Document Type
Article
Publication Date
8-1-2023
Abstract
Exercise is a first-line treatment for type 2 diabetes and preserves b-cell function by hitherto unknown mechanisms. We postulated that proteins fromcontracting skeletalmuscle may act as cellular signals to regulate pancreatic b-cell function. We used electric pulse stimulation (EPS) to induce contraction in C2C12myotubes and found that treatment of b-cells with EPS-conditioned medium enhanced glucose-stimulated insulin secretion (GSIS). Transcriptomics and subsequent targeted validation revealed growth differentiation factor 15 (GDF15) as a central component of the skeletal muscle secretome. Exposure to recombinant GDF15 enhanced GSIS in cells, islets, andmice. GDF15 enhanced GSIS by upregulating the insulin secretion pathway in b-cells,whichwas abrogated in the presence of aGDF15 neutralizing antibody. The effect of GDF15 on GSIS was also observed in islets from GFRAL-deficient mice. Circulating GDF15 was incrementally elevated in patients with pre- and type 2 diabetes and positively associated with C-peptide in humans with overweight or obesity. Six weeks of high-intensity exercise training increased circulating GDF15 concentrations, which positively correlated with improvements in b-cell function in patients with type 2 diabetes. Taken together, GDF15 can function as a contraction-induced protein that enhances GSIS through activating the canonical signaling pathway in a GFRALindependentmanner.
Recommended Citation
Zhang, H., Mulya, A., Nieuwoudt, S., Vandanmagsar, B., McDowell, R., Heintz, E., Zunica, E., Collier, J., Bozadjieva-Kramer, N., Seeley, R., Axelrod, C., & Kirwan, J. (2023). GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion. Retrieved from https://repository.lsu.edu/pbrc_basic_science_pubs/65