. Jpn 27, 135\u2013140 (1980).","journal-title":"Endocrinol. Jpn"},{"key":"10163_CR55","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.2337\/db12-1116","volume":"62","author":"KM Habegger","year":"2013","unstructured":"Habegger, K. M. et al. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62, 1453\u20131463 (2013).","journal-title":"Diabetes"},{"key":"10163_CR56","first-page":"R116","volume":"264","author":"N Geary","year":"1993","unstructured":"Geary, N., Le Sauter, J. & Noh, U. Glucagon acts in the liver to control spontaneous meal size in rats. Am. J. Physiol. 264, R116\u2013R122 (1993).","journal-title":"Am. J. Physiol."},{"key":"10163_CR57","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.2337\/db05-1692","volume":"55","author":"R Basu","year":"2006","unstructured":"Basu, R. et al. Effects of age and sex on postprandial glucose metabolism: differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction. Diabetes 55, 2001\u20132014 (2006).","journal-title":"Diabetes"},{"key":"10163_CR58","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0522-z","volume":"15","author":"E Hall","year":"2014","unstructured":"Hall, E. et al. Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets. Genome Biol. 15, 522 (2014).","journal-title":"Genome Biol."},{"key":"10163_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11517-x","volume":"10","author":"EDR Arrojo","year":"2019","unstructured":"Arrojo, E. D. R. et al. Structural basis for delta cell paracrine regulation in pancreatic islets. Nat. Commun. 10, 3700 (2019).","journal-title":"Nat. Commun."},{"key":"10163_CR60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2504151122","volume":"122","author":"MS Pourhosseinzadeh","year":"2025","unstructured":"Pourhosseinzadeh, M. S. et al. Heterogeneity in the coordination of delta cells with beta cells is driven by both paracrine signals and low-density Cx36 gap junctions. Proc. Natl. Acad. Sci. USA 122, e2504151122 (2025).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10163_CR61","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/s42255-023-00944-2","volume":"6","author":"JL Huang","year":"2024","unstructured":"Huang, J. L. et al. Paracrine signalling by pancreatic delta cells determines the glycaemic set point in mice. Nat. Metab. 6, 61\u201377 (2024).","journal-title":"Nat. Metab."},{"key":"10163_CR62","doi-asserted-by":"publisher","first-page":"1426","DOI":"10.2337\/db23-1013","volume":"73","author":"ER Knuth","year":"2024","unstructured":"Knuth, E. R. et al. Leucine suppresses alpha-Cell cAMP and glucagon secretion via a combination of cell-intrinsic and islet paracrine signaling. Diabetes 73, 1426\u20131439 (2024).","journal-title":"Diabetes"},{"key":"10163_CR63","doi-asserted-by":"publisher","first-page":"S27","DOI":"10.1016\/S0168-8227(11)70010-9","volume":"93","author":"JC Henquin","year":"2011","unstructured":"Henquin, J. C. The dual control of insulin secretion by glucose involves triggering and amplifying pathways in beta-cells. Diab. Res Clin. Pr. 93, S27\u2013S31 (2011).","journal-title":"Diab. Res Clin. Pr."},{"key":"10163_CR64","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/s42255-023-00962-0","volume":"6","author":"X Peng","year":"2024","unstructured":"Peng, X. et al. Readily releasable beta cells with tight Ca-exocytosis coupling dictate biphasic glucose-stimulated insulin secretion. Nat. Metab. 6, 238\u2013253 (2024).","journal-title":"Nat. Metab."},{"key":"10163_CR65","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.ceca.2011.11.006","volume":"51","author":"P Rorsman","year":"2012","unstructured":"Rorsman, P., Braun, M. & Zhang, Q. Regulation of calcium in pancreatic alpha- and beta-cells in health and disease. Cell Calcium 51, 300\u2013308 (2012).","journal-title":"Cell Calcium"},{"key":"10163_CR66","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1007\/s00125-019-4857-6","volume":"62","author":"Q Yu","year":"2019","unstructured":"Yu, Q., Shuai, H., Ahooghalandari, P., Gylfe, E. & Tengholm, A. Glucose controls glucagon secretion by directly modulating cAMP in alpha cells. Diabetologia 62, 1212\u20131224 (2019).","journal-title":"Diabetologia"},{"key":"10163_CR67","doi-asserted-by":"publisher","first-page":"21063","DOI":"10.1073\/pnas.1109773109","volume":"108","author":"D Li","year":"2011","unstructured":"Li, D. et al. Imaging dynamic insulin release using a fluorescent zinc indicator for monitoring induced exocytotic release (ZIMIR). Proc. Natl. Acad. Sci. USA 108, 21063\u201321068 (2011).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10163_CR68","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28039-8","volume":"13","author":"S Skovso","year":"2022","unstructured":"Skovso, S. et al. Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance. Nat. Commun. 13, 735 (2022).","journal-title":"Nat. Commun."},{"key":"10163_CR69","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-62670-5","volume":"16","author":"RB Kang","year":"2025","unstructured":"Kang, R. B. et al. Human pancreatic alpha-cell heterogeneity and trajectory inference analyses reveal SMOC1 as a beta-cell dedifferentiation gene. Nat. Commun. 16, 8434 (2025).","journal-title":"Nat. Commun."},{"key":"10163_CR70","doi-asserted-by":"publisher","unstructured":"Mardamshina, M. et al. Multiplexed deep visual proteomics unveils spatial heterogeneity and rare endocrine states in human adult pancreatic islets. BioRxiv - The preprint server for biology, https:\/\/doi.org\/10.1101\/2025.04.27.650857 (2025).","DOI":"10.1101\/2025.04.27.650857"},{"key":"10163_CR71","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.105056","volume":"25","author":"E Bosi","year":"2022","unstructured":"Bosi, E., Marchetti, P., Rutter, G. A. & Eizirik, D. L. Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways. iScience 25, 105056 (2022).","journal-title":"iScience"},{"key":"10163_CR72","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s12551-023-01174-2","volume":"16","author":"J Camunas-Soler","year":"2024","unstructured":"Camunas-Soler, J. Integrating single-cell transcriptomics with cellular phenotypes: cell morphology, Ca(2+) imaging and electrophysiology. Biophys. Rev. 16, 89\u2013107 (2024).","journal-title":"Biophys. Rev."},{"key":"10163_CR73","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.121436","volume":"316","author":"P Chabosseau","year":"2023","unstructured":"Chabosseau, P. et al. Molecular phenotyping of single pancreatic islet leader beta cells by \u201cFlash-Seq\u201d. Life Sci. 316, 121436 (2023).","journal-title":"Life Sci."},{"key":"10163_CR74","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.devcel.2018.11.001","volume":"48","author":"L Farack","year":"2019","unstructured":"Farack, L. et al. Transcriptional heterogeneity of beta cells in the intact pancreas. Dev. Cell 48, 115\u2013125.e114 (2019).","journal-title":"Dev. Cell"},{"key":"10163_CR75","doi-asserted-by":"publisher","first-page":"99","DOI":"10.2337\/db25-0520","volume":"75","author":"S Salazar","year":"2026","unstructured":"Salazar, S. et al. Additive effects of dorzagliatin and glucagon-like peptide 1 receptor agonism in a novel mouse model of GCK-MODY and in obese db\/db mice. Diabetes 75, 99\u2013114 (2026).","journal-title":"Diabetes"},{"key":"10163_CR76","doi-asserted-by":"publisher","first-page":"E42","DOI":"10.1152\/ajpendo.00165.2022","volume":"324","author":"S Postic","year":"2023","unstructured":"Postic, S. et al. High-resolution analysis of the cytosolic Ca(2+) events in beta cell collectives in situ. Am. J. Physiol. Endocrinol. Metab. 324, E42\u2013E55 (2023).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"10163_CR77","doi-asserted-by":"publisher","unstructured":"Rupnik, M. S. Alpha_cell_analysis_for_publication. figshare. Software. https:\/\/doi.org\/10.6084\/m9.figshare.31988721.v1 (2026).","DOI":"10.6084\/m9.figshare.31988721.v1"}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10163-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10163-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10163-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:02:19Z","timestamp":1791763339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10163-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":77,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["10163"],"URL":"https:\/\/doi.org\/10.1038\/s42003-026-10163-6","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,23]]},"assertion":[{"value":"10 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"G.A.R. has received grant funding from, and is a consultant for, Sun Pharmaceuticals Inc. No other potential conflicts of interest relevant to this article were reported. The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"1324"}}