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Co-treatment with recombinant S100 calcium-binding protein A9 (S100A9) enabled increased adherence to glycemic targets with half as much insulin and without causing hypoglycemia. Mechanistically, we demonstrate that the hyperglycemia-suppressing action of S100A9 is due to a Toll-like receptor 4\u2013dependent increase in glucose uptake in specific skeletal muscles (i.e., soleus and diaphragm). In addition, we found that T1DM mice have abnormal systemic inflammation, which is resolved by S100A9 therapy alone (or in combination with low insulin), hence uncovering a potent anti-inflammatory action of S100A9 in T1DM. In summary, our findings reveal the S100A9-TLR4 skeletal muscle axis as a promising therapeutic target for improving T1DM treatment.<\/jats:p>","DOI":"10.1126\/sciadv.adj4686","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T18:58:17Z","timestamp":1704308297000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":15,"title":["S100A9 exerts insulin-independent antidiabetic and anti-inflammatory effects"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-4417","authenticated-orcid":true,"given":"Gloria","family":"Ursino","sequence":"first","affiliation":[{"name":"Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland."},{"name":"Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5543-1719","authenticated-orcid":true,"given":"Giulia","family":"Lucibello","sequence":"additional","affiliation":[{"name":"Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland."},{"name":"Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pryscila D. 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