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

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.