1783-P: Impaired Tryptophan Metabolite ITE-Linked Aryl Hydrocarbon Receptor Function in Plasma of Individuals with Obesity and Diabetes

Introduction and Objective: Aryl hydrocarbon receptor (AHR) serves as a crucial molecular pathway that is regulated by both endogenous and environmental small molecules to shape the immune response and contribute to the onset of autoimmune diseases. AHR also offers a potential target for therapeutic intervention in immune-mediated disorders. Tryptophan metabolite ITE functions as an endogenous ligand for AhR and is involved in inflammation. However, the effects of plasma on ITE-related AHR functionality in individuals with obesity or diabetes are not well characterized. Methods: In this cross-sectional study, plasma samples were obtained from 60 participants categorized as lean controls, obese individuals, and individuals with diabetes. Soluble AhR was determined using ELISA. The activity of AhR was evaluated with AhR reporter cell systems and quantified using a luciferase-based assay. Results: Our findings reveal that soluble AHR levels were significantly higher in non-diabetic individuals (613.6 ± 25.08 pg/ml) compared to obese/diabetic participants (340.9 ± 105.8 pg/ml; P< 0.0219). Plasma AHR agonistic activity was elevated in obese individuals relative to lean controls, and a similar trend was observed in obese individuals with diabetes. Notably, the plasma of obese individuals inhibited ITE-related AHR function compared to lean individuals, with a similar suppression evident in diabetic obese individuals. Conclusion: Reduced levels of soluble AHR in obese and diabetic individuals suggest a diminished capacity to counteract the toxic effects of plasma AHR agonists. ITE-related AHR functionality is impaired in both obese and diabetic plasma samples, which may increase insulin resistance and inflammation. Plasma AHR agonistic activity may serve as new biomarker for type 2 diabetes diagnosis and progression monitoring. Disclosure F. Bahman: None. A. Abu Alroub: None. A. Al Madhoun: None. M. Al Arouj: None. A. Bennakhi: None. F. Almulla: None. R. Ahmad: None. Funding Kuwait Foundation for the Advancement of Sciences (RA-AM-2023-23)