LAUSR

Abstract Disclosure: J. Wang: None. H. Du: None. J. Liu: None. Y. Wang: None. X. Shao: None. T.C. Friedman: None. Y. Liu: None. The use of electronic cigarettes (E-cigs) may increase the risk of prediabetes, but the underlying mechanisms remain underexplored. Pre-receptor activation of glucocorticoids (GCs) by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been identified as a pathophysiological factor contributing to insulin resistance and type 2 diabetes. However, the effects of e-cig vaping on 11β-HSD1 and glucose homeostasis are poorly understood. To address this issue, we conducted studies in mice exposed to aerosolized PBS, nicotine-free, or nicotine-containing E-cigs, with concurrent exposure to either vehicle or the GC receptor (GR) antagonist RU486. We observed that four weeks of nicotine vapor exposure from e-cig vaping elevated plasma corticosterone levels and increased hepatic 11β-HSD1 expression and GR abundance in response to elevated plasma nicotine levels compared with those in mice exposed to aerosolized vehicles or PBS controls. The induction of hepatic 11β-HSD1 was associated with an upregulation of the gluconeogenic enzymes PEPCK and G6Pase in the liver, resulting in higher fasting glucose levels and greater glucose intolerance compared to PBS controls. In contrast, e-cig vaping without nicotine did not affect these metabolic parameters. Additionally, RU486 treatment mitigated the increases in hepatic 11β-HSD1 and GR expression induced by nicotine vapor, improving fasting hyperglycemia and insulin sensitivity, although it did not affect the elevated plasma corticosterone levels in nicotine-exposed mice. These data indicate that e-cig vapor exposure adversely impacts glucose homeostasis, with these effects potentially arising, in part, from aerosol nicotine-induced hepatic GC action. Presentation: Monday, July 14, 2025