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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms. / Richter, Michael M.; Kemp, Ida M.; Heebøll, Sara; Winther-Sørensen, Marie; Kjeldsen, Sasha A.S.; Jensen, Nicole J.; Nybing, Janus D.; Linden, Frederik H.; Høgh-Schmidt, Erik; Boesen, Mikael P.; Madsbad, Sten; Schiødt, Frank Vinholt; Nørgaard, Kirsten; Schmidt, Signe; Gluud, Lise Lotte; Haugaard, Steen B.; Holst, Jens J.; Nielsen, Søren; Rungby, Jørgen; Wewer Albrechtsen, Nicolai J.

In: Metabolism: Clinical and Experimental, Vol. 156, 155915, 2024.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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: Clinical and Experimental, vol. 156, 155915. https://doi.org/10.1016/j.metabol.2024.155915

APA

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: Clinical and Experimental, 156, [155915]. https://doi.org/10.1016/j.metabol.2024.155915

Vancouver

Richter MM, Kemp IM, Heebøll S, Winther-Sørensen M, Kjeldsen SAS, Jensen NJ et al. Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms. Metabolism: Clinical and Experimental. 2024;156. 155915. https://doi.org/10.1016/j.metabol.2024.155915

Author

Richter, Michael M. ; Kemp, Ida M. ; Heebøll, Sara ; Winther-Sørensen, Marie ; Kjeldsen, Sasha A.S. ; Jensen, Nicole J. ; Nybing, Janus D. ; Linden, Frederik H. ; Høgh-Schmidt, Erik ; Boesen, Mikael P. ; Madsbad, Sten ; Schiødt, Frank Vinholt ; Nørgaard, Kirsten ; Schmidt, Signe ; Gluud, Lise Lotte ; Haugaard, Steen B. ; Holst, Jens J. ; Nielsen, Søren ; Rungby, Jørgen ; Wewer Albrechtsen, Nicolai J. / Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms. In: Metabolism: Clinical and Experimental. 2024 ; Vol. 156.

Bibtex

@article{542b2f5388a64a68b2ab9662541d9a64,
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.}",
note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",
year = "2024",
doi = "10.1016/j.metabol.2024.155915",
language = "English",
volume = "156",
journal = "Metabolism",
issn = "0026-0495",
publisher = "Elsevier",

}

RIS

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.

N1 - Publisher Copyright: © 2024 The Author(s)

PY - 2024

Y1 - 2024

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

U2 - 10.1016/j.metabol.2024.155915

DO - 10.1016/j.metabol.2024.155915

M3 - Journal article

C2 - 38631460

AN - SCOPUS:85192764487

VL - 156

JO - Metabolism

JF - Metabolism

SN - 0026-0495

M1 - 155915

ER -

ID: 392664563