The role of telomere shortening in ambient ozone exposure-related insulin resistance

BACKGROUND: Ozone (O₃) exposure and telomere shortening are associated with insulin resistance (IR). However, the role of telomere shortening in ambient O₃ exposure-related IR is largely unclear. METHODS: The Henan Rural Cohort recruited participants and performed a random forest method to estimate residential O₃ concentration. IR was reflected by homeostasis model assessment-IR, quantitative insulin sensitivity check index, triglyceride and glucose index, etc. Generalized linear model, quantile regression model, and mediation effects analysis were utilized to assess the associations of O₃ exposure and relative telomere length (RTL) with longitudinal IR markers and their change rates. Furthermore, the role of telomere homeostasis in O₃-exposure-induced IR in vivo and in vitro experiments was verified. RESULTS: O₃ exposure was positively associated with longitudinal IR. The proportions of RTL mediated associations between O₃ exposure and longitudinal IR markers ranged from 11.92 % to 60.36 %. O₃-exposed mice exhibited a higher glucose load, upregulation of GSK-3β and G-6-Pase expression at mRNA levels, glycogen accumulation reduction, telomere shortening, and decreased telomerase reverse transcriptase activity relative to air-exposed mice. In vitro experiments reveal that overexpression of TERT in HepG2 cells up-regulated G-6-Pase mRNA expression level. CONCLUSIONS: Impaired telomere homeostasis may be involved in O₃ exposure-related IR via inhibition of glycogen synthesis and acceleration of gluconeogenesis and the specific mechanisms are still further elucidated.