Antioxidative and Anti-Inflammatory Mechanisms of Quercetin in the Prevention of Secondary Diabetes Complications

Diabetes mellitus is a chronic metabolic disorder linked with several microvascular and macrovascular complications and is one of the major causes of morbidity and mortality worldwide. Uncontrolled hyperglycemia is well known to increase oxidative and inflammatory responses. Further, activation of the polyol pathway and protein kinase C (PKC), and formation of advanced glycation end-products (AGEs) and their interaction with AGE receptors (RAGEs) can cause tissue dysfunction and damage, leading to secondary diabetes complications such as diabetic retinopathy, neuropathy, nephropathy, cardiovascular complications, and cataractogenesis. Several plant products have been shown to exert potential glucose-lowering effects due to their strong antioxidant and anti-inflammatory properties. Quercetin, a naturally occurring flavonoid abundant in fruits and vegetables, has attracted considerable interest because of its antioxidant, anti-inflammatory, and cytoprotective properties. Recent studies indicate the therapeutic potential of quercetin for controlling secondary diabetes complications. Various preclinical studies suggest that quercetin prevents the production of reactive oxygen species, suppresses NF-κB-mediated inflammatory signaling, activates Nrf-2-mediated antioxidant enzymes, and inhibits AGE-RAGE interactions. These actions of quercetin have been shown to prevent the production of pro-inflammatory cytokines, enhance endogenous antioxidant defenses, and attenuate the pathological consequences of diabetes complications. Although preclinical findings convincingly support the protective effects of quercetin across multiple diabetic complications, clinical findings remain limited and heterogeneous. Further, randomized clinical trials, long-term safety studies, and bioavailability studies are needed to determine its therapeutic effectiveness in clinical practice. In this review, we discuss recent findings on how quercetin prevents various secondary complications of diabetes. We further discuss how quercetin could serve as a promising multi-target adjunctive therapy by addressing the oxidative and inflammatory mechanisms underlying diabetic complications.