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

Michael M Richter; Ida M Kemp; Sara Heebøll; Marie Winther-Sørensen; Sasha A S Kjeldsen; Nicole J Jensen; Janus D Nybing; Frederik H Linden; Erik Høgh-Schmidt; Mikael P Boesen; Sten Madsbad; Frank Vinholt Schiødt; Kirsten Nørgaard; Signe Schmidt; Lise Lotte Gluud; Steen B Haugaard; Jens J Holst; Søren Nielsen; Jørgen Rungby; Nicolai J Wewer Albrechtsen

doi:10.1016/j.metabol.2024.155915

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

Metabolism. 2024 Apr 15:155915. doi: 10.1016/j.metabol.2024.155915. Online ahead of print.

Authors

Michael M Richter¹, Ida M Kemp², Sara Heebøll³, Marie Winther-Sørensen⁴, Sasha A S Kjeldsen¹, Nicole J Jensen⁵, Janus D Nybing⁶, Frederik H Linden⁶, Erik Høgh-Schmidt⁶, Mikael P Boesen⁶, Sten Madsbad⁷, Frank Vinholt Schiødt⁸, Kirsten Nørgaard⁹, Signe Schmidt⁹, Lise Lotte Gluud¹⁰, Steen B Haugaard⁵, Jens J Holst¹¹, Søren Nielsen¹², Jørgen Rungby¹³, Nicolai J Wewer Albrechtsen¹⁴

Affiliations

¹ Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen 2400, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
² Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen 2400, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
³ Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus 8200, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus 8200, Denmark.
⁴ Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
⁵ Department of Endocrinology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen 2400, Denmark.
⁶ Department of Radiology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen 2400, Denmark.
⁷ Department of Endocrinology, Copenhagen University Hospital - Hvidovre, Hvidovre 2650, Denmark.
⁸ Department of Clinical Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen 2400, Denmark.
⁹ Steno Diabetes Center Copenhagen, Herlev 2730, Denmark.
¹⁰ Gastro Unit, Copenhagen University Hospital - Hvidovre, Hvidovre 2650, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
¹¹ Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
¹² Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus 8200, Denmark; Department of Clinical Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
¹³ Department of Endocrinology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen 2400, Denmark; Department of Clinical Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen 2400, Denmark; Steno Diabetes Center Copenhagen, Herlev 2730, Denmark.
¹⁴ Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen 2400, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: nicolai.albrechtsen@regionh.dk.

PMID: 38631460
DOI: 10.1016/j.metabol.2024.155915

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Hepatic steatosis; Hepatokines; Insulin; Mouse liver perfusion; Type 1 diabetes.