Oxidative Stress and Cardiovascular Complications in Type 2 Diabetes: From Pathophysiology to Lifestyle Modifications

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that significantly increases the risk of cardiovascular disease, which is the leading cause of morbidity and mortality among diabetic patients. A central pathophysiological mechanism linking T2DM to cardiovascular complications is oxidative stress, defined as an imbalance between reactive oxygen species (ROS) production and the body's antioxidant defenses. Hyperglycemia in T2DM promotes oxidative stress through various pathways, including the formation of advanced glycation end products, the activation of protein kinase C, mitochondrial dysfunction, and the polyol pathway. These processes enhance ROS generation, leading to endothelial dysfunction, vascular inflammation, and the exacerbation of cardiovascular damage. Additionally, oxidative stress disrupts nitric oxide signaling, impairing vasodilation and promoting vasoconstriction, which contributes to vascular complications. This review explores the molecular mechanisms by which oxidative stress contributes to the pathogenesis of cardiovascular disease in T2DM. It also examines the potential of lifestyle modifications, such as dietary changes and physical activity, in reducing oxidative stress and mitigating cardiovascular risks in this high-risk population. Understanding these mechanisms is critical for developing targeted therapeutic strategies to improve cardiovascular outcomes in diabetic patients.

Keywords: Mediterranean diet; cardiovascular complications; lifestyle interventions; oxidative stress; pathophysiology; type 2 diabetes mellitus.

Figure 1

This figure illustrates the cascading effects of chronic hyperglycemia on cellular and molecular pathways, leading to oxidative stress, advanced glycation end products (AGEs) formation, and cardiovascular damage. Hyperglycemia induces the overproduction of reactive oxygen species (ROS) through NADPH oxidase (NOX) hyperactivation, facilitated by the protein kinase C (PKC) pathway. ROS accumulation dysregulates the NRF2 pathway, reducing the expression of antioxidant and anti-inflammatory genes, thereby exacerbating oxidative damage. Concurrently, hyperglycemia accelerates the formation of AGEs, which suppress AGE receptor (RAGE) signaling and nitric oxide synthase activity. These changes contribute to vessel stiffness, cardiac fibrosis, and impaired endothelial function. Additionally, the suppression of the PI3K/Akt/mTOR signaling cascade leads to increased spontaneous mitochondrial apoptosis, resulting in cardiomyocyte death and cardiac dysfunction.

Figure 2

The figure illustrates the impact of chronic hyperglycemia on various cellular and systemic processes, leading to increased oxidative stress (ROS) and associated complications. Chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs) through protein glycosylation, contributing to atherosclerosis and oxidative damage, which result in LDL oxidation and foam cell formation. It also activates the polyol pathway and induces mitochondrial dysfunction, increasing the production of ROS and elevating tumor necrosis factor alpha (TNF-α), which further amplifies oxidative stress. This cascade of events leads to several adverse outcomes, including endothelial dysfunction, plaque formation, and an increased risk of acute plaque events in atherosclerosis. In addition, chronic hyperglycemia contributes to hypertension by reducing nitric oxide (NO) availability and dysregulating nitric oxide synthase (NOS), causing chronic vasoconstriction through the elevated expression of angiotensin II (AT II) and endothelin-1 (ET-1). Furthermore, ROS exacerbates heart failure and diabetic cardiomyopathy by upregulating pro-inflammatory pathways like NF-κB and TGF-β, promoting cardiomyocyte apoptosis, damaging structural proteins, and inducing adverse myocardial remodeling. Lastly, ROS disrupts the blood–brain barrier (BBB), leading to excitotoxicity, apoptosis, and an increased risk of stroke and cardiovascular disease.