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

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posted on 2023-05-24, 18:39 authored by Hui Zhang, Anny Mulya, Stephan Nieuwoudt, Bolormaa Vandanmagsar, Ruth McDowell, Elizabeth C. Heintz, Elizabeth R.M. Zunica, J. Jason Collier, Nadejda Bozadjieva-Kramer, Randy J. Seeley, Christopher L. Axelrod, John P. Kirwan

Exercise is a first-line treatment for type 2 diabetes and preserves β-cell function by hitherto unknown mechanisms. We postulated that proteins from contracting skeletal muscle may act as cellular signals to regulate pancreatic β-cell function. We employed electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-cells with EPS-conditioned media (EPS-CM) 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, and mice. GDF15 enhanced GSIS by upregulating the insulin secretion pathway in β-cells, which was abrogated in the presence of a GDF15 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/obesity. Six weeks of high intensity exercise training increased circulating GDF15 concentrations, which positively correlated with improvements in β-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 GFRAL-independent manner. 

Funding

This research was supported in part by National Institute of Health grants R21 AR067477, R01 AG12834 (JPK), R01 DK108089 (JPK), R01 DK119188 (RJS), U54 GM104940 (JPK), and UL1 RR024989 (Cleveland, OH). This work was also supported in part by an investigator-initiated award from Crossfit, Inc. (JPK) and a Department of Veterans Affairs grant IK2BX005715 (NBK). This project used core facilities at Pennington Biomedical Research Center that are supported, in part, by NIH center awards P30GM118430, P20GM135002, and P30DK072476.

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