Serum proteomics of insulin resistance disorders distinguish MASLD from lipodystrophy and insulin receptor defects.

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to obesity, metabolic syndrome and insulin resistance (IR). In IR associated with obesity or lipodystrophy (LD), caused by missing adipose tissue), hyperinsulinemia stimulates hepatic lipogenesis, causing steatotic liver disease (SLD). In contrast, insulin receptor pathogenic variants (INSR), despite hyperinsulinemia and IR, do not promote hepatic lipogenesis and steatosis. We aimed to understand SLD pathophysiology by comparing serum proteomic signatures of MASLD, LD, and INSR.

Methods: Single-center study of fasting serum proteome using SomaScan assay in 30 LD, 29 INSR, and 16 people with MASLD. Key targets were assessed in the hepatic transcriptome of MASLD patients (n=19) and in HepG2 cells.

Results: Of 6,412 proteins, 567 differed between at least two groups. The proteome profiles clearly separated INSR from the other groups, while MASLD and LD displayed similarity, primarily in proteins involved in metabolism, liver injury, and fibrosis. Several proteins were uniquely elevated in INSR and LD compared to MASLD, particularly Factor IX (F9) and liver-expressed antimicrobial peptide 2 (LEAP2). Serum levels of F9 and LEAP2 correlated with their hepatic expression, with in-vitro expression unaffected by leptin, insulin, or glucose treatment.

Conclusions: This first comparative proteomics study identified shared and unique pathways in IR disorders. MASLD and LD share features, suggesting similar drivers of liver disease progression. Key liver-derived proteins differ between MASLD, INSR and LD, due to unique disorder features. We demonstrate the utility of proteomics and rare disorder studies in interrogating pathogenesis of common disorders like MASLD.