Bitter Compounds as Multifunctional Agents against Diabetes-associatedCognitive Dysfunction: Bridging Metabolic Regulation and Neuroprotection

The increasing prevalence of diabetes-associated cognitive dysfunction (DACD), driven by accelerated aging and unhealthy lifestyles, poses a significant global public health challenge. The current understanding of DACD pathogenesis remains incomplete, and effective interventions are lacking, underscoring the urgent need to elucidate its mechanisms and develop targeted therapies. Recent studies highlight bitter compounds as promising multifunctional agents due to their welldocumented metabolic regulation, neuroprotection, broad availability, and established safety in the management of diabetes mellitus (DM). This review outlines established mechanisms of pathogenicity in DACD and summarizes the pharmacological effects of bitter compounds. These effects include anti-inflammatory actions, reduced oxidative stress, and improvements in mitochondrial dysfunction. Bitter compounds can also lower blood glucose levels, reduce advanced glycation end products (AGEs), and increase insulin sensitivity. Additionally, they modulate gastrointestinal hormones and the gut microbiota, contributing to metabolic regulation and neuroprotection. By decreasing amyloid-beta (Aβ) deposition and inhibiting tau hyperphosphorylation, bitter compounds address metabolic and memory impairments associated with DACD. Despite their potential, challenges such as low bioavailability, target specificity, and interspecies variability hinder their clinical translation. Future research should prioritize interdisciplinary collaboration, advanced delivery systems (e.g., nanocarriers), and rigorous preclinical/ clinical validation to optimize therapeutic efficacy. This work provides critical insights into the use of bitter compounds as novel candidates for DACD prevention and treatment.