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 was 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 is 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.
Originalsprog | Engelsk |
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Artikelnummer | 155915 |
Tidsskrift | Metabolism: Clinical and Experimental |
Vol/bind | 156 |
Antal sider | 13 |
ISSN | 0026-0495 |
DOI | |
Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:Associate Prof. Nicolai J. Wewer Albrechtsen is supported by NNF Excellence Emerging Investigator Grant \u2013 Endocrinology and Metabolism (Application No. NNF19OC0055001), EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude (1052-00003B). NNF Center for Protein Research is supported financially by the NNF (grant agreement NNF14CC0001).Study 1 was supported by grants from Aase og Ejnar Danielsens Fond (21-10-0287) and A. P. M\u00F8ller Fonden (2021-00683) to Sasha A. S. Kjeldsen.Study 2 was supported by grants from the Novo Nordisk Foundation (NNF18OC0031804) to S\u00F8ren Nielsen, the Independent Research Fund Denmark (9039-00177B and 9039-00278B) to S\u00F8ren Nielsen and Sara Heeb\u00F8ll, and the Aase og Ejner Danielsen's Fund to Sara Heeb\u00F8ll.
Funding Information:
Study 2 was supported by grants from the Novo Nordisk Foundation ( NNF18OC0031804 ) to S\u00F8ren Nielsen, the Independent Research Fund Denmark ( 9039-00177B and 9039-00278B ) to S\u00F8ren Nielsen and Sara Heeb\u00F8ll, and the Aase og Ejner Danielsen's Fund to Sara Heeb\u00F8ll.
Funding Information:
Associate Prof. Nicolai J. Wewer Albrechtsen is supported by NNF Excellence Emerging Investigator Grant \u2013 Endocrinology and Metabolism (Application No. NNF19OC0055001 ), EFSD Future Leader Award ( NNF21SA0072746 ) and DFF Sapere Aude ( 1052-00003B ). NNF Center for Protein Research is supported financially by the NNF (grant agreement NNF14CC0001).
Funding Information:
Study 1 was supported by grants from Aase og Ejnar Danielsens Fond ( 21-10-0287 ) and A. P. M\u00F8ller Fonden ( 2021-00683 ) to Sasha A. S. Kjeldsen.
Publisher Copyright:
© 2024 The Author(s)