Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms.

Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases. We investigated the effect of a single bolus of glucagon and a continuous infusion of glucagon on plasma concentrations of FGF21 and GDF15 in conditions of endogenous low or high insulin levels. The studies included individuals with overweight with and without MASLD, healthy controls (CON) and individuals with type 1 diabetes (T1D). The direct effect of glucagon on FGF21 and GDF15 was evaluated using our in-house developed isolated perfused mouse liver model. FGF21 and GDF15 correlated with plasma levels of insulin, but not glucagon, and their secretion were highly increased in MASLD compared with CON and T1D. Furthermore, FGF21 levels in individuals with overweight with or without MASLD did not increase after glucagon stimulation when insulin levels were kept constant. FGF21 and GDF15 levels were unaffected by direct stimulation with glucagon in the isolated perfused mouse liver. The glucagon-induced secretion of FGF21 and GDF15 are augmented in MASLD and may depend on insulin. Thus, glucagon receptor agonism may augment its metabolic benefits in patients with MASLD through enhanced secretion of FGF21 and GDF15.

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicolai J. Wewer Albrechtsen reports financial support was provided by Novo Nordisk Foundation. Nicolai J. Wewer Albrechtsen reports financial support was provided by Independent Research Fund Denmark. Sasha A. S. Kjeldsen reports financial support was provided by Aase and Ejnar Danielsens Foundation. Sasha A. S. Kjeldsen reports financial support was provided by AP Møller and Chastine McKinney Møller Foundation. Soeren Nielsen reports financial support was provided by Novo Nordisk Foundation. Soeren Nielsen reports financial support was provided by Independent Research Fund Denmark. Sara Heeboell reports financial support was provided by Independent Research Fund Denmark. Sara Heeboell reports financial support was provided by Aase and Ejnar Danielsens Foundation. Nicolai J. Wewer Albrechtsen reports financial support was provided by European Foundation for the Study of Diabetes. Nicolai J. Wewer Albrechtsen reports a relationship with MSD Denmark that includes: speaking and lecture fees. Jens J. Holst reports a relationship with MSD Denmark that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.