Glucagon resistance and metabolic-associated steatotic liver disease: a review of the evidence

Abstract

Metabolic-associated steatotic liver disease (MASLD) is closely associated with obesity. MASLD affects over 1 billion adults globally but there are few treatment options available. Glucagon is a key metabolic regulator, and its actions include the reduction of liver fat through direct and indirect means. Chronic glucagon signalling deficiency is associated with hyperaminoacidaemia, hyperglucagonaemia and increased circulating levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF-21). Reduction in glucagon activity decreases hepatic amino acid and triglyceride catabolism; metabolic effects include improved glucose tolerance, increased plasma cholesterol and increased liver fat. Conversely, glucagon infusion in healthy volunteers leads to increased hepatic glucose output, decreased levels of plasma amino acids and increased urea production, decreased plasma cholesterol and increased energy expenditure. Patients with MASLD share many hormonal and metabolic characteristics with models of glucagon signalling deficiency, suggesting that they could be resistant to glucagon. Although there are few studies of the effects of glucagon infusion in patients with obesity and/or MASLD, there is some evidence that the expected effect of glucagon on amino acid catabolism may be attenuated. Taken together, this evidence supports the notion that glucagon resistance exists in patients with MASLD and may contribute to the pathogenesis of MASLD. Further studies are warranted to investigate the direct effects of glucagon on metabolism in patients with MASLD.

Keywords: glucagon; glucagon resistance; glucagon-like peptide 1; metabolic dysfunction-associated steatotic liver disease (MASLD); non-alcoholic fatty liver disease (NAFLD).

Figure 1

Major effects of glucagon signalling deficiency. Glucagon receptor (GCCR) blockade decreases hepatic expression of amino acid catabolism and uptake enzymes, leading to hyperaminoacidaemia. It also decreases expression of low-density lipoprotein receptor (LDLR), which reduces hepatic cholesterol uptake. Amino acids stimulate alpha cells in the pancreas, leading to their hyperplasia and increased transcription of the preproglucagon gene, which in turn leads to increases in circulating glucagon and glucagon-like peptide 1 (GLP-1). There are increased levels of hepatic and plasma fibroblast growth factor 21 (FGF-21). Reduced hepatic glucagon receptor signalling decreases expression of lipid metabolism genes, leading to an increase in liver fat, and decreases in hepatic glucose production. Glucose tolerance is also improved indirectly, via increases in GLP-1 and FGF-21 which improve insulin sensitivity and availability. GLP-1 also acts on the brain and stomach to decrease food intake and decrease gastric emptying. Created with BioRender.com.

Figure 2

Shared features between models of glucagon signalling deficiency and patients with metabolic-associated steatotic liver disease. GCGR^−/−, glucagon receptor knockdown; GLP-1, glucagon-like peptide 1; FGF-21, fibroblast growth factor 21; MASLD, metabolic-associated steatotic liver disease. Created with BioRender.com.