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 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 during 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. NCT04042142.