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One GLP\u20102 analogue is approved for short bowel syndrome (SBS). To improve therapeutic efficacy, we developed biased GLP\u20102 receptor (GLP\u20102R) agonists through N\u2010terminal modifications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Variants with Ala and Trp substitutions of the first seven positions of GLP\u20102(1\u201033) were studied in vitro for affinity, G protein activation (cAMP accumulation), recruitment of \u03b2\u2010arrestin 1 and 2, and internalization of the human and mouse GLP\u20102R. The intestinotrophic actions of the most efficacious (cAMP) biased variant were examined in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Ala substitutions had more profound effects than Trp substitutions. For both, alterations at positions 1, 3 and 6 most severely impaired activity. \u03b2\u2010arrestin recruitment was more affected than cAMP accumulation. Among Ala substitutions, [H1A], [D3A] and [F6A] impaired potency (EC<jats:sub>50<\/jats:sub>) for cAMP\u2010accumulation &gt;20\u2010fold and efficacy (E<jats:sub>max<\/jats:sub>) to 48%\u201387%, and were unable to recruit arrestins. The Trp substitutions, [A2W], [D3W] and [G4W] were partial agonists (E<jats:sub>max<\/jats:sub> of 46%\u201359%) with 1.7\u201312\u2010fold decreased potencies in cAMP and diminished \u03b2\u2010arrestin recruitment. The biased variants, [F6A], [F6W] and [S7W] induced less GLP\u20102R internalization compared with GLP\u20102, which induced internalization in a partly arrestin\u2010independent manner. In mice, [S7W] enhanced gut trophic actions with increased weight of the small intestine, increased villus height and crypt depth compared with GLP\u20102.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>G protein\u2010biased GLP\u20102R agonists with diminished receptor desensitization have superior intestinotrophic effects and may represent improved treatment of intestinal insufficiency including SBS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16040","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T04:47:55Z","timestamp":1674449275000},"page":"1674-1689","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Biased GLP\u20102 agonist with strong G protein\u2010coupling but impaired arrestin recruitment and receptor desensitization enhances intestinal growth in mice"],"prefix":"10.1111","volume":"180","author":[{"given":"Maria Buur Nordskov","family":"Gabe","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liv","family":"von Voss","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna Elizabeth","family":"Hunt","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarina","family":"Gadgaard","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e6rke Smidt","family":"Gasbjerg","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens Juul","family":"Holst","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"},{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannelouise","family":"Kissow","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences 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"},{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9600-3254","authenticated-orcid":false,"given":"Mette Marie","family":"Rosenkilde","sequence":"additional","affiliation":[{"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":[[2023,2,7]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.regpep.2012.11.002"},{"issue":"2","key":"e_1_2_12_4_1","first-page":"687","article-title":"Glucagon\u2010like peptide (GLP)\u20102 reduces chemotherapy\u2010associated mortality and enhances cell survival in cells expressing a transfected GLP\u20102 receptor","volume":"61","author":"Boushey R. 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