Phenotypic patterns of metabolic dysfunction-associated steatotic liver disease in type 2 diabetes: The impact of insulin.

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) often leads to hepatic insulin resistance (IR), yet its link to liver-specific insulin-mediated glucose uptake (IGLU) in type 2 diabetes (T2D) remains unclear. We aimed to explore this MASLD-T2D relationship, addressing organ-specific IR for personalized management and risk prevention.

Methods: This cross-sectional study included 41 T2D participants enrolled in a clinical trial (NCT02248311) undergoing biochemical analyses, anthropometric measurements and [¹⁸F]FDG-PET/CT imaging before and after hyperinsulinemic euglycemic clamp (HEC).

Findings: Two MASLD-T2D phenotypes were identified according to their IGLU patterns, that is, with low (HepGluc[+], n = 21) and with high (HepGluc[-], n = 20) hepatic response to insulin. HepGluc[+] participants exhibited increased systemic IR (HOMA-IR, p = .012), inflammation (interleukin 6, p = .005); alanine and aspartate aminotransferase ALT, AST (p = .015 and p = .007); gamma-glutamyl transferase GGT (p = .019) and steatosis markers (liver volume, p = .006); NAFLD liver fat score, p = .0017; hepatic steatosis index, p = .02; fatty liver index, p = .008; liver stiffness measurements (LSM) (p = .049). No statistical differences in serum-based liver fibrosis scores were shown. To identify MASLD-T2D phenotypes in a friendly manner, the MASLD-T2D score based on support vector machines was developed using AST, ALT and GGT (AUC = .83), as well as with MASLD indices including LSM and NAFLD liver fat score (AUC = .90).

Implications: Two new MASLD-T2D phenotypes have been identified, HepGluc[+] and HepGluc[-], according to IGLU patterns, with HepGluc[+] being more deleterious due to higher systemic IR, steatosis and inflammation. Phenotypes can be identified using a new function, the MASLD-T2D score.