{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:05:05Z","timestamp":1790269505114,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China National Key R&D Program","award":["2022YFA1604502"],"award-info":[{"award-number":["2022YFA1604502"]}]},{"name":"China National Key R&D Program","award":["2022YFA1104200"],"award-info":[{"award-number":["2022YFA1104200"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82400320"],"award-info":[{"award-number":["82400320"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82400320"],"award-info":[{"award-number":["82400320"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Postdoctoral Fellowship Program of CPSF","award":["GZC20242212"],"award-info":[{"award-number":["GZC20242212"]}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2024M764164"],"award-info":[{"award-number":["2024M764164"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2024M764164"],"award-info":[{"award-number":["2024M764164"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Postdoctoral Fellowship of Heilongjiang Province","award":["LBH-Z24017"],"award-info":[{"award-number":["LBH-Z24017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Kr\u00fcppel-like factor 7 (KLF7) is a Cys2\/His2 zinc-finger transcription factor implicated in metabolic regulation. Although KLF7 variants are associated with type 2 diabetes (T2D), its role in \u03b2-cell glucose homeostasis remains unclear. Klf7 is downregulated in \u03b2-cells from mice and humans with established diabetes, and high glucose directly suppresses Klf7 expression in isolated islets. \u03b2-cell-specific Klf7 knockout (\u03b2-KLF7KO) and overexpression (\u03b2-KLF7OE) mouse models were generated, along with AAV-mediated rescue models. Islet transcriptomics, glucose-stimulated insulin secretion assays, luciferase reporter assays, and lentiviral knockdown\/overexpression in INS1 and 1.1B4 cells were performed. Here we show that KLF7 is downregulated in \u03b2-cells from diabetic human donors and mice. \u03b2-cell-specific deletion of Klf7 in mice impaired insulin secretion and glucose tolerance, accompanied by a 47% reduction in Slc2a2 (Glut2) expression. Klf7 overexpression in vitro suppressed insulin secretion, revealing opposing transcriptional regulation of Glut2 and Ins2. Luciferase reporter assays confirmed that Klf7 directly activates the Glut2 promoter and represses the Ins2 promoter, establishing an opposing transcriptional regulatory mechanism. This regulatory mechanism is conserved in the 1.1B4 human pancreatic islet fusion cell line, in which KLF7 knockdown derepressed INS and suppressed GLUT2 expression. AAV-mediated restoration of either Klf7 or Glut2 in \u03b2-KLF7KO mice largely rescued the metabolic defects, identifying Glut2 as a principal downstream mediator. Given that KLF7 declines under hyperglycaemic stress and its loss is sufficient to impair \u03b2-cell function, the Klf7\/Glut2\/Ins2 axis may represent an early, targetable step in \u03b2-cell dysfunction; whether KLF7 decline precedes the onset of glucose intolerance in a natural progression model remains to be determined by longitudinal studies.<\/jats:p>","DOI":"10.3390\/ijms27198553","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:29:53Z","timestamp":1790267393000},"page":"8553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Klf7\/Glut2\/Ins2 Axis Regulates Glucose Homeostasis"],"prefix":"10.3390","volume":"27","author":[{"given":"Chaofan","family":"Yang","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hebing","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuxing","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyue","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4958-4118","authenticated-orcid":false,"given":"Weiming","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e219","DOI":"10.1038\/emm.2016.6","article-title":"Pancreatic regulation of glucose homeostasis","volume":"48","author":"Wu","year":"2016","journal-title":"Exp. 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