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