American Diabetes Association
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Impaired glucagon-mediated suppression of VLDL-triglyceride secretion in individuals with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)

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posted on 2022-08-24, 18:10 authored by Sara Heebøll, Jeyanthini Risikesan, Steffen Ringgaard, Indumathi Kumarathas, Thomas D. Sandahl, Henning Grønbæk, Esben Søndergaard, Søren Nielsen

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

We recruited 11 subjects with severe MAFLD (MAFLD+), 10 with mild MAFLD (MAFLD-), and seven overweight control subjects (CON). We performed a pancreatic clamp with a somatostatin analogue (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, HighGlucagon). VLDL-TG and glucose tracers were used to evaluate VLDL-TG-kinetics and endogenous glucose production (EGP).

HighGlucagon suppressed VLDL-TG secretion compared to LowGlucagon. This suppression was markedly attenuated in MAFLD compared to CON (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+ compared to CON. EGP transiently increased during HighGlucagon without any difference between the three groups.

Individuals with MAFLD have a reduced sensitivity to glucagon in the hepatic triglyceride metabolism, which could contribute to the dyslipidemia seen in MAFLD patients. 



This study was supported by grants to S.N. from the Novo Nordic Foundation and the Independent Research Fund Denmark and to S.H from the Independent Research Fund Denmark and Aase og Ejner Danielsen’s Fund. Funding sources had no involvement in any part of this study.