{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:30:15Z","timestamp":1789587015605,"version":"build-2803163510"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100031158","name":"Diabetes Research Center, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania","doi-asserted-by":"publisher","award":["DK112812"],"award-info":[{"award-number":["DK112812"]}],"id":[{"id":"10.13039\/100031158","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      Glucagon\u2010like peptide\u20101 receptor (GLP\u20101R) agonists improve glycemic control and promote weight loss in diabetes and obesity but are also associated with gastrointestinal adverse events, including nausea and emesis in many patients. These concerns highlight the need for the development of novel GLP\u20101R agonists that minimize these side effects while maintaining beneficial metabolic outcomes. Here, we investigate the\n                      <jats:italic>in vivo<\/jats:italic>\n                      effects of exendin\u20104\u2010Phe1 (Ex\u2010Phe1), a GLP\u20101R biased agonist.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      In three pre\u2010clinical species, mice (\n                      <jats:italic>n<\/jats:italic>\n                      =\u200943), rats (\n                      <jats:italic>n<\/jats:italic>\n                      =\u200954), and musk shrews (\n                      <jats:italic>n<\/jats:italic>\n                      =\u200930), we examined\n                      <jats:italic>in vivo<\/jats:italic>\n                      glycemic control, feeding, and nausea\/emesis following native Ex\u20104 and Ex\u2010Phe1 administration. We also used cFos expression following Ex\u20104 and Ex\u2010Phe1 administration to examine neural activation in regions involved in mediating nausea and emetic side effects of GLP\u20101R agonism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      studies show Ex\u2010Phe1 favors cAMP signaling with reduced \u03b2\u2010arrestin recruitment. Compared to Ex\u20104, Ex\u2010Phe1 produced fewer emetic episodes in musk shrews (\n                      <jats:italic>Suncus murinus<\/jats:italic>\n                      ) and little to no pica, a proxy for nausea, in rats. Ex\u2010Phe1 effects on food intake and body weight varied by species, while Ex\u20104 and Ex\u2010Phe1 similarly enhanced glucose tolerance in all species. Ex\u20104 and Ex\u2010Phe1 increased cFos expression within brain regions linked to nausea and emesis in all species.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, Ex\u2010Phe1 maintains glycemic benefits in all three species, but putatively blunts the ability of the CNS GLP\u20101R+ cells to drive anorexia and weight loss, as well as unwanted adverse events (nausea\/emesis) in rats and musk shrews.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.70427","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T07:08:39Z","timestamp":1767942519000},"page":"2317-2328","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>GLP<\/scp>\n                    \u2010\n                    <scp>1R<\/scp>\n                    biased\n                    <scp>cAMP<\/scp>\n                    agonism maintains glycemic control with reduced malaise and emesis in preclinical mammalian models"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6287-5887","authenticated-orcid":false,"given":"Caitlin","family":"Baumer\u2010Harrison","sequence":"first","affiliation":[{"name":"Department of Psychiatry Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danya","family":"Aldaghma","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex 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