Aims/hypothesis <p>Inflammation-driven pancreatic beta cell death is a hallmark of type 1 diabetes progression. We have previously shown that serum obtained from individuals after high-intensity interval training prevents cytokine-induced human beta cell apoptosis, but the mediators of this beneficial effect remain to be characterised. In this study we evaluated the role of exercise-induced meteorin-like protein (Metrnl) in human beta cell protection.</p> Methods <p>Human EndoC-βH1 cells and induced pluripotent stem cell (iPSC)-derived islets were exposed to proinflammatory cytokines and treated with serum collected before and after high-intensity interval training, with and without Metrnl-neutralising antibodies. The effects of Metrnl on apoptosis, insulin secretion and chemokine CXCL10 gene and protein expression were assessed.</p> Results <p>Post-exercise serum had an increased concentration of Metrnl compared with pre-exercise level serum, resulting in a 46% reduction in cytokine-induced beta cell death. Additionally, direct treatment with recombinant Metrnl at concentrations of 100 ng/ml and 200 ng/ml reduced cytokine-induced cell death by 24% and 41%, respectively, in EndoC-βH1 cells, with similar results obtained in iPSC-derived islets. Metrnl treatment also preserved insulin secretion under inflammatory stress. These effects were associated with a decrease in <i>CXCL10</i> mRNA expression and protein release. Blocking Metrnl with a neutralising antibody eliminated the protective effects of serum from trained individuals on EndoC-βH1 cells exposure to proinflammatory cytokines.</p> Conclusions/interpretation <p>Our findings reveal that the exerkine Metrnl is a key mediator of the beneficial effects of exercise on pancreatic beta cells, suggesting that Metrnl is a potential therapeutic target for preserving human beta cell function and survival in type 1 diabetes.</p> Graphical Abstract <p></p>