{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T03:13:53Z","timestamp":1782443633666,"version":"3.54.5"},"reference-count":30,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K23801"],"award-info":[{"award-number":["24K23801"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K23825"],"award-info":[{"award-number":["24K23825"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K23776"],"award-info":[{"award-number":["24K23776"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K28017"],"award-info":[{"award-number":["23K28017"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016573","name":"Japan Association for Diabetes Education and Care","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016573","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Diabetes Invest"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/Introduction<\/jats:title>\n                    <jats:p>Dipeptidyl peptidase\u20104 (DPP\u20104) inhibitors enhance circulating levels of biologically intact incretins, yet the relative contribution of glucose\u2010dependent insulinotropic polypeptide (GIP) to their metabolic effects remains incompletely understood. While glucagon\u2010like peptide\u20101 (GLP\u20101) has long been emphasized in incretin biology, emerging evidence suggests important physiological roles for GIP. This study investigated whether endogenous GIP signaling is indispensable for the glucose\u2010lowering and anti\u2010obesity effects of DPP\u20104 inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      Male\n                      <jats:italic>Gipr<\/jats:italic>\n                      <jats:sup>+\/+<\/jats:sup>\n                      and\n                      <jats:italic>Gipr<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice were treated with anagliptin or linagliptin under normal diet or high\u2010fat diet (HFD) conditions. Glucose tolerance, insulin secretion, incretin levels, body weight, and adiposity were assessed. To confirm GLP\u20101 pathway integrity, dulaglutide was administered to a subset of animals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DPP\u20104 inhibition significantly improved glucose tolerance and attenuated body\u2010weight gain in HFD\u2010fed\n                      <jats:italic>Gipr<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+\/+<\/jats:italic>\n                      <\/jats:sup>\n                      mice, without affecting food intake. These effects were abolished in\n                      <jats:italic>Gipr<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice, despite similar elevations in circulating biologically intact GIP and GLP\u20101. Under normal diet, DPP\u20104 inhibitors enhanced early\u2010phase insulin secretion and lowered glucose levels in\n                      <jats:italic>Gipr<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+\/+<\/jats:italic>\n                      <\/jats:sup>\n                      mice, but not in\n                      <jats:italic>Gipr<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice. Importantly, dulaglutide restored glucose\u2010lowering effects in\n                      <jats:italic>Gipr<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice, confirming preserved GLP\u20101 receptor function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Endogenous GIP signaling is essential for both glucose\u2010lowering and anti\u2010obesity actions of DPP\u20104 inhibitors in mice. GLP\u20101 elevation alone is insufficient to compensate for GIP receptor deficiency. These findings refined the mechanistic understanding of DPP\u20104 inhibitors, highlighted the physiological importance of GIP, and suggested context\u2010dependent metabolic actions of incretins.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jdi.70252","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T10:40:04Z","timestamp":1770115204000},"page":"567-575","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Endogenous\n                    <scp>GIP<\/scp>\n                    signaling is indispensable for\n                    <scp>DPP<\/scp>\n                    \u20104 inhibitor\u2010mediated metabolic control in mice"],"prefix":"10.1111","volume":"17","author":[{"given":"Saki","family":"Kubota\u2010Okamoto","sequence":"first","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology Gifu University Graduate School of Medicine  Gifu Japan"},{"name":"Yutaka Seino Distinguished Center for Diabetes Research Kansai Electric Power Medical Research Institute  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6072-0080","authenticated-orcid":false,"given":"Sodai","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology Gifu University Graduate School of Medicine  Gifu Japan"},{"name":"Yutaka Seino Distinguished Center for Diabetes Research Kansai Electric Power Medical Research Institute  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Tsuchida","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology Gifu University Graduate School of Medicine  Gifu 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