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Impaired Glucagon-Mediated Suppression of VLDL-Triglyceride Secretion in Individuals With Metabolic Dysfunction–Associated Fatty Liver Disease (MAFLD)

Individuals with metabolic dysfunction–associated fatty liver disease (MAFLD) have elevated plasma lipids as well as glucagon, although glucagon suppresses hepatic VLDL-triglyceride (TG) secretion. We hypothesize that the sensitivity to glucagon in hepatic lipid metabolism is impaired in MAFLD. We r...

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Autores principales: Heebøll, Sara, Risikesan, Jeyanthini, Ringgaard, Steffen, Kumarathas, Indumathi, Sandahl, Thomas D., Grønbæk, Henning, Søndergaard, Esben, Nielsen, Søren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9630084/
https://www.ncbi.nlm.nih.gov/pubmed/36001750
http://dx.doi.org/10.2337/db22-0313
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author Heebøll, Sara
Risikesan, Jeyanthini
Ringgaard, Steffen
Kumarathas, Indumathi
Sandahl, Thomas D.
Grønbæk, Henning
Søndergaard, Esben
Nielsen, Søren
author_facet Heebøll, Sara
Risikesan, Jeyanthini
Ringgaard, Steffen
Kumarathas, Indumathi
Sandahl, Thomas D.
Grønbæk, Henning
Søndergaard, Esben
Nielsen, Søren
author_sort Heebøll, Sara
collection PubMed
description Individuals with metabolic dysfunction–associated fatty liver disease (MAFLD) have elevated plasma lipids as well as glucagon, although glucagon suppresses hepatic VLDL-triglyceride (TG) secretion. We hypothesize that the sensitivity to glucagon in hepatic lipid metabolism is impaired in MAFLD. We recruited 11 subjects with severe MAFLD (MAFLD+), 10 with mild MAFLD (MAFLD−), and 7 overweight control (CON) subjects. We performed a pancreatic clamp with a somatostatin analog (octreotide) to suppress endogenous hormone production, combined with infusion of low-dose glucagon (0.65 ng/kg/min, t = 0–270 min, LowGlucagon), followed by high-dose glucagon (1.5 ng/kg/min, t = 270–450 min, HighGlucagon). VLDL-TG and glucose tracers were used to evaluate VLDL-TG kinetics and endogenous glucose production (EGP). HighGlucagon suppressed VLDL-TG secretion compared with LowGlucagon. This suppression was markedly attenuated in MAFLD subjects compared with CON subjects (MAFLD+: 13% ± [SEM] 5%; MAFLD−: 10% ± 3%; CON: 36% ± 7%, P < 0.01), with no difference between MAFLD groups. VLDL-TG concentration and VLDL-TG oxidation rate increased between LowGlucagon and HighGlucagon in MAFLD+ subjects compared with CON subjects. EGP transiently increased during HighGlucagon without any difference between the three groups. Individuals with MAFLD have a reduced sensitivity to glucagon in the hepatic TG metabolism, which could contribute to the dyslipidemia seen in MAFLD patients. ClinicalTrials.gov: NCT04042142.
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spelling pubmed-96300842023-01-21 Impaired Glucagon-Mediated Suppression of VLDL-Triglyceride Secretion in Individuals With Metabolic Dysfunction–Associated Fatty Liver Disease (MAFLD) Heebøll, Sara Risikesan, Jeyanthini Ringgaard, Steffen Kumarathas, Indumathi Sandahl, Thomas D. Grønbæk, Henning Søndergaard, Esben Nielsen, Søren Diabetes Pathophysiology Individuals with metabolic dysfunction–associated fatty liver disease (MAFLD) have elevated plasma lipids as well as glucagon, although glucagon suppresses hepatic VLDL-triglyceride (TG) secretion. We hypothesize that the sensitivity to glucagon in hepatic lipid metabolism is impaired in MAFLD. We recruited 11 subjects with severe MAFLD (MAFLD+), 10 with mild MAFLD (MAFLD−), and 7 overweight control (CON) subjects. We performed a pancreatic clamp with a somatostatin analog (octreotide) to suppress endogenous hormone production, combined with infusion of low-dose glucagon (0.65 ng/kg/min, t = 0–270 min, LowGlucagon), followed by high-dose glucagon (1.5 ng/kg/min, t = 270–450 min, HighGlucagon). VLDL-TG and glucose tracers were used to evaluate VLDL-TG kinetics and endogenous glucose production (EGP). HighGlucagon suppressed VLDL-TG secretion compared with LowGlucagon. This suppression was markedly attenuated in MAFLD subjects compared with CON subjects (MAFLD+: 13% ± [SEM] 5%; MAFLD−: 10% ± 3%; CON: 36% ± 7%, P < 0.01), with no difference between MAFLD groups. VLDL-TG concentration and VLDL-TG oxidation rate increased between LowGlucagon and HighGlucagon in MAFLD+ subjects compared with CON subjects. EGP transiently increased during HighGlucagon without any difference between the three groups. Individuals with MAFLD have a reduced sensitivity to glucagon in the hepatic TG metabolism, which could contribute to the dyslipidemia seen in MAFLD patients. ClinicalTrials.gov: NCT04042142. American Diabetes Association 2022-11 2022-08-24 /pmc/articles/PMC9630084/ /pubmed/36001750 http://dx.doi.org/10.2337/db22-0313 Text en © 2022 by the American Diabetes Association https://www.diabetesjournals.org/journals/pages/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license.
spellingShingle Pathophysiology
Heebøll, Sara
Risikesan, Jeyanthini
Ringgaard, Steffen
Kumarathas, Indumathi
Sandahl, Thomas D.
Grønbæk, Henning
Søndergaard, Esben
Nielsen, Søren
Impaired Glucagon-Mediated Suppression of VLDL-Triglyceride Secretion in Individuals With Metabolic Dysfunction–Associated Fatty Liver Disease (MAFLD)
title Impaired Glucagon-Mediated Suppression of VLDL-Triglyceride Secretion in Individuals With Metabolic Dysfunction–Associated Fatty Liver Disease (MAFLD)
title_full Impaired Glucagon-Mediated Suppression of VLDL-Triglyceride Secretion in Individuals With Metabolic Dysfunction–Associated Fatty Liver Disease (MAFLD)
title_fullStr Impaired Glucagon-Mediated Suppression of VLDL-Triglyceride Secretion in Individuals With Metabolic Dysfunction–Associated Fatty Liver Disease (MAFLD)
title_full_unstemmed Impaired Glucagon-Mediated Suppression of VLDL-Triglyceride Secretion in Individuals With Metabolic Dysfunction–Associated Fatty Liver Disease (MAFLD)
title_short Impaired Glucagon-Mediated Suppression of VLDL-Triglyceride Secretion in Individuals With Metabolic Dysfunction–Associated Fatty Liver Disease (MAFLD)
title_sort impaired glucagon-mediated suppression of vldl-triglyceride secretion in individuals with metabolic dysfunction–associated fatty liver disease (mafld)
topic Pathophysiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9630084/
https://www.ncbi.nlm.nih.gov/pubmed/36001750
http://dx.doi.org/10.2337/db22-0313
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