Metabolic Dysfunction-Associated Steatotic Liver Disease Complicated by Diabetes: Pathophysiology and Emerging Therapies

Jun 19, 2025Journal of obesity & metabolic syndrome

Fatty Liver Disease Linked to Metabolism Problems and Diabetes: Causes and New Treatments

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Abstract

Metabolic dysfunction-associated steatotic liver disease () is linked to diabetes and is often exacerbated by hyperglycemia.

MASLD is associated with obesity and insulin resistance.
There is a bidirectional relationship where MASLD contributes to insulin resistance and hyperglycemia accelerates MASLD's progression to metabolic dysfunction-associated steatohepatitis ().
Hepatokines, influenced by overnutrition and hyperglycemia, play a role in the connection between liver fat accumulation and insulin resistance in muscle.
In diabetic individuals, hyperglycemia and free fatty acids promote fat production and increase energy use in the liver, which could lead to oxidative stress and inflammation.
Damage to liver endothelial cells has been observed in diabetic conditions, as indicated by transcriptome analyses of MASH.
Effective treatments for MASH include certain antidiabetic medications, with pioglitazone and GLP-1 receptor agonists recommended for glycemic control in type 2 diabetes patients.

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Metabolic dysfunction-associated steatotic liver disease () is a liver manifestation of diabetes that is often associated with obesity and insulin resistance, with hyperglycemia worsening its progression. Recent studies have shown a bidirectional relationship between MASLD and diabetes: MASLD contributes to insulin resistance, and hyperglycemia accelerates the progression of MASLD to metabolic dysfunction-associated steatohepatitis (). Hepatokines upregulated by overnutrition and hyperglycemia are implicated in the link between liver steatosis and insulin resistance in skeletal muscle, highlighting inter-organ crosstalk in the progression of both MASLD and diabetes. In individuals with diabetes, hyperglycemia and free fatty acid influx promotelipogenesis and enhance lipid oxidation and oxidative phosphorylation in the liver, potentially leading to increased oxidative stress, inflammation, and fibrosis. Transcriptome analyses of human MASH and diabetic MASH model animals have revealed liver endothelial cell damage in diabetic conditions. Most drugs proven effective for MASH in randomized controlled trials are antidiabetic agents. Recently, pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists, and dual agonists of glucose-dependent insulinotropic polypeptide and GLP-1 have been recommended as preferred options for glycemic control in MASH patients with type 2 diabetes mellitus. Meanwhile, the efficacy of sodium-glucose cotransporter 2 inhibitors for MASH has also been reported, primarily in East Asia. Given the diversity in MASLD/MASH pathology among populations, ranging from lean to obese individuals with and without diabetes, population-specific approaches might help elucidate the pathogenesis of MASLD/MASH and develop treatment strategies. de novo

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2.19×

Increased Risk of T2DM

Individuals with have a 2.19-fold higher risk of developing T2DM.

2×

Risk of with Diabetes

Diabetes approximately doubles the risk of developing .

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Metabolic Dysfunction-Associated Steatotic Liver Disease Complicated by Diabetes: Pathophysiology and Emerging Therapies

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