Tissue-Specific Insulin Resistance Pattern Underlies Heterogeneous Disease Severity and Complications in MASLD

Background Insulin resistance (IR) plays a pathophysiological role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear whether the specific distribution of IR across muscle, adipose tissue, hepatic tissue, and the whole body is associated with the heterogeneous disease severity and its complications.Methods Consecutive subjects (non-MASLD: 1239, MASLD: 1067) were retrospectively enrolled between June 2014 and June 2024, undergoing comprehensive evaluations that included anthropometric, laboratory, and imaging measurements. Tissue-specific IR indices (muscle IR, adipose IR, hepatic IR) and systemic IR were quantified using parameters derived from an oral glucose tolerance test.Results Patients with MASLD exhibited lower muscle IR levels but higher adipose IR, hepatic IR, and systemic IR levels compared to those with non-MASLD (all p < 0.001). Multivariate analyses revealed distinct tissue-specific associations: hepatic IR was associated with the odds of moderate-severe steatosis (OR: 15.91, 95%CI 5.92–42.74, p < 0.001), systemic IR with liver injury (OR: 2.75, 95%CI: 1.89–4.00, p < 0.001), adipose IR with significant fibrosis (OR: 5.90, 95%CI: 3.31–10.53, p < 0.001), and muscle IR was inversely associated with CVD (OR: 2.87, 95%CI: 1.70–4.87, p < 0.001). Additionally, MASLD patients with co-occurring adipose-hepatic IR had a higher prevalence of liver injury compared to those with isolated muscle IR (64.0% vs. 28.8%, p < 0.05).Conclusions Tissue-specific IR profiles may help characterize heterogeneous MASLD manifestations and CVD-associated phenotypes. Further studies are needed to assess whether timely identification of these profiles and initiation of appropriate interventions is beneficial.