{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T02:26:59Z","timestamp":1793759219478,"version":"4.6.1"},"reference-count":41,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/Hypothesis<\/jats:title>\n                    <jats:p>Glucose\u2010dependent insulinotropic polypeptide (GIP) is a bidirectional glucose\u2010stabilising hormone potentiating insulin secretion at high glucose levels and glucagon secretion during normal\u2010to\u2010low plasma glucose levels. Preclinically, GIP and the amino acid alanine show synergistic glucagonotropic effects at low glucose levels. We therefore evaluated the separate and combined effects of GIP and alanine infusions on plasma glucose, glucagon and C\u2010peptide in fasted, healthy men.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this placebo\u2010controlled, randomised, double\u2010blind crossover study, 10 healthy men (mean age 22.9\u2009\u00b1\u20092.82\u2009years, BMI 23.7\u2009\u00b1\u20092.07\u2009kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      ) underwent four experimental days involving 90\u2010min i.v. infusions of saline\u2009+\u2009GIP (6\u2009pmol\/kg\/min for 10\u2009min, then 4\u2009pmol\/kg\/min for 80\u2009min), alanine\u2009+\u2009saline (28\u2009\u03bcmol\/kg\/min), alanine\u2009+\u2009GIP, and saline\u2009+\u2009saline after a 10\u2010h fast.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      As expected, the infusions increased circulating levels of alanine and GIP according to the intervention. Alanine increased glucagon secretion, while GIP induced a more moderate glucagonotropic effect. The combination of alanine and GIP resulted in an additive increase in glucagon secretion with bsAUC\n                      <jats:sub>glucagon<\/jats:sub>\n                      being 38%\u2009\u00b1\u20095% higher compared to alanine\u2009+\u2009saline (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&gt;\u20090.01) and 83%\u2009\u00b1\u20097% higher than saline\u2009+\u2009GIP (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). C\u2010peptide was likewise higher with alanine\u2009+\u2009GIP than with either single infusion (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). Saline\u2009+\u2009GIP transiently raised C\u2010peptide and resulted in lowered plasma glucose compared with placebo (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and alanine\u2009+\u2009saline and alanine\u2009+\u2009GIP (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/Interpretation<\/jats:title>\n                    <jats:p>In fasting healthy men, both GIP and alanine stimulate pancreatic hormone secretion, and combined administration additively enhances glucagon and C\u2010peptide responses. Alanine availability modulates the metabolic actions of GIP and may influence its glucose\u2010regulatory effects under fasting conditions.<\/jats:p>\n                    <jats:p>\n                      <jats:bold>Trial Registration:<\/jats:bold>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      identifier: NCT06881472.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71273","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T06:20:44Z","timestamp":1788934844000},"page":"11095-11106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Additive Glucagonotropic and Insulinotropic Effects of Glucose\u2010Dependent Insulinotropic Polypeptide and Alanine in Fasted Healthy Men"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8366-8513","authenticated-orcid":false,"given":"Julie","family":"Warn\u00f8e","sequence":"first","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliya M.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3545-5721","authenticated-orcid":false,"given":"David S.","family":"Mathiesen","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde K.","family":"Preskou","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"St\u00f8rling","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, University of Copenhagen  Herlev Denmark"},{"name":"Department of Biomedical Sciences Faculty of Health and Medical Sciences, University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikkel B.","family":"Christensen","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen  Hellerup Denmark"},{"name":"Department of Clinical Medicine Faculty of Health and Medical Sciences, University of Copenhagen  Copenhagen Denmark"},{"name":"Department of Clinical Pharmacology Bispebjerg and Frederiksberg Hospital, University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bolette","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Faculty of Health and Medical Sciences, University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-3805","authenticated-orcid":false,"given":"Jens J.","family":"Holst","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Faculty of Health and Medical Sciences, University of Copenhagen  Copenhagen Denmark"},{"name":"Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel A. J.","family":"Trammell","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Faculty of Health and Medical Sciences, University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4358-6331","authenticated-orcid":false,"given":"Jonathan E.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine Duke University  Durham North Carolina USA"},{"name":"Duke Molecular Physiology Institute, Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0097-7052","authenticated-orcid":false,"given":"Thomas F.","family":"Dejgaard","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen  Hellerup Denmark"},{"name":"Department of Endocrinology and Nephrology Nordsj\u00e6llands Hospital, University of Copenhagen  Hiller\u00f8d Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asger B.","family":"Lund","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen  Hellerup Denmark"},{"name":"Steno Diabetes Center Copenhagen, University of Copenhagen  Herlev Denmark"},{"name":"Department of Clinical Medicine Faculty of Health and Medical Sciences, University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip K.","family":"Knop","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen  Hellerup Denmark"},{"name":"Department of Clinical Medicine Faculty of Health and Medical Sciences, University of Copenhagen  Copenhagen Denmark"},{"name":"Novo Nordisk A\/S  Bagsv\u00e6rd Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7880-8515","authenticated-orcid":false,"given":"L\u00e6rke S.","family":"Gasbjerg","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen  Hellerup Denmark"},{"name":"Department of Biomedical Sciences Faculty of Health and Medical Sciences, University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.04.008"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125\u2010017\u20104450\u20109"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqab065"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.2337\/db11\u20100979"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125\u2010003\u20101103\u2010y"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem\u201069\u20103\u2010654"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2019.05.014"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE\u201024\u20100231"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2019.170197"},{"issue":"4","key":"e_1_2_12_11_1","first-page":"B5230","article-title":"Glucose\u2010Dependent Insulinotropic Polypeptide: Effects on Insulin and Glucagon Secretion in Humans","volume":"63","author":"Christensen M. 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