{"doi":"10.2337/db22-0019","title":"GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion","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.","journal":"Diabetes","year":2023,"id":321921,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":289086,"name":"Anny Mulya","orcid":"0000-0002-6008-1514","position":1,"is_corresponding":false},{"id":289083,"name":"Stephan Nieuwoudt","orcid":"0000-0003-4857-2211","position":2,"is_corresponding":false},{"id":733159,"name":"Bolormaa Vandanmagsar","orcid":null,"position":3,"is_corresponding":false},{"id":346785,"name":"Ruth E. McDowell","orcid":null,"position":4,"is_corresponding":false},{"id":854426,"name":"Elizabeth C. Heintz","orcid":"0000-0002-7263-1843","position":5,"is_corresponding":false},{"id":289080,"name":"Elizabeth R. M. Zunica","orcid":"0000-0002-6850-6054","position":6,"is_corresponding":false},{"id":418284,"name":"J. Jason Collier","orcid":"0000-0003-2817-4152","position":7,"is_corresponding":false},{"id":307432,"name":"Nadejda Bozadjieva-Kramer","orcid":"0000-0001-9796-2916","position":8,"is_corresponding":false},{"id":107074,"name":"Randy J. Seeley","orcid":"0000-0002-3721-5625","position":9,"is_corresponding":false},{"id":289076,"name":"Christopher L. Axelrod","orcid":"0000-0002-1444-8557","position":10,"is_corresponding":false},{"id":107063,"name":"John P. Kirwan","orcid":"0000-0001-7321-9917","position":11,"is_corresponding":false},{"id":251726,"name":"Hui Zhang","orcid":"0000-0001-6171-4785","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-19T01:07:37.596550Z","pmid":"37224335","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}