Insulin Resistance Drives Obesity-Linked NAFLD Risk

TOPLINE:

Insulin resistance (IR) and chronic inflammation mediate the relationship between obesity and the risk for nonalcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction–associated steatotic liver disease, with IR showing a stronger influence than inflammation. 

METHODOLOGY:

• Obesity is a key risk factor for NAFLD, prompting investigation into its pathogenic pathways for prevention and treatment strategies.
• Researchers used data from two population-based cross-sectional studies — the Fuqing Cohort Study and the 2007-2018 National Health and Nutrition Examination Survey (NHANES) — and conducted Mendelian randomization to assess how IR and chronic inflammation mediate the association between obesity and risk for NAFLD.
• Obesity was measured by body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). IR was assessed via homeostatic model assessment of IR (HOMA-IR) and homeostatic model assessment of beta-cell function index (HOMA-beta). Inflammation markers included C-reactive protein (CRP) levels, white blood cell count, and lymphocyte count.
• A two-sample Mendelian randomization determined whether IR and inflammation mediated the effect of obesity on the risk for NAFLD.

TAKEAWAY:

• Researchers included 6036 participants (67.4% women) from the Fuqing Cohort study and 5167 participants (56.0% women) from the 2007-2018 NHANES.
• All obesity phenotypes (BMI, WC, WHR, and WHtR) were significantly associated with increased NAFLD risk.
• IR and inflammation indicators were also positively associated with the risk for NAFLD. Individuals with obesity showed higher levels of both IR and inflammation than those without obesity.
• HOMA-IR was the strongest mediator between obesity and NAFLD. In the Fuqing Cohort, the indirect effects of insulin and HOMA-IR accounted for 50.97%-66.72% of the association, whereas inflammation markers mediated a smaller proportion.
• Mendelian randomization confirmed that both IR and inflammation mediate the association between obesity and NAFLD risk, with IR having a stronger effect than chronic inflammation.

IN PRACTICE:

“The observed mediation proportions highlight that IR indicators, such as HOMA-IR, may be more significant than chronic inflammation markers (eg, CRP) in NAFLD monitoring, suggesting that monitoring IR levels in obese populations may aid in NAFLD prevention,” the authors wrote. 

SOURCE:

This study was led by Xiaoyin Huang and Qingling Su of the Fujian Medical University and by Qianni Chen of the Fuqing City Hospital affiliated to Fujian Medical University, both located in Fuzhou, People’s Republic of China. It was published online on March 24, 2025, in Clinical Epidemiology.

LIMITATIONS:

Only easily accessible indicators of IR were analyzed, as gold standard methods were costly and complex to implement in public health practice. Noninvasive methods like ultrasonography and the US Fatty Liver Index were used for the diagnosis of NAFLD instead of liver biopsy, which could have introduced misclassification bias. The relaxed single nucleotide polymorphisms (SNPs) selection criteria increased the risk for false positives, and heterogeneity among SNPs could have affected the robustness of Mendelian randomization results.

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of the People’s Republic of China, General Program of the Natural Science Foundation of Fujian Province, Government of Fuqing city, and other sources. The authors declared having no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.