ArticleDiabetes2023
GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion.
Article in Diabetes, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- The effect of exercise on GDF-15 levels in individuals with prediabetes: A randomized controlled trial.Journal of diabetes investigation · 2025Trial
- Exerkines in precision management of metabolic diseases.Chinese medical journal · 2026Review
- Exerkine-Mediated Inter-Organ Crosstalk and Translational Perspectives in Metabolic Diseases.Current obesity reports · 2026Review
- Baseline Plasma Growth-differentiation Factor 15 and Recovery of Physical Function Following Total Knee Replacement in the Study of Physical Resilience and Aging.The journals of gerontology. Series A, Biological sciences and medical sciences · 2026Article
- Gdf15 expression in thermogenic adipocytes regulates diet-induced weight gain in a sex-dependent manner.Molecular medicine (Cambridge, Mass.) · 2026Article
- GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Plasma GDF15 increases during hyperinsulinemic hypoglycemia in humans with post-bariatric hypoglycemia and after insulin exposure in mice.Cell reports. Medicine · 2026Observational
- Circulating GDF15 and HbA1c Response to Add-On Exenatide Therapy in Type 2 Diabetes: A Post Hoc Analysis from a Multicenter Trial.Biomedicines · 2026Article
- Cancer cachexia in STK11/LKB1-mutated non-small cell lung cancer is dependent on tumor-secreted GDF15.Nature communications · 2026Article
- Mesenchymal Stem Cell Therapy for Type 2 Diabetes: Synergistic β-Cell Regeneration, Immune Modulation, and Exosome-Mediated Glucose Homeostasis.Stem cells international · 2026Review
- Pleiotropic effects of GDF-15 to regulate nutritional status: perspectives from body composition to nutrition-related disorders.British journal of biomedical science · 2026Review
- Exercise-responsive endocrine-metabolic mediators in diabetes and cardiometabolic disorders: a systematic scoping review and evidence map.Frontiers in endocrinology · 2026Article
- GDF15: An emerging disease target and biomarker of metabolic diseases.Journal of endocrinological investigation · 2025Review
- The upregulation of GDF15 is controlled epigenetically by oncogenic TCF19 signaling in human hepatocellular carcinoma.iScience · 2025Article
- Metabolic Messenger: growth differentiation factor 15.Nature metabolism · 2025Review
- In vitro muscle contraction: A technical review on electrical pulse stimulation in C2C12 cells.Experimental physiology · 2025Article
- Emerging Insights into Brown Adipose Tissue Crosstalk With Pancreatic β-Cells in Metabolic Regulation.Endocrinology · 2025Review
- Disease-Specific Novel Role of Growth Differentiation Factor 15 in Organ Fibrosis.International journal of molecular sciences · 2025Review
- Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions.Scientific reports · 2025Article
- Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle-secreted factors.Obesity (Silver Spring, Md.) · 2025Review
Corrections and comments
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Authors and funding
12 authors.
Funding
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.
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