From NHANES to Network Pharmacology: HOMA-IR Mechanisms in Concurrent MASLD and Type 2 Diabetes
Year: 2025
Type: preprint
Abstract: Metabolic dysfunction–associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) frequently co-occur, yet the population-level role of insulin resistance remains unclear. Using NHANES 2017–2020 data (n = 1,443 U.S. adults), we examined the association between the homeostasis model assessment of insulin resistance (HOMA-IR) and concurrent MASLD–T2D, and explored putative mechanisms via network pharmacology. Each unit increase in HOMA-IR was associated with higher odds of having both MASLD and T2D versus neither condition; associations were generally stronger in females and varied by race and ethnicity. Similar patterns were observed for MASLD with prediabetes. Mediation analyses indicated that fasting plasma glucose and HbA 1c explained a substantial, but incomplete, proportion of the association, suggesting additional non-glycemic processes. Network analyses highlighted core targets (e.g., PRKACA/PRKACG, MAPK1/3, SRC, PI3K subunits) and convergent pathways including PI3K–AKT/FOXO, MAPK, AMPK and cAMP–PKA that are consistent with impaired hepatic insulin signaling and stress-responsive gluconeogenesis. Together, these findings position HOMA-IR as an integrative indicator of the MASLD–T2D comorbidity and generate mechanistic hypotheses linking epidemiologic associations to signaling networks, warranting validation in longitudinal and experimental studies.
Source: Research Square
Authors: Qiwei Chen, Linxi Jin, Yuwan Li, Yi Ruan, Zhuang Han, Shuhong Yao, Xinmiao Hong, Zhita Wang, Liuqing Yang, Liang Li, Weidong Heng, xianpei Heng
Institution: Fujian University of Traditional Chinese Medicine
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4416385034