GDF15 Is a Contraction-Induced Myokine That Regulates Pancreatic ß-Cell Function

β-cell dysfunction plays a major role in the onset of type 2 diabetes (T2D). Exercise improves or restores β-cell function in both humans and rodents with T2D. The specific mechanism is unclear. We hypothesized that exercise-induced myokines engage in cross-talk with the pancreas to help regulate β-cell function and mass. To test our hypothesis, differentiated C₂C₁₂ myotubes were subjected to electrical pulse stimulation (EPS) to simulate in vivo exercise. EPS-conditioned media from the contracting myotubes significantly elevated glucose-stimulated insulin secretion (GSIS) in β-cells vs. non-EPS control conditions (P<0.05). RNA-sequencing and bioinformatic analysis enabled us to identify Growth Differentiation Factor 15 (GDF15) as a novel contraction-induced myokine that potentially communicates with β-cells. At the cellular level, recombinant GDF15 protein treatment upregulated the GSIS response in β-cells by 55% (P<0.05), with no effect on cellular apoptosis, cytotoxicity or proliferation. Furthermore, qRT-PCR analysis, ELISA, immunoblots, and intracellular assays demonstrated that GDF15 may regulate first-phase insulin secretion by increasing the intracellular ATP/ADP ratio, inhibiting K⁺ channels and increasing the intracellular Ca²⁺ without affecting insulin synthesis. Using translational approaches, we found a positive correlation between fasting plasma GDF15 and insulin secretion in prediabetic subjects (R=0.64, P<0.01, n=22). A 6 week supervised functional high-intensity exercise intervention increased fasting plasma GDF15 by 35% in adults with T2D (P<0.01, n=12) and, interestingly, the increase in GDF15 was positively correlated with an increase in the β-cell disposition index (R=0.72, P<0.01, n=12), providing further support that GDF15 may be involved in improving β-cell function.

In summary, these findings expand our understanding of skeletal muscle as an endocrine organ and identify GDF15 as a potential myokine for T2D therapy.