Introduction and Objective: Irisin is a hormone secreted by skeletal muscle following physical activity or exposure to excess saturated fatty acids, promoting energy expenditure and insulin secretion. Circulating irisin levels are reduced in patients with type 2 diabetes (T2D), while exogenous irisin administration improves glycemic control in diabetic mice. Interestingly, irisin and GLP-1 share pleiotropic effects and activate similar intracellular pathways at both pancreatic and extra-pancreatic sites. This study investigated whether GLP-1R agonists (GLP-1RAs) influence irisin release from skeletal muscle.Methods: 190 T2D patients were stratified by anti-diabetes therapy: diet; metformin (met); met + GLP-1RAs; met + DPP-4 inhibitors; met + SGLT2 inhibitors; other therapies. 36 sex- and BMI-matched normoglycemic individuals (ND) served as controls. In addition, human skeletal muscle cells (hSkMCs) were treated with semaglutide (1-100 nM) for 24 h to assess its ability to induce irisin secretion. Irisin levels in serum and culture media were measured by ELISA. Intracellular signalling was evaluated in hSkMCs treated with semaglutide (50 nM, 24 h) using a Proteome Profiler™ Array, with key findings confirmed by immunoblotting. Signaling activation and irisin release were also analyzed in the presence of 5 µM PKA inhibitor (H89).Results: T2D patients showed lower irisin levels than controls, whereas patients receiving met + GLP-1RAs exhibited higher irisin levels, reaching values observed in ND subjects. In hSkMCs in vitro, semaglutide induced CREB phosphorylation, whereas inhibition of PKA activation with H89 significantly reduced semaglutide-induced CREB activation and irisin secretion.Conclusion: GLP-1RA treatment increases circulating irisin in T2D. In vitro studies indicate that GLP-1R activation can directly reprogram skeletal muscle cell metabolism through PKA/CREB-dependent signaling, enhancing irisin secretion. This supports the hypothesis that irisin contributes to the metabolic effects of GLP-1RAs.
V. Galasso: None. N. Marrano: None. G. Biondi: None. M. Rella: None. G. Galluzzi: None. A. Cignarelli: Speaker’s Bureau; Ended; Lilly, AstraZeneca, Novo Nordisk, Sanofi. S. Perrini: None. L. Laviola: Speaker’s Bureau; Ended; A. Menarini Diagnostics, Abbott. Advisory Panel; Ended; Boehringer Ingelheim International GmbH, Eli Lilly and Company. Speaker’s Bureau; Ended; Eli Lilly and Company. Research Support; Current; Medtronic. Speaker’s Bureau; Ended; Medtronic. Advisory Panel; Ended; Novo Nordisk. Speaker’s Bureau; Ended; Novo Nordisk. Advisory Panel; Ended; PIKDARE S.p.A., Roche Diabetes Care, Roche Diagnostics, Sanofi. F. Giorgino: Advisory Panel; Current; Abbott. Consultant; Current; Lilly, Novo Nordisk. Advisory Panel; Current; AstraZeneca, Medtronic. Research Support; Current; Roche Diabetes Care. Advisory Panel; Current; LifeScan, Sanofi. Advisory Panel; Ended; Merck Sharp & Dohme Corp. Advisory Panel; Current; Boehringer Ingelheim International GmbH. A. Natalicchio: Speaker’s Bureau; Ended; AstraZeneca, Lilly, Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH.
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