{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:40:33Z","timestamp":1790196033189,"version":"4.1.0"},"reference-count":58,"publisher":"American Diabetes Association","issue":"7","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"Sinai Health-Novo Nordisk Foundation Chair in Regulatory Peptides"},{"name":"Kyoto-based innovative medical technology research and development grant program from the Kyoto Lifetech Innovation Support Center"},{"name":"the Adaptable and Seamless Technology transfer Program through Target-driven R&D","award":["JPMJTR20UT"],"award-info":[{"award-number":["JPMJTR20UT"]}]},{"name":"Diabetes Canada-Canadian Cancer Society Grant","award":["OG-3- 24-5819-DD"],"award-info":[{"award-number":["OG-3- 24-5819-DD"]}]},{"name":"an Inamori research grant from the Inamori Foundation"},{"name":"the Grant-in-Aid for Core Research for Evolutional Science and Technology","award":["JPMJCR21P1"],"award-info":[{"award-number":["JPMJCR21P1"]}]},{"name":"Canadian Institutes of Health Research (CIHR) Grants","award":["154321"],"award-info":[{"award-number":["154321"]}]},{"name":"Canadian Institutes of Health Research (CIHR) Grants","award":["192044"],"award-info":[{"award-number":["192044"]}]},{"DOI":"10.13039\/100009619","name":"the Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP21lm0203014"],"award-info":[{"award-number":["JP21lm0203014"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"the Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP24ym0126815"],"award-info":[{"award-number":["JP24ym0126815"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"name":"a Junior scientist development grant from Novo Nordisk Pharma Ltd."},{"name":"a Lotte research promotion grant from the Lotte Foundation"},{"name":"JSPS KAKENHI","award":["19H04045"],"award-info":[{"award-number":["19H04045"]}]},{"name":"JSPS KAKENHI","award":["23K28032"],"award-info":[{"award-number":["23K28032"]}]},{"name":"JSPS KAKENHI","award":["26460302"],"award-info":[{"award-number":["26460302"]}]},{"name":"a research grant from the Suzuken Memorial Foundation"},{"name":"the Grant-in-Aid for JSPS Fellows","award":["22J20706"],"award-info":[{"award-number":["22J20706"]}]},{"name":"Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Glucagon-like peptide 1 receptor agonists (GLP-1RAs) ameliorate hyperglycemia by directly stimulating insulin secretion from the pancreas. In contrast, the physiological role of short-lived endogenous GLP-1 remains unclear largely because of its limited access to pancreatic \u03b2-cells. Here, we used d-allulose, a nonmetabolizable noncaloric rare sugar, as a GLP-1 secretagogue. We show that d-allulose\u2013induced intestinal GLP-1 secretion (AIGS) cooperates with insulin to reduce blood glucose levels by enhancing insulin action, rather than insulin secretion, in male mice. This cooperation and remote signaling require left-sided vagal afferents forming the common hepatic branch, but not right-sided afferents. AIGS-enhanced insulin action required both GLP-1Rs and insulin receptor substrate 2 in these neurons. Remarkably, in db\/db mice exhibiting severe insulin resistance, AIGS improved insulin resistance and hyperglycemia more rapidly and potently than the GLP-1RA exendin-4. These findings reveal that a subclass of vagal afferent neurons synergistically activated by endogenous intestinal GLP-1 and insulin does not stimulate insulin secretion but augments insulin action to improve glucose tolerance. This novel extrapancreatic GLP-1 action mediated by vagal afferents provides a promising basis for innovative type 2 diabetes therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Compared with glucagon-like peptide 1 (GLP-1) receptor agonists, the physiological roles and mechanisms of endogenous, short-lived GLP-1 in glucose metabolism remain poorly understood. We used the rare sugar d-allulose, a noncaloric GLP-1 secretagogue, as a tool to elucidate the physiological actions of endogenous GLP-1. d-Allulose\u2013induced intestinal GLP-1 release cooperates with insulin to activate left-side vagal afferents, enhancing insulin action rather than insulin secretion and thereby regulating glycemic control. Because this acute mechanism improved hyperglycemia in type 2 diabetes to an extent comparable to that observed with GLP-1 receptor agonists, targeting GLP-1\/insulin-vagal signaling may inform novel therapies and dietary or nutritional interventions for type 2 diabetes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-1134","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T04:02:50Z","timestamp":1777608170000},"page":"1086-1100","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":2,"title":["Gut-Derived GLP-1 Released by Rare Sugar\n                    <scp>d<\/scp>\n                    -Allulose Cooperates With Insulin to Activate Left-Sided Vagal Afferents and Enhance Insulin Sensitivity"],"prefix":"10.2337","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7984-8690","authenticated-orcid":false,"given":"Kento","family":"Ohbayashi","sequence":"first","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University 1 , Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamoru","family":"Tanida","sequence":"additional","affiliation":[{"name":"Department of Physiology II, Kanazawa Medical University 2 , Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chikara","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medical Sciences, University of Fukui 3 , Fukui, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Ishihara","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University 1 , Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Omi","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University 1 , Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3336-2767","authenticated-orcid":false,"given":"Naoto","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University 4 , Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6688-8127","authenticated-orcid":false,"given":"Daniel J.","family":"Drucker","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Mount Sinai Hospital, University of Toronto, Toronto 5 , Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Yada","sequence":"additional","affiliation":[{"name":"Center for Integrative Physiology, Kansai Electric Power Medical Research Institute 6 , Osaka, Japan"},{"name":"Department of Diabetes, Endocrinology and Metabolism\/Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine 7 , Gifu, Japan"},{"name":"School of Medicine Department of Endocrinology, Diabetes and Metabolism, Fujita Health University 8 , Toyoake, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0655-4384","authenticated-orcid":false,"given":"Yusaku","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University 1 , Kyoto, 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