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Our previous study proposed that chronic \u03b2\u2010cell depolarization alters G protein signaling and contributes to this differential incretin responsiveness, but whether glucose lowering by sodium\u2013glucose cotransporter 2 inhibition restores incretin responsiveness remains unclear. We investigated the effects of chronic luseogliflozin treatment on incretin responsiveness in two diabetic mouse models, KK\u2010Ay mice with preserved residual \u03b2\u2010cell function and streptozotocin\/high\u2010fat diet\u2010induced diabetic mice with severe \u03b2\u2010cell impairment. Luseogliflozin improved glycemic control in both models without marked changes in body weight or plasma insulin levels. In KK\u2010Ay mice, luseogliflozin restored the glucose\u2010lowering effect of GIP during GIP\u2010preload glucose tolerance test. In contrast, this effect was not observed in streptozotocin\/high\u2010fat diet\u2010induced diabetic mice, suggesting that preserved residual \u03b2\u2010cell function is required for recovery of GIP responsiveness. Ex\u00a0vivo analyses using isolated islets further showed that chronic luseogliflozin treatment altered incretin\u2010stimulated insulin secretion, including attenuation of enhanced GLP\u20101 responsiveness under diabetic conditions. These findings suggest that luseogliflozin may partially normalize aberrant \u03b2\u2010cell incretin signaling and restore GIP responsiveness when sufficient \u03b2\u2010cell function remains.<\/jats:p>","DOI":"10.14814\/phy2.71016","type":"journal-article","created":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T04:27:52Z","timestamp":1783830472000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Luseogliflozin restores\n                    <scp>GIP<\/scp>\n                    responsiveness in diabetic male mice with preserved \u03b2\u2010cell function"],"prefix":"10.14814","volume":"14","author":[{"given":"Quan","family":"Yingyue","sequence":"first","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"},{"name":"Division of Molecular and Metabolic Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harumi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Division of Molecular and Metabolic Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihide","family":"Yokoi","sequence":"additional","affiliation":[{"name":"Division of Molecular and Metabolic Medicine Kobe University Graduate School of Medicine  Kobe Japan"},{"name":"Laboratory of Animal Breeding and Genetics, Division of Applied Biosciences, Graduate School of Agriculture Kyoto University  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"},{"name":"Division of Metabolic Diseases, Department of Translational Medical Science Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6549-7885","authenticated-orcid":false,"given":"Kenji","family":"Sugawara","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe 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