Targeting Diabetic Complications through Oleuropein-Mediated Enzyme Modulation: A Chemical Biology Study in the Human-Relevant Model <i>Psammomys obesus</i>

This study investigates the therapeutic potential of oleuropein-rich olive leaf extract (OLE) and pure oleuropein compound (OLC) in mitigating diabetes-induced organ damage using <i>Psammomys obesus</i>, a well-established model for metabolic syndrome. Despite the rising global burden of diabetes and associated complications, effective interventions targeting multiorgan dysfunction remain limited. Oleuropein, a polyphenolic compound with documented antioxidant and anti-inflammatory properties, was administered orally at 1 mg/kg body weight over 7 months to six experimental groups subjected to high- or low-calorie diets to simulate diabetic and control conditions. Results demonstrated that the OLE and OLC significantly reduced kidney weight, preserved renal and hepatic histological architecture, and prevented diabetes-associated body weight and muscle mass loss. Biochemical analyses revealed normalization of erythrocyte biomarkers, including reduced activities of aldose reductase (AR) and sorbitol dehydrogenase (SDH), key enzymes in the polyol pathway linked to diabetic pathology. Antioxidant efficacy was evident through restored levels of malondialdehyde (MDA), superoxide dismutase (SOD), and catalase in retina and erythrocytes. Notably, vascular protection was observed via modulation of vascular endothelial growth factor (VEGF) expression and localization, supported by retinal flat mount analysis showing improved vascular integrity. These benefits were mechanistically tied to oleuropein's capacity to suppress oxidative stress and inhibit polyol pathway hyperactivation. This research establishes oleuropein as a dual-action nutraceutical and pharmaceutical agent, offering both preventive and therapeutic strategies for diabetes-related complications. The use of <i>P. obesus</i> underscores its translational relevance in metabolic syndrome research, positioning oleuropein as a promising candidate for further clinical exploration in diabetes management.