Temporal evolution of tissue-specific insulin resistance and transitions in MASLD status: a retrospective...

Insulin resistance (IR) is closely associated with metabolic dysfunction-associated steatotic liver disease (MASLD), exhibiting tissue-specific effects in the liver, adipose tissue, and muscle. However, the temporal relationships among tissue-specific IR across MASLD status remain unclear.

We retrospectively identified 491 participants, including 293 without MASLD and 198 with MASLD, who underwent repeated oral glucose tolerance tests and assessment of tissue-specific IR indices between June 2014 and December 2025. Cross-lagged path analysis was performed separately according to baseline MASLD status to examine temporal associations among hepatic IR, adipo-IR, and muscle IR. Logistic regression was used to explore baseline factors associated with persistent or progressive IR.

After a median interval of 22 months (range, 12-32 months), 63 of 293 participants without MASLD (21.5%) developed MASLD, while 47 of 198 participants with MASLD (23.7%) transitioned to an elevated FIB-4 category (>1.3). In the fully adjusted model, baseline hepatic IR was associated with subsequent adipo-IR (ρ₁ = 0.303, P < 0.01) and muscle IR (ρ₂ = -0.211, P < 0.001) in participants without MASLD. In participants with MASLD, hepatic IR (ρ₂ = -0.195, P < 0.01) and adipo-IR (ρ₄ = -0.184, P < 0.05) were associated with subsequent muscle IR, while baseline muscle IR was associated with subsequent hepatic IR (ρ₅ = 0.084, P < 0.05). Body mass index (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01-1.13), HOMA-IR (OR, 1.26; 95% CI, 1.07-1.47), and CT attenuation value (OR, 0.97; 95% CI, 0.94-0.99) were associated with persistent or progressive IR (all P < 0.05).

The temporal relationships among tissue-specific IR differed according to MASLD status. Hepatic IR preceded peripheral IR in participants without MASLD, whereas more multidirectional relationships were identified in those with MASLD. These findings are hypothesis-generating and do not establish a causal sequence.