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

Sara Heebøll, Jeyanthini Risikesan, Steffen Ringgaard, Indumathi Kumarathas, Thomas D Sandahl, Henning Grønbæk, Esben Søndergaard, Søren Nielsen, Sara Heebøll, Jeyanthini Risikesan, Steffen Ringgaard, Indumathi Kumarathas, Thomas D Sandahl, Henning Grønbæk, Esben Søndergaard, Søren Nielsen

Abstract

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.

© 2022 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Study day protocol. BI, adipose tissue and muscle biopsy; IC, indirect calorimetry; palmitate, [9,10-3H]palmitate.
Figure 2
Figure 2
Plasma concentrations at baseline (t = 0) and during LowGlucagon and HighGlucagon infusion of C-peptide (A), glucagon (B), insulin (C), glucose (D), FFA (E), and VLDL-TG (F). A: Error bars (range). B–F: Error bars (SEM). RM-ANOVA, t = 0–450: *time effect P ≤ 0.05, **group effect P ≤ 0.05, †interaction P ≤ 0.05.
Figure 3
Figure 3
A: VLDL-TG secretion rate at LowGlucagon and HighGlucagon infusion rate. Error bars (SEM). Log10 scale. B: Percentage change in VLDL-TG secretion. Error bars (SEM). RM-ANOVA: *time effect P ≤ 0.05, †interaction P ≤ 0.05. One-way ANOVA: ‡P < 0.05.
Figure 4
Figure 4
EGP in all subjects at LowGlucagon (LowG, t = 250, 260, and 270) and at late HighGlucagon (t = 410, 430, and 450). EGP in the subgroup of 19 subjects with early (t = 310–390) measurements. Error bars (SEM). For the three CON patients with EGP measurements in early HighGlucagon, SEM are not shown due to the low number of subjects.
Figure 5
Figure 5
Correlation between change in VLDL-TG secretion and intrahepatic fat content (r = 0.51, P < 0.01) (A) and visceral fat mass (log10, r = 0.53, P < 0.01) (B).

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