The Mediation Effects of Type 2 Diabetes Mellitus and Related Biomarkers on the Association of Metabolic Dysfunction-associated Steatotic Liver Disease and Fibrosis

Background & Aims: Both metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis have been associated with type 2 diabetes mellitus (T2DM), but the roles of T2DM and related biomarkers in the association between MASLD and fibrosis are yet to be fully elucidated. This study aimed at assessing whether the association between MASLD and fibrosis is mediated by T2DM. Methods: A total of 6,060 participants from NHANES 2017-2020 were enrolled in the cross-sectional analyses. Pairwise associations among MASLD, fibrosis, T2DM, and T2DM-related biomarkers [plasma fasting glucose, hemoglobin A1c (HbA1c), serum insulin, and homeostatic model assessment for insulin resistance (HOMAIR)] were examined, and then the extent to which MASLD progresses to fibrosis through T2DM and the biomarkers was assessed. Results: We found a higher risk of T2DM and higher levels of T2DM-related biomarkers were associated with MASLD. Moreover, T2DM and higher levels of T2DM-related biomarkers were positively associated with fibrosis risk. T2DM, plasma fasting glucose, HbA1c, serum insulin, and HOMA-IR mediated 10.1%, 9.99%, 10.5%, 5.98%, and 7.28% of the association between MASLD and fibrosis, respectively. In addition, the mediation effect of T2DM varied in different groups of age, body mass index, and antidiabetic medication. Conclusions: T2DM and T2DM-related biomarkers partly mediated the association between MASLD and fibrosis.