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.

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Journal
Cell Reports
Published
2025-09-01
DOI
https://doi.org/10.1016/j.celrep.2025.116283
Primary Topic
Pancreatic function and diabetes
Type
article
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article

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

Sandra Guilmeau, B. Blondeau, Bruno Fève, Tara MacDonald et al.
Cell Reports
Pancreatic function and diabetes
article

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

Sandra Guilmeau, B. Blondeau, Bruno Fève, Tara MacDonald, Ghislaine Guillemain, Jean‐Sébastien Annicotte, Emma Rousseau, Jean-Yves Tinévez, Carine Beaupère, Xavier Prieur, Alexandrine Liboz, Natacha Roblot, Dalale Gueddouri, Anne‐Françoise Burnol
article en

Abstract

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.

Cell ReportsVol. 44(9)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Institut Pasteur (FR), University of Toronto (CA), Université Paris Cité (FR), Institut Pasteur de Lille (FR), Centre Hospitalier Universitaire de Lille (FR), Sorbonne Université (FR), Hôpital Saint-Antoine (FR), Centre de Recherche Saint-Antoine (FR), Institut Cochin (FR), Institut du Thorax (FR)
Openalex Percentile: Top 60%
Pancreatic function and diabetes
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