Published on: 12 March 2026

Metabolic dysfunction-associated steatotic liver disease (MASLD) has surged globally, closely linked to obesity and type 2 diabetes. Its progression to metabolic dysfunction-associated steatohepatitis (MASH) heralds serious clinical challenges, including inflammation, fibrosis, and potential liver failure. Contemporary research highlights the pivotal roles of incretin hormones—glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP)—and glucagon in orchestrating metabolic pathways critical to MASLD and MASH pathogenesis and therapy.

The Complex Metabolic Interplay Underlying MASLD and MASH

MASLD arises from a dysregulated interplay between nutrient delivery, adipose tissue lipid handling, and hepatic lipid metabolism. Excessive caloric intake and altered gut-liver communication amplify hepatic substrate overload. This triggers de novo lipogenesis, mitochondrial dysfunction, and oxidative stress, culminating in hepatocyte injury and inflammatory activation. Adipose tissue dysfunction further exacerbates liver lipid burden by releasing non-esterified fatty acids (NEFAs), promoting insulin resistance and hepatic fat accumulation.

Understanding these metabolic nodes is essential for healthcare professionals managing MASLD, as they dictate disease progression and therapeutic responsiveness.

GLP-1: The Multifaceted Modulator of Nutrient Flux and Inflammation

GLP-1 primarily modulates MASLD through its central and peripheral actions. It slows gastric emptying and suppresses appetite, thereby reducing nutrient influx to the liver. GLP-1 also enhances pancreatic insulin secretion and inhibits glucagon release in hyperglycemic states, improving glycemic control. Importantly, GLP-1 receptor expression is minimal in hepatocytes but significant in hepatic non-parenchymal cells, such as liver sinusoidal endothelial cells and immune populations.

This distribution enables GLP-1 to exert anti-inflammatory effects by reducing NF-κB activation and cytokine production. Moreover, GLP-1 improves gut barrier integrity and modulates the microbiome, limiting endotoxin translocation and hepatic inflammation. These combined effects reduce hepatic lipid overload and inflammatory signaling, thereby attenuating MASLD progression.

GIP: Enhancing Adipose Tissue’s Capacity to Buffer Metabolic Stress

Unlike GLP-1, GIP’s primary action centers on adipose tissue. GIP receptors localize predominantly on endothelial cells, pericytes, stromal vascular cells, and myeloid populations rather than mature adipocytes. GIP receptor activation enhances adipose tissue perfusion and promotes efficient postprandial fatty acid uptake. This mechanism increases adipose lipid storage capacity, reducing triglyceride spillover into circulation and subsequent hepatic lipid exposure.

Furthermore, GIP signaling modulates adipose tissue inflammation and insulin sensitivity by suppressing macrophage recruitment. These actions collectively improve adipose tissue expandability and lipid buffering, offering a strategic target to mitigate liver fat accumulation in MASLD.

Glucagon: Direct Hepatic Effects Steering Lipid Oxidation and Mitochondrial Health

Glucagon’s influence in MASLD is distinct and primarily hepatocellular. The glucagon receptor is highly expressed in hepatocytes, where its activation elevates cyclic AMP and ATP turnover. This cascade activates AMP-activated protein kinase (AMPK), suppressing acetyl-CoA carboxylase activity, thereby reducing malonyl-CoA and de novo lipogenesis. Concurrently, glucagon enhances mitochondrial β-oxidation and ketogenesis, shifting hepatic metabolism toward lipid utilization.

Moreover, glucagon promotes mitophagy and mitochondrial quality control, preserving hepatocyte function under metabolic stress. These direct hepatic actions reduce lipid accumulation and oxidative injury, addressing core drivers of inflammation and fibrosis in MASLD.

Therapeutic Implications: Harnessing Incretin and Glucagon Pathways in MASLD and MASH

Recent clinical trials underscore the efficacy of GLP-1 receptor agonists, dual GLP-1/GIP receptor agonists, and dual or triple agonists incorporating glucagon receptor activation. Semaglutide, a GLP-1 receptor agonist, demonstrates significant MASH resolution and fibrosis improvement, primarily by reducing nutrient flux and inflammation. Tirzepatide, a dual GLP-1/GIP agonist, enhances adipose tissue insulin sensitivity and fat reduction, leading to histologic improvements in MASH.

Dual GLP-1/glucagon receptor agonists show promise by combining weight loss with enhanced hepatic lipid oxidation, although their precise immunometabolic effects require further elucidation. Triple agonists, activating GLP-1, GIP, and glucagon receptors, produce profound metabolic benefits, including substantial liver fat reduction and improved biomarkers, positioning them as next-generation therapies for MASLD.

Personalized Medicine: Tailoring Approaches Across MASLD and MASH Spectrums

Therapeutic responsiveness varies by disease stage and patient phenotype. In early MASLD with obesity and type 2 diabetes, metabolic therapies targeting nutrient flux and adipose dysfunction can effectively reverse steatosis and inflammation. Conversely, in lean MASLD or advanced fibrosis stages, metabolic interventions alone may not suffice. Combining incretin and glucagon-based therapies with agents directly targeting fibrogenesis, such as thyroid hormone receptor β agonists or fibroblast growth factor 21 analogues, may optimize outcomes.

Genetic factors, including PNPLA3 variants, influence treatment efficacy, highlighting the need for personalized approaches integrating metabolic, inflammatory, and fibrotic pathways.

Conclusion: Integrating Hormonal Signalling into MASLD and MASH Management

In summary, GLP-1, GIP, and glucagon coordinate a multi-organ metabolic network influencing MASLD and MASH pathogenesis. GLP-1 reduces hepatic nutrient overload and inflammation; GIP enhances adipose lipid handling and insulin sensitivity; glucagon drives hepatic lipid oxidation and mitochondrial resilience. Their complementary mechanisms underscore the therapeutic potential of combinational incretin and glucagon receptor agonists.

For healthcare professionals, understanding these intricate pathways is vital for optimizing MASLD and MASH management, tailoring treatments, and improving patient outcomes within the global Muslim weight management context.

Source: https://doi.org/10.1111/dom.70624

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