Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis

Publication: Diabetes

25 August 2025

Abstract

The team, led by Professor Sadaf Farooqi,  have identified homozygous loss-of-function mutations in the gene encoding the glucagon receptor (GCGR), in a family in whom three individuals developed early-onset fatty liver disease (and in one case cirrhosis of the liver). While this condition is commonly associated with obesity, the family members had a normal body weight and all other known causes of liver disease were excluded.

In clinical studies, mutation carriers were found to have elevated plasma glucagon levels, α-cell hyperplasia (and/or pancreatic nodules) and elevated serum levels of glucogenic amino acids. Glucagon is known to play a key role in regulating carbohydrate and lipid metabolism acting via its receptors in the liver. In the lab, the team studied hepatocytes (liver cells) derived from stem cells into which they had introduced the patients’ mutations using CRISPR/Cas9 gene editing. They showed that hepatocytes carrying the GCGR mutations could not clear lipid as expected, causing it to accumulate, proving a causal link between the mutations and fatty liver disease in patients.

These findings pave the way for additional mechanistic studies to identify downstream targets which could inform the design of treatments for patients. This work also has a broader relevance as glucagon receptor antagonists have been used in clinical trials of patients with type 2 diabetes in whom elevated glucagon levels contribute to hyperglycemia. In those trials, dose-dependent increases in liver function tests and hepatic fat content suggest that glucagon may have clinically significant effects on human lipid metabolism. While development of some GCGR antagonists has been discontinued due to this increase in liver fat, in view of our findings, increased surveillance is recommended when trialling therapies that impair or inhibit GCGR signaling. In contrast, GCGR agonists are likely to reduce hepatic steatosis, as predicted by studies in mice and now by these studies in humans. Indeed, trials of GCGR agonists in combination with GLP-1R and/or glucose-dependent insulinotropic polypeptide receptor agonists have reported improvements in steatosis in people with obesity and metabolic dysfunction associated steatohepatitis.

Collectively, these results indicate that the relative potency of GCGR agonism may explain the degree to which these drugs impact body composition and hepatic steatosis.

View Publicationhttps://diabetesjournals.org/diabetes/article/doi/10.2337/db25-0209/163277/Glucagon-Receptor-Deficiency-Causes-Early-Onset