{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T13:05:32Z","timestamp":1779368732771,"version":"3.53.0"},"reference-count":48,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH Medical Student Training in Aging Research (MSTAR) program","award":["T35 AG026757"],"award-info":[{"award-number":["T35 AG026757"]}]},{"name":"VAPSHCS Summer Research Program","award":["SRP-020-22S"],"award-info":[{"award-number":["SRP-020-22S"]}]},{"DOI":"10.13039\/100000738","name":"VA Merit Review Award 5","doi-asserted-by":"publisher","award":["I01BX004102"],"award-info":[{"award-number":["I01BX004102"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Incretin receptor agonists (IRAs) such as GLP-1-based therapies improve metabolic and cognitive outcomes and enhance brain insulin signaling. One way that IRAs could have these actions is by affecting the blood\u2013brain barrier (BBB); however, IRA-BBB interactions are poorly studied. Here, we examined the ability of insulin and IRAs to affect each other\u2019s transport across the BBB in lean mice. We found that intracerebroventricular (ICV) administration of the insulin receptor antagonist S961 did not affect the blood-to-brain transport of the bioactive fragment of the IRA, 125I-dulaglutide (BAF). In contrast, 125I-dulaglutide (BAF) co-administered with intravenous (IV) insulin significantly enhanced 125I-dulaglutide (BAF) BBB transport into whole brain, olfactory bulb, parietal cortex, and pons, demonstrating insulin-dependent modulation of IRA BBB transport. Regional transport rates for 125I-dulaglutide (BAF) across the brain varied by ~2.5-fold, with the fastest transport into the olfactory bulb, frontal cortex, cerebellum, and pons. Co-administration of IV dulaglutide (BAF) did not alter 125I-insulin BBB transport rates (Ki) but did reduce reversible insulin binding (Vi) at the BBB by &gt;50%, suggesting rapid effects on BBB insulin receptors. To explore the effects of chronic IRA administration, lean mice were treated with semaglutide for two weeks. Body weight and food intake were unchanged, but female mice showed reduced fasting levels of serum insulin and GLP-1 and decreased insulin transport into whole brain, while male mice showed a reduction in insulin binding at the BBB. Chronic semaglutide also reduced 125I-insulin BBB transport in female mice when studied with in situ perfusion, a procedure that removes the immediate influence of serum factors. Together, these findings demonstrate reciprocal and female-selective interactions between IRAs and insulin at the BBB. Acute insulin enhances the BBB transport of an IRA in female mice, whereas chronic IRA exposure selectively impairs insulin BBB transport in females, highlighting the BBB as a dynamic and hormone-sensitive interface with implications for long-term treatment in mouse models and potential for translation impact in humans.<\/jats:p>","DOI":"10.3390\/ijms27104611","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T12:06:07Z","timestamp":1779365167000},"page":"4611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Insulin and Incretin Receptor Agonists Reciprocally Alter Their Blood\u2013Brain Barrier Permeabilities"],"prefix":"10.3390","volume":"27","author":[{"given":"Angeline","family":"Fry","sequence":"first","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5266-9693","authenticated-orcid":false,"given":"Alexis","family":"Rose","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2555-8065","authenticated-orcid":false,"given":"Riley","family":"Weaver","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Hansen","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Blevins","sequence":"additional","affiliation":[{"name":"Office of Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"},{"name":"Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0496-3619","authenticated-orcid":false,"given":"William A.","family":"Banks","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"},{"name":"Division of Gerontology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8118-120X","authenticated-orcid":false,"given":"Elizabeth M.","family":"Rhea","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"},{"name":"Division of Gerontology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e12268","DOI":"10.1002\/trc2.12268","article-title":"Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers","volume":"8","author":"Norgaard","year":"2022","journal-title":"Alzheimer\u2019s Dement. 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