Metabolic state determines the brain and direct islet effects of liraglutide on enhanced insulin secretion – published online 25/06/2026

Chiara Saponaro, Monica Imbernon, Isaline Louvet, Eleonora Deligia, Shiqian Chen, Iona Davies, Ana Acosta‑Montalvo, Maria Moreno‑Lopez, Eve Wemelle, Lakshmi Kothegala, Begoña Porteiro, Florent Auger, Lorea Zubiaga, Nathalie Dellalau, Julien Thevenet, Markus Mühlemann, Gianni Pasquetti, Valery Gmyr, Frank W. Pfrieger, Ruben Nogueiras, Markus Schwaninger, Patrik Rorsman, Bart Staels, Julie Kerr‑Conte, Claude Knauf, Ben Jones, François Pattou, Vincent Prevot, Caroline Bonner

Glucagon-like peptide-1 (GLP-1) receptor agonists such as liraglutide are widely used to treat type 2 diabetes and obesity, yet the mechanisms by which they enhance insulin secretion remain incompletely understood. In this issue, Saponaro and Imbernon et al (https://doi.org/10.1007/s00125-026-06779-2) report that the route of liraglutide action, whether through the brain or directly on pancreatic islets, is critically determined by the prevailing metabolic state. Using complementary mouse models and human islet studies, they show that under lean, healthy conditions, liraglutide acts primarily via hypothalamic tanycytes and the central nervous system to enhance insulin release. However, in obesity (diet-induced insulin resistance) and type 2 diabetes, this central pathway becomes impaired, and liraglutide instead acts directly on pancreatic beta cells to maintain its insulinotropic effect. The authors conclude that these findings provide a mechanistic explanation for the variable clinical responses observed with GLP-1 receptor agonist therapy and suggest that the metabolic stage of disease may be important when optimising incretin-based treatment strategies in patients with type 2 diabetes.

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