Abstract

Metabolic diseases, particularly diabetes mellitus, significantly increase hepatic vulnerability to injury from drugs, 
toxins, and ischemic or inflammatory stress. Diabetic livers are characterized by insulin resistance, dysregulated 
lipid and glucose metabolism, chronic low-grade inflammation, oxidative stress, and altered mitochondrial 
function, creating a permissive environment for hepatocellular damage. These metabolic derangements disrupt 
normal hepatocyte adaptive mechanisms, reduce antioxidant defenses, and promote pro-inflammatory signaling, 
rendering the liver more susceptible to injury. Clinical and experimental evidence demonstrates that diabetic 
individuals exhibit increased incidence and severity of drug-induced liver injury, nonalcoholic steatohepatitis 
progression, and ischemia-reperfusion damage. Understanding the mechanisms underlying this heightened 
vulnerability, including mitochondrial dysfunction, endoplasmic reticulum stress, lipotoxicity, and altered immune 
responses, provides a foundation for risk stratification, preventive strategies, and therapeutic interventions. This 
review synthesizes current knowledge on the impact of metabolic disease on liver susceptibility, highlighting 
mechanistic pathways and clinical implications, and underscores the need for targeted approaches to protect the 
diabetic liver from injury.