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This study compared the differences between exenatide and insulin in osseointegration in a rat model of Type 2 diabetes (T2D) and explored the mechanisms promoting osteogenesis in this model of T2D.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>In vivo, micro\u2010CT was used to detect differences in the peri\u2010implant bone microstructure in vivo. Histology, dual\u2010fluorescent labelling, immunofluorescence and immunohistochemistry were used to detect differences in tissue, cell and protein expression around the implants. In vitro, RT\u2010PCR and western blotting were used to measure the expression of osteogenesis\u2010 and Wnt signalling\u2010related genes and proteins in bone marrow mesenchymal stromal cells (BMSCs) from rats with T2D (TBMSCs) after PBS, insulin and exenatide treatment. RT\u2010PCR was used to detect the expression of Wnt bypass cascade reactions under Wnt inactivation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Micro\u2010CT and section staining showed exenatide extensively promoted peri\u2010implant osseointegration. Both in vivo and in vitro experiments showed exenatide substantially increased the expression of osteogenesis\u2010related and activated the LRP5\/6\/GSK\u20103\u03b2\/\u03b2\u2010catenin\u2010related Wnt pathway. Furthermore, exenatide suppressed expression of <jats:italic>Bmpr1a<\/jats:italic> to inhibit lipogenesis and promoted expression of <jats:italic>Btrc<\/jats:italic> to suppress inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Compared to insulin, exenatide significantly improved osteogenesis in T2D rats and TBMSCs. In addition to its dependence on LRP5\/6\/GSK\u20103\u03b2\/\u03b2\u2010catenin signalling for osteogenic differentiation, exenatide\u2010mediated osteomodulation also involves inhibition of inflammation and adipogenesis by BMPR1A and \u03b2\u2010TrCP, respectively.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16421","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T08:15:06Z","timestamp":1716884106000},"page":"3556-3575","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Role of LRP5\/6\/GSK\u20103\u03b2\/\u03b2\u2010catenin in the differences in exenatide\u2010 and insulin\u2010promoted T2D osteogenesis and osteomodulation"],"prefix":"10.1111","volume":"181","author":[{"given":"Zijun","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxi","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingliang","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangdong","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,28]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/md.0000000000035394"},{"issue":"2","key":"e_1_2_13_3_1","first-page":"S23","article-title":"The Concise Guide to PHARMACOLOGY 2023\/24: G protein\u2010coupled receptors","volume":"180","author":"Alexander S. 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