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Some individuals experience greater glycemic stability on the day after exercise, even without additional physical activity. However, the mechanisms underlying this delayed glycemic improvement remain unclear.Methods: Seventy-one patients with type 2 diabetes mellitus were assigned to either a 60-minute exercise group or a resting group. Serum fibroblast growth factor 21 (FGF21) levels and untargeted metabolomic profiles were assessed at multiple time points before and after exercise. Interstitial glucose levels were monitored using continuous glucose monitoring system. FGF21 knockout mice and wild-type littermates fed a high-fat diet underwent a 3-week exercise intervention and received FGF21 supplementation.Results: Individuals exhibiting delayed glycemic improvement (responders) displayed a significantly stronger FGF21 response than non-responders. Baseline metabolites, including p-cresol sulfate and dimethylglycine, differed between responders and non-responders and were associated with the FGF21 response. Longitudinal time-series analyses revealed post-exercise differences in acylcarnitines, fatty acids, and complex lipids between responders and non-responders. Dynamic correlation and mediation analyses supported the role of FGF21 in modulating delayed glycemic improvement through regulation of lipid metabolism. In vivo FGF21 knockout and rescue experiments demonstrated that FGF21 is necessary for these metabolic shifts and the associated improvements in glucose tolerance and insulin sensitivity.Conclusion: This study suggests that the baseline metabolome is associated with the magnitude of the post-exercise FGF21 response, which influences delayed glycemic improvement through regulation of lipid metabolism pathways.<\/jats:p>","DOI":"10.4093\/dmj.2024.0814","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T04:48:48Z","timestamp":1774414128000},"page":"770-784","update-policy":"https:\/\/doi.org\/10.4093\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Influence of Fibroblast Growth Factor 21 on Delayed Glycemic Improvement Following Acute Exercise in Type 2 Diabetes Mellitus"],"prefix":"10.4093","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3288-0041","authenticated-orcid":true,"given":"Ying","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Institute for Proactive Healthcare, Shanghai Jiao Tong University, Shanghai, China"},{"name":"Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8951-6248","authenticated-orcid":true,"given":"Dan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of 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