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GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion
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 con...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382648/ https://www.ncbi.nlm.nih.gov/pubmed/37224335 http://dx.doi.org/10.2337/db22-0019 |
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author | 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. |
author_facet | 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. |
author_sort | Zhang, Hui |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10382648 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-103826482023-07-30 GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion 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. Diabetes Metabolism 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. American Diabetes Association 2023-08 2023-05-24 /pmc/articles/PMC10382648/ /pubmed/37224335 http://dx.doi.org/10.2337/db22-0019 Text en © 2023 by the American Diabetes Association https://www.diabetesjournals.org/journals/pages/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license. |
spellingShingle | Metabolism 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. GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion |
title | GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion |
title_full | GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion |
title_fullStr | GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion |
title_full_unstemmed | GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion |
title_short | GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion |
title_sort | gdf15 mediates the effect of skeletal muscle contraction on glucose-stimulated insulin secretion |
topic | Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382648/ https://www.ncbi.nlm.nih.gov/pubmed/37224335 http://dx.doi.org/10.2337/db22-0019 |
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