Yan Yang, Ling Luo, Pinning Feng, Congxiang Shao, Zhi Dong, Bihui Zhong, Junzhao Ye
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.
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSION: 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.