GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion

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.

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