Comparable glucagon-stimulated amino acid suppression in individuals with and without hepatic steatosis or steatohepatitis.

Abstract

Hepatic amino acid (AA) metabolism and glucagon secretion are linked in a feedback cycle in which circulating AAs stimulate glucagon secretion and alpha-cell proliferation, whereas glucagon stimulates hepatic AA catabolism. It has been proposed that metabolic dysfunction-associated steatotic liver disease (MASLD) leads to hepatic glucagon resistance, which may result in hyperaminoacidemia and hyperglucagonemia. We tested the glucagon effect on AA metabolism in subjects with obesity; 11 with steatohepatitis (MASH), 10 with steatosis (MAS), and 7 subjects [control (CON)] without steatosis. We performed a somatostatin clamp with infusions of insulin and low dose followed by high-dose glucagon. We measured plasma levels of 17 AAs and assessed hepatic fat content (FF%) and body fat distribution (visceral and subcutaneous adipose tissue mass) by MRI. HighGlucagon suppressed plasma total AA equally in all groups; MASH 13% (SD 9%), MAS 14% (7%), and CON 11% (5%), respectively. In univariate regression analyses, visceral adipose tissue mass (β = 0.471, P = 0.011) and AA concentration at LowGlucagon (β = -0.524, P = 0.004), but not FF% (β = -0.243, P = 0.213), were significant predictors of AA reduction. Using a stepwise backward multiple regression approach revealed similar results. Total and specific AA levels (glutamic acid and tyrosine) were higher in both MASLD groups during the study, and FF% was positively correlated to a number of individual AAs. Although finding elevated AA concentrations in subjects with MASLD, we conclude that in patients with MASLD that do not have elevated glucagon at baseline, glucagon suppresses circulating AA levels equally in subjects with and without MASLD. ClinicalTrials.gov: NCT04042142.NEW & NOTEWORTHY The purpose of the study was to investigate the concept of "glucagon resistance" in metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis. We asked if a disruption of the glucagon-mediated suppression of hepatic amino acid (AA) catabolism is present in individuals with MASLD compared with individuals with obesity but no MASLD. Contrary to expectations, we found no disruption of the glucagon-stimulated suppression of plasma AA concentration, which disputes the hypothesis that MASLD causes resistance to glucagon.