Endocannabinoid and AGE Interactions in Prediabetes: The Role of Mediterranean Diet Adherence

Objectives: To determine whether plasma concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are elevated in adults with prediabetes, we explored their association with tissue advanced glycation end-products (AGEs) and assessed the influence of Mediterranean diet adherence. Methods: This cross-sectional single-centre study included 92 adults with prediabetes and 86 age-/sex-matched normoglycaemic controls. Anthropometry, blood pressure, biochemical indices, and skin autofluorescence-derived AGEs were measured. Serum AEA and 2-AG were quantified by competitive ELISA, while Mediterranean diet adherence was assessed using the Mediterranean Diet Serving Score (MDSS). Results: Prediabetes was associated with higher AEA (p = 0.004) but not 2-AG (p = 0.520). Also, AEA correlated positively with AGE values (r = 0.36; p = 0.002) and increased across AGE-based cardiovascular risk categories. In multivariable models, both prediabetes status and AGE burden independently predicted AEA. Participants achieving MDSS ≥ 14 exhibited lower AEA (p = 0.038); 2-AG remained unaffected. Finally, the multivariable analysis confirmed that both prediabetes (β = 11.9; p = 0.005) and AGE values (β = 0.25; p = 0.003) are positively associated with plasma AEA levels, independent of age, sex, BMI, and fasting plasma glucose levels. Conclusions: Circulating AEA, but not 2-AG, is elevated in prediabetes and independently linked to cumulative AGE burden, suggesting early endocannabinoid activation contributes to cardiometabolic risk. High adherence to a Mediterranean diet may mitigate this dysregulation.