S100A9 exerts insulin-independent antidiabetic and anti-inflammatory effects

Article Article scientifique Article S100A9 exerts insulin-independent antidiabetic and anti-inflammatory effects eng 2024-01-05 author Ursino Gloria 0000-0002-2703-4417 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 909891 Département de physiologie cellulaire et métabolisme (PHYME) author Lucibello Giulia 0000-0002-5543-1719 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 953475 Département de physiologie cellulaire et métabolisme (PHYME) author Sousa Teixeira Pryscila Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 935446 Département de physiologie cellulaire et métabolisme (PHYME) author Hoefler Anna 0000-0002-7126-2935 Department of Molecular Biology, University of Geneva, 1211 Geneva, Switzerland. 925330 author Veyrat-Durebex Christelle 0000-0001-5301-6493 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 629027 Services communs de la faculté de médecine (SCMU) author Odouard Soline Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 909222 Département de physiologie cellulaire et métabolisme (PHYME) author Visentin Florian Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 708660 Département de physiologie cellulaire et métabolisme (PHYME) author Galgano Luca Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 405623 Département de physiologie cellulaire et métabolisme (PHYME) author Somm Emmanuel Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 95704 Département de médecine (DEMED) author Vianna Claudia R. Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. author Widmer Ariane Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 22544 Département de physiologie cellulaire et métabolisme (PHYME) author Jornayvaz François 0000-0001-9425-3137 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 641037 Département de médecine (DEMED) author Boland Andreas 0000-0003-1218-6714 Department of Molecular Biology, University of Geneva, 1211 Geneva, Switzerland. 912539 Département de biologie moléculaire et cellulaire (MOCEL) author Ramadori Giorgio 0000-0003-0194-3257 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 790895 Département de physiologie cellulaire et métabolisme (PHYME) author Coppari Roberto 0000-0003-1288-6948 Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland. 780442 Département de physiologie cellulaire et métabolisme (PHYME) eadj4686 10.1126/sciadv.adj4686 38170783 2375-2548 https://www.science.org/doi/10.1126/sciadv.adj4686 <p>Type 1 diabetes mellitus (T1DM) is characterized by insulin deficiency leading to hyperglycemia and several metabolic defects. Insulin therapy remains the cornerstone of T1DM management, yet it increases the risk of life-threatening hypoglycemia and the development of major comorbidities. Here, we report an insulin signaling–independent pathway able to improve glycemic control in T1DM rodents. 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–dependent 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.</p> Dewey 612 Dewey 616 Dewey 570 European Commission Compositions for use in the treatment of insulin deficiency conditions 899766 LifeWithoutInsulin EU H2020 European Commission Metabolic actions of brain leptin receptors signaling in type 1 diabetes 614847 LIFEWITHOUTINSULIN EU FP7 Swiss National Science Foundation To elucidate the pathways promoting survival in insulin deficiency 184767 CH Projects Swiss National Science Foundation To determine the role of FKBP10 in cancer 219229 CH Projects Swiss National Science Foundation To elucidate the pathways improving metabolism in insulin deficiency 214870 CH Projects 134 Département de physiologie cellulaire et métabolisme 21C 56 Département de médecine 221 7daed2ee-1311-4824-9df9-2e51260a966a Département de biologie moléculaire et cellulaire 16484 false 578 La biologie du métabolisme dans la santé et la maladie 921 1263 MASLD/MASH et résistance à l'insuline 997 Science advances 10 1 61aff080-157d-4600-af1b-f3c5ca69117c Article (Published version) Public sciadv.adj4686.pdf 5361584 application/pdf CC BY-NC-4.0 67b4a96d84b4e45d6ef12b5ba26127915126cfa29b03acf7ce2f2c9953a82879 38c55c95-ef21-4d1a-ac2d-dfa97c3cedd0 Supplemental data Public sciadv.adj4686_sm.pdf 1293730 application/pdf 981354bddf208ec4652200f71fa3fa59845493d2775ed117250cc7a9f37a4846 openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine clinique / Département de médecine Faculté des sciences / Section de biologie / Département de biologie moléculaire et cellulaire

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S100A9 exerts insulin-independent antidiabetic and anti-inflammatory effects	Science advances			2024	338	151

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Galgano, Luca