Adipose tissue insulin resistance and fibrosis stage in NASH

Understanding the drivers of non-alcoholic fatty liver disease (NAFLD) is crucial to developing pharmacotherapies that effectively target it. Insulin resistance (IR), whose onset precipitates type 2 diabetes (T2D), is known to play a crucial role in the development of hepatic steatosis.
PUBLISHED IN: Journal of Clinical Endocrinology and Metabolism (April 2023)


Free fatty acid overload, a consequence of IR-associated dysfunctional adipose tissue, triggers hepatic lipotoxicity and contributes to the accumulation of lipotoxic lipid intermediates observed in non-alcoholic steatohepatitis (NASH), NAFLD’s inflammatory subtype. Despite these findings, adipose tissue IR’s specific contribution to NAFLD and NASH, independently of T2D and hepatic IR, remains uncharacterised.

This study aimed to assess the impact of IR, particularly that noted in adipose tissue, on fibrosis stage in patients with advanced NASH and comorbid T2D. Both adipose tissue and hepatic IR were measured via the adipose tissue insulin resistance (adipo-IR) and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) indexes, respectively.

Key learnings:

Among patients with T2D and advanced liver fibrosis (≥F2), obesity was the clinical variable with the strongest association with hepatic fibrosis. When metabolic measurements and cytokeratin-18, a marker of steatohepatitis, were included in the multivariable analysis, only body mass index (BMI), aspartate aminotransferase (AST), and liver fat retained their significance. Moreover, despite correlating with fibrosis severity in univariate analyses, hepatic fibrosis was not associated with liver fibrosis after incorporating BMI, AST, and steatosis. Importantly, after adjusting for these parameters, only adipose tissue IR measured via adipo-IR remained significantly associated with advanced hepatic fibrosis. These findings support adipose tissue’s pivotal role in the development of advanced fibrosis, beyond BMI or steatosis. Targeting adipose tissue dysfunction may thus be valuable in patients with NASH and comorbid T2D.

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S Duarte, BSc

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