The Association of Diabetes and Atherosclerosis: Understanding the Molecular Mechanism of the Double Burden

Diabetes Mellitus (DM) and atherosclerosis are two major chronic, non-communicable diseases that together constitute a critical axis of cardiovascular morbidity and mortality worldwide. Mounting evidence highlights their bidirectional relationship, emphasizing the need to elucidate the molecular and clinical intersections underpinning this link. Both conditions pose significant global health and economic challenges, with DM not only serving as a major risk factor but also accelerating the onset and progression of atherosclerosis. Understanding these shared pathways is essential to identify novel therapeutic strategies. Literature for this review was sourced from PubMed, Scopus, and Google Scholar databases. Hyperglycemia-induced endothelial dysfunction, reactive oxygen species-driven oxidative stress, Advanced Glycation End product (AGE)-Receptor for AGE (RAGE) interactions, and the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) along with adipokines are well-established mechanisms connecting diabetes mellitus with atherosclerosis. In addition to these classical pathways, emerging evidence highlights the contribution of NLRP3 inflammasome activation, Damage-Associated Molecular Patterns (DAMPs), pathogen-Associated Molecular Patterns (PAMPs), and Toll-Like Receptor (TLR) signaling in promoting vascular inflammation and accelerating disease progression. Furthermore, epigenetic modifications and microRNAs have been identified as novel modulators of this pathogenic interplay. This review synthesizes both the traditional and recently recognized mechanisms, providing a comprehensive understanding of the molecular links between these two conditions. Therapeutic strategies to disrupt this diabetes-atherosclerosis axis must move beyond a glucocentric paradigm. Agents should simultaneously address hyperglycemia and the vascular inflammatory processes that underlie atherosclerosis to reduce cardiovascular events and mortality. Notably, recent antidiabetic classes such as Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) show promising dual benefits in glycemic control and cardiovascular protection. These advances open avenues for integrated approaches to mitigate the global burden of diabetes-related atherosclerotic disease.