S100A9 exerts insulin-independent antidiabetic and anti-inflammatory effects.

Autor: Ursino G; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Lucibello G; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Teixeira PDS; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Höfler A; Department of Molecular Biology, University of Geneva, 1211 Geneva, Switzerland., Veyrat-Durebex C; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Odouard S; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Visentin F; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Galgano L; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Somm E; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.; Service of Endocrinology, Diabetes, Nutrition and Therapeutic patient education, Geneva University Hospital, 1205 Geneva, Switzerland., Vianna CR; Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA., Widmer A; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Jornayvaz FR; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.; Service of Endocrinology, Diabetes, Nutrition and Therapeutic patient education, Geneva University Hospital, 1205 Geneva, Switzerland., Boland A; Department of Molecular Biology, University of Geneva, 1211 Geneva, Switzerland., Ramadori G; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland., Coppari R; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Jan 05; Vol. 10 (1), pp. eadj4686. Date of Electronic Publication: 2024 Jan 03.
DOI: 10.1126/sciadv.adj4686
Abstrakt: 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.
Databáze: MEDLINE