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

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^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Article number	155915
Journal	Metabolism
Volume	156
Number of pages	13
ISSN	0026-0495
DOIs	https://doi.org/10.1016/j.metabol.2024.155915
Publication status	Published - Jul 2024

Keywords

Hepatic steatosis
Hepatokines
Insulin
Mouse liver perfusion
Type 1 diabetes

Access to Document

10.1016/j.metabol.2024.155915Licence: CC BY

Cite this

Richter, M. M., Kemp, I. M., Heebøll, S., Winther-Sørensen, M., Kjeldsen, S. A. S., Jensen, N. J., Nybing, J. D., Linden, F. H., Høgh-Schmidt, E., Boesen, M. P., Madsbad, S., Schiødt, F. V., Nørgaard, K., Schmidt, S., Gluud, L. L., Haugaard, S. B., Holst, J. J., Nielsen, S., Rungby, J., & Wewer Albrechtsen, N. J. (2024). Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms. Metabolism, 156, Article 155915. https://doi.org/10.1016/j.metabol.2024.155915

@article{8b09a47909c349dc9cb538580ed5d89b,

title = "Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms",

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.",

keywords = "Hepatic steatosis, Hepatokines, Insulin, Mouse liver perfusion, Type 1 diabetes",

author = "Richter, {Michael M.} and Kemp, {Ida M.} and Sara Heeb{\o}ll and Marie Winther-S{\o}rensen and Kjeldsen, {Sasha A.S.} and Jensen, {Nicole J.} and Nybing, {Janus D.} and Linden, {Frederik H.} and Erik H{\o}gh-Schmidt and Boesen, {Mikael P.} and Sten Madsbad and Schi{\o}dt, {Frank Vinholt} and Kirsten N{\o}rgaard and Signe Schmidt and Gluud, {Lise Lotte} and Haugaard, {Steen B.} and Holst, {Jens J.} and S{\o}ren Nielsen and J{\o}rgen Rungby and {Wewer Albrechtsen}, {Nicolai J.}",

year = "2024",

month = jul,

doi = "10.1016/j.metabol.2024.155915",

language = "English",

volume = "156",

journal = "Metabolism",

issn = "0026-0495",

publisher = "Elsevier",

}

Richter, MM, Kemp, IM, Heebøll, S, Winther-Sørensen, M, Kjeldsen, SAS, Jensen, NJ, Nybing, JD, Linden, FH, Høgh-Schmidt, E, Boesen, MP, Madsbad, S, Schiødt, FV, Nørgaard, K, Schmidt, S, Gluud, LL, Haugaard, SB, Holst, JJ, Nielsen, S , Rungby, J & Wewer Albrechtsen, NJ 2024, 'Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms', Metabolism, vol. 156, 155915. https://doi.org/10.1016/j.metabol.2024.155915

TY - JOUR

T1 - Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms

AU - Richter, Michael M.

AU - Kemp, Ida M.

AU - Heebøll, Sara

AU - Winther-Sørensen, Marie

AU - Kjeldsen, Sasha A.S.

AU - Jensen, Nicole J.

AU - Nybing, Janus D.

AU - Linden, Frederik H.

AU - Høgh-Schmidt, Erik

AU - Boesen, Mikael P.

AU - Madsbad, Sten

AU - Schiødt, Frank Vinholt

AU - Nørgaard, Kirsten

AU - Schmidt, Signe

AU - Gluud, Lise Lotte

AU - Haugaard, Steen B.

AU - Holst, Jens J.

AU - Nielsen, Søren

AU - Rungby, Jørgen

AU - Wewer Albrechtsen, Nicolai J.

PY - 2024/7

Y1 - 2024/7

N2 - 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.

AB - 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.

KW - Hepatic steatosis

KW - Hepatokines

KW - Insulin

KW - Mouse liver perfusion

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85192764487&partnerID=8YFLogxK

U2 - 10.1016/j.metabol.2024.155915

DO - 10.1016/j.metabol.2024.155915

M3 - Journal article

C2 - 38631460

AN - SCOPUS:85192764487

SN - 0026-0495

VL - 156

JO - Metabolism

JF - Metabolism

M1 - 155915

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this