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- Title
GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion.
- Authors
Zhang, Hui; Mulya, Anny; Nieuwoudt, Stephan; Vandanmagsar, Bolormaa; McDowell, Ruth; Heintz, Elizabeth C.; Zunica, Elizabeth R.M.; Collier, J. Jason; Bozadjieva-Kramer, Nadejda; Seeley, Randy J.; Axelrod, Christopher L.; Kirwan, John P.
- Abstract
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 used electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-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, 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 or 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. Article Highlights: Exercise improves glucose-stimulated insulin secretion through direct interorgan communication. Contracting skeletal muscle releases growth differentiation factor 15 (GDF15), which is required to synergistically enhance glucose-stimulated insulin secretion. GDF15 enhances glucose-stimulated insulin secretion by activating the canonical insulin release pathway. Increased levels of circulating GDF15 after exercise training are related to improvements in β-cell function in patients with type 2 diabetes.
- Subjects
SKELETAL muscle; GROWTH differentiation factors; MUSCLE contraction; SECRETION; INSULIN; MICROBIAL exopolysaccharides
- Publication
Diabetes, 2023, Vol 72, Issue 8, p1070
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db22-0019