Incretin and Glucagon Signalling in MASLD and MASH : Integrating Metabolic Pathways With Disease Progression

Mar 12, 2026Diabetes, obesity & metabolism

Incretin and Glucagon Signals Linked to Metabolism and Disease Progression in Fatty Liver Conditions MASLD and MASH

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Abstract

Incretin- and glucagon-based therapies may significantly improve liver conditions in metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to disrupted nutrient delivery and lipid metabolism in the liver and adipose tissue.
GLP-1-based therapies consistently reduce liver fat and inflammation by decreasing nutrient delivery to the liver and enhancing insulin sensitivity in adipose tissue.
GIP signaling may influence how adipose tissue manages lipids, potentially reducing fatty acid leakage to the liver, though its effects on liver inflammation are not fully understood.
Glucagon receptor activation directly improves liver cell metabolism and reduces stress on liver cells.
Improvements in liver fibrosis are likely related to reductions in overall metabolic and inflammatory damage rather than direct anti-fibrotic effects.

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Metabolic dysfunction-associated steatotic liver disease (MASLD) arises from dysregulated interactions between nutrient delivery, adipose tissue lipid handling and liver lipid metabolism, which collectively coalesce to drive inflammatory signalling leading to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. Recent clinical success of incretin- and glucagon-based therapies in both diabetes and obesity has intensified interest into how these hormonal pathways modify liver disease progression. In this review, we integrate preclinical and clinical data to examine how glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon engage key pathogenic nodes, including the gut-liver and adipose-liver axes, hepatic lipid synthesis and oxidation, mitochondrial function and nonparenchymal inflammatory responses. GLP-1-based therapies consistently improve steatosis and steatohepatitis through reductions in nutrient flux to the liver, improved adipose tissue insulin sensitivity and weight-independent anti-inflammatory effects, despite limited direct action in hepatocytes. GIP signalling appears to modulate adipose tissue lipid handling and expandability, thereby limiting fatty acid spillover to the liver, although its role in hepatic inflammation remains incompletely defined. In contrast, glucagon receptor activation directly targets hepatocytes to enhance oxidative metabolism and reduce hepatocellular stress. Across studies, improvements in fibrosis appear secondary to sustained reductions in metabolic and inflammatory injury suggesting the addition of anti-fibrotic combination therapies may exert further benefits. Looking ahead, a key challenge will be defining how these hormonal pathways interact within distinct metabolic states and how this greater mechanistic understanding can be leveraged to rationally combine therapies and expand the proportion of patients who respond across the MASLD spectrum.

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Incretin and Glucagon Signalling in MASLD and MASH : Integrating Metabolic Pathways With Disease Progression

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