Beta-cell adaptation unveiled: The role of myokines in insulin-resistant mice.

Pancreatic beta cells can adapt their mass and function to maintain normal glycemia when facing peripheral insulin resistance. To clarify the specific contribution and mechanisms of beta-cell mass adaptation in response to insulin resistance, we took advantage of genetic and pharmacologically induced insulin resistance in mice. We uncovered beta-cell expansion, via an increase in pancreatic islet density, as an adaptive mechanism triggered by mild-to-severe insulin resistance in young and older mice and documented pancreatic adaptation using 3D whole-pancreas analysis. Next, we found that insulin-resistant myotubes secrete factors that induce beta-cell differentiation. Using a combination of transcriptomic and functional analysis on a pancreatic differentiation model, we identified that myostatin, amphiregulin, and epiregulin can induce beta-cell differentiation in vitro. This work highlights how a physiological adaptation to insulin resistance can unlock the regenerative potential of myotube-derived peptides to trigger adaptive pancreatic beta-cell mass increase.