{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:15:36Z","timestamp":1790309736603,"version":"4.1.0"},"reference-count":19,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100006197","name":"Fonden til L\u00e6gevidenskabens Fremme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006197","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005747","name":"A.P. M\u00f8ller og Hustru Chastine Mc-Kinney M\u00f8llers Fond til almene Formaal","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005747","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011958","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","award":["1052\u201000003B"],"award-info":[{"award-number":["1052\u201000003B"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011958","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","award":["10.46540\/4308\u201000056B"],"award-info":[{"award-number":["10.46540\/4308\u201000056B"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011958","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","award":["10.46540\/4285\u201000131B"],"award-info":[{"award-number":["10.46540\/4285\u201000131B"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,7]]},"abstract":"\n Abstract<\/jats:title>\n \n Hyperaminoacidaemia and hyperglucagonaemia are hallmarks of metabolic dysfunction\u2013associated liver disease and type 2 diabetes. Amino acids potently stimulate glucagon secretion and can stimulate insulin secretion, although less potently than glucose. Endogenous somatostatin released from pancreatic \u03b4\u2010cells inhibits islet hormone output. It remains uncertain whether amino acid\u2013induced stimulation can dominate pharmacological somatostatin receptor (SSTR) activation in humans. To address this we examined hormonal responses to intravenous amino acid infusion (Vamin) with and without concomitant infusion of the somatostatin analogue octreotide in 15 healthy individuals. Plasma glucagon, insulin and C\u2010Peptide were measured during 45\u00a0min of amino acid infusion alone, during amino acid infusion combined with a 240\u2011min octreotide infusion and during octreotide infusion without amino acids. Octreotide alone suppressed glucagon and insulin concentrations by greater than 90% and reduced C\u2011Peptide by greater than 65%. In contrast amino acids alone significantly increased all three peptides. When amino acids and octreotide were co\u2011infused, the amino acid\u2013driven elevations in glucagon, insulin and C\u2011Peptide were reduced to 49%, 43% and 78% of the levels achieved by amino acids alone. These findings demonstrate robust \u03b1\u2011 and \u03b2\u2011cell secretion during SSTR\u20102\u2011biased agonism despite profound baseline suppression, indicating partial \u2018breakthrough\u2019 secretion and suggesting that amino acid\u2013driven stimulation can, in part, counteract SSTR\u2011mediated inhibition in humans.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Amino acids strongly stimulate glucagon secretion in humans, whereas somatostatin receptor (SSTR) activation potently inhibits basal islet hormone release.<\/jats:p>\n <\/jats:list-item>\n \n During near\u2010maximal suppression with the somatostatin analogue octreotide, amino acid infusion induced substantial \u2018breakthrough\u2019 secretion of glucagon, insulin and C\u2010Peptide.<\/jats:p>\n <\/jats:list-item>\n \n Co\u2010infusion of amino acids and octreotide reduced amino acid\u2013stimulated responses to 49% (glucagon), 47% (insulin) and 78% (C\u2010Peptide) of amino acids alone.<\/jats:p>\n <\/jats:list-item>\n \n Breakthrough secretion was not specific to \u03b1\u2010cells, indicating that strong secretagogue stimulation can partially escape somatostatin\u2010mediated inhibition for both \u03b1\u2010 and \u03b2\u2010cells.<\/jats:p>\n <\/jats:list-item>\n \n \n These\n in vivo<\/jats:italic>\n human data support a balance\u2010of\u2010signals model in which elevated amino acids can counteract, but not fully overcome, inhibitory SSTR activation.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n We performed this study to determine why hyperglucagonaemia persists in metabolic diseases despite somatostatin's inhibitory role.<\/jats:p>\n <\/jats:list-item>\n \n We specifically evaluated whether amino acid\u2013induced glucagon secretion can persist during pharmacological somatostatin receptor (SSTR) activation (octreotide) in humans.<\/jats:p>\n <\/jats:list-item>\n \n We found that amino acids strongly stimulated glucagon, insulin and C\u2010Peptide secretion even during somatostatin infusion, reducing but not eliminating the hormonal responses.<\/jats:p>\n <\/jats:list-item>\n \n These findings imply that amino acid\u2013driven stimulation can partially bypass inhibitory signalling downstream of SSTR activation, helping explain persistent glucagon elevation in metabolic disorders.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp290901","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T01:26:48Z","timestamp":1781314008000},"page":"5926-5935","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Amino acids partially override inhibitory effects of octreotide on islet hormone secretion in healthy individuals"],"prefix":"10.1113","volume":"604","author":[{"given":"Josephine","family":"Reiche","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry Copenhagen University Hospital \u2013 Bispebjerg and Frederiksberg Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3861-8469","authenticated-orcid":false,"given":"Michael M.","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry Copenhagen University Hospital \u2013 Bispebjerg and Frederiksberg Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4000-5669","authenticated-orcid":false,"given":"Sasha A. S.","family":"Kjeldsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry Copenhagen University Hospital \u2013 Bispebjerg and Frederiksberg Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2144-1385","authenticated-orcid":false,"given":"Marie","family":"Winther\u2010S\u00f8rensen","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry Copenhagen University Hospital \u2013 Bispebjerg and Frederiksberg Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4230-5753","authenticated-orcid":false,"given":"Nicolai J.","family":"Wewer Albrechtsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry Copenhagen University Hospital \u2013 Bispebjerg and Frederiksberg Copenhagen Denmark"},{"name":"Department of Clinical Medicine University of Copenhagen Copenhagen Denmark"},{"name":"Center for Translational Research Copenhagen University Hospital \u2013 Bispebjerg and Frederiksberg Hospital Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11517-x"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1382-z"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.2337\/dbi19-0021"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00198.2017"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00459.2019"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2023.171039"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.2337\/db08-0792"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2025.08.019"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101021"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.2337\/db23-0858"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.1.77"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-23-0365"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.2337\/dbi22-0004"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvab121"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107046"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo.141.1.7263"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05288-0"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-023-05947-y"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101080"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP290901","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP290901","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP290901","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:35:52Z","timestamp":1785742552000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP290901"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":19,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1113\/JP290901"],"URL":"https:\/\/doi.org\/10.1113\/jp290901","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]},"assertion":[{"value":"2026-01-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}