Potential role of miR-128-1 modulating antioxidant NRF2 pathway in linking acrylamide exposure with type 2 diabetes risk: Insight from epidemiological and toxicological evidence.
Huo Zhiying, Song Jiahao, Fan Lieyang, Wan Shuhui, You Xiaojie, Zhang Yongfang, Liu Qing, Hong Le, Xiong Yani, Chen Pengfei, Wang Feifei, Chen Weihong, Wang Bin
Abstract
Role of miR-128-1, an emerging therapeutic target of type 2 diabetes (T2D) and a targeted posttranscriptional suppressor of the antioxidant master nuclear factor erythroid 2-related factor 2 (NRF2), in linking acrylamide (ACR), a worldwide-concerning and lifelong-exposed pollutant, with T2D is unclear and warrants urgent elucidation. Epidemiologically, 482 Chinese adults from Wuhan-Zhuhai cohort were incorporated to evaluate the relationships among urinary ACR exposure biomarkers (N-acetyl-S-[2-carbamoylethyl]-L-cysteine [AAMA], N-acetyl-S-[2-carbamoyl-2-hydroxyethyl]-L-cysteine [GAMA], AAMA+GAMA [ΣUAAM], and GAMA/AAMA), plasma miR-128-1, and prevalent T2D by generalized-linear-models and the mediation role of miR-128-1 in ACR-T2D relationships by mediation analyses. Toxicologically, INS-1 cells were treated with ACR and miR-128-1 mimic/inhibitor for 24 h to explore the mechanism of miR-128-1 modulating antioxidant NRF2 pathway in ACR-related oxidative damage of β-cell function characterized by glucose-stimulated insulin secretion (GSIS). We uncovered linear positive relationships of ACR exposure biomarkers with miR-128-1 (β-coefficients: 0.63-1.45; P < 0.05) and T2D (odds ratio: 1.42-4.60; P < 0.05) and miR-128-1 with T2D (odds ratio: 1.34; P < 0.05) with elevated miR-128-1 mediated 18.39-24.54% of the ACR-T2D relationships. INS-1 cells treated with ACR showed NRF2 pathway activation and dose-dependent reduction in GSIS while elevations in miR-128-1 and oxidative stress (reactive oxygen species and malondialdehyde) levels. Compared to INS-1 cells treated with ACR+negative control, those treated with ACR+miR-128-1 mimic/inhibitor exhibited reduced/elevated mRNA and protein levels of NRF2 and downstream antioxidant factors, increased/decreased oxidative stress levels, and reduced/elevated GSIS. Overall, miR-128-1 might play a potential mechanism role in linking ACR exposure and T2D risk, possibly involving targeted suppression of antioxidant NRF2 pathway and oxidative impairment of β-cell function.
Key Findings
- Acrylamide (ACR) exposure biomarkers are positively associated with increased levels of miR-128-1 and higher risk of type 2 diabetes (T2D) in humans.
- miR-128-1 mediates 18.39-24.54% of the relationship between ACR exposure and T2D, suggesting a partial mechanistic role.
- In INS-1 cells, ACR treatment activates the NRF2 antioxidant pathway but reduces glucose-stimulated insulin secretion (GSIS) and increases oxidative stress markers.
- Modulation of miR-128-1 levels in ACR-treated cells inversely affects NRF2 and downstream antioxidant factor expression, oxidative stress, and GSIS, indicating miR-128-1 suppresses the NRF2 pathway.
Clinical Significance
This study highlights miR-128-1 as a potential molecular link between environmental acrylamide exposure and increased type 2 diabetes risk through suppression of the antioxidant NRF2 pathway, suggesting new targets for diabetes prevention and therapy.
Citation
Huo Zhiying, Song Jiahao, Fan Lieyanget al.. Potential role of miR-128-1 modulating antioxidant NRF2 pathway in linking acrylamide exposure with type 2 diabetes risk: Insight from epidemiological and toxicological evidence. Ecotoxicology and environmental safety. 2026-May-09.