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The current study aims to unearth the potential molecular mechanism of inhibiting liver gluconeogenesis to provide a new theoretical basis for the treatment of T2DM. High glucose (HG) induction of HepG2 cells followed by treatment with sequence\u2010similar family 3 member D (FAM3D). Dual specificity phosphatases 1 (DUSP1), zinc finger protein 36 (ZFP36), salt\u2010induced kinase 1 (SIK1), p\u2010SIK1, posphoenolpyruvate carboxykinase (PEPCK) and glucose\u20106\u2010phosphatase (G6Pase) gene and protein expression level were detected by quantitative real\u2010time polymerase chain reaction and western blot. The PEPCK and G6Pase activities were detected by enzyme linked immunosorbent assay. Glucose production assay to determine glucose content. The RNA binding protein immunoprecipitation assay was used to detect the binding of ZFP36 to SIK1. FAM3D facilitated the expression of DUSP1 but suppressed the expression of gluconeogenesis\u2010related factors in an HG environment. The expression of ZFP36 was up\u2010regulated in an HG environment. ZFP36 could reverse the inhibition of gluconeogenesis caused by FAM3D. HG\u2010induced upregulation of ZFP36 was downregulated by overexpression of DUSP1. ZFP36 bound to SIK1, and downregulation of ZFP36 promoted SIK1 expression and inhibits gluconeogenesis. Our study demonstrated FAM3D inhibited gluconeogenesis through the DUSP1\/ZFP36\/SIK1 axis in an HG environment, which provided a new theoretical basis for exploring the pathogenesis and treatment strategy of T2DM.<\/jats:p>","DOI":"10.1002\/kjm2.12633","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T09:01:26Z","timestamp":1671181286000},"page":"254-265","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>FAM3D<\/scp> inhibits gluconeogenesis in high glucose environment via <scp>DUSP1<\/scp>\/<scp>ZFP36<\/scp>\/<scp>SIK1<\/scp> axis"],"prefix":"10.1002","volume":"39","author":[{"given":"Bin","family":"Huang","sequence":"first","affiliation":[{"name":"Department of General Medicine The Affiliated Hospital of Youjiang Medical University for Nationalities  Baise People's Republic of 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