Diabetes is one of the critical independent risk factors for the progression of cardiovascular disease, and the underlying mechanism regarding this association remains poorly understood. Hence, it is urgent to decipher the fundamental pathophysiology and consequently provide new insights into the identification of innovative therapeutic targets for diabetic atherosclerosis. It is now appreciated that different cell types are heavily involved in the progress of diabetic atherosclerosis, including endothelial cells, macrophages, vascular smooth muscle cells, dependence on altered metabolic pathways, intracellular lipids, and high glucose. Additionally, extensive studies have elucidated that diabetes accelerates the odds of atherosclerosis with the explanation that these two chronic disorders share some common mechanisms, such as endothelial dysfunction and inflammation. In this review, we initially summarize the current research and proposed mechanisms and then highlight the role of these three cell types in diabetes-accelerated atherosclerosis and finally establish the mechanism pinpointing the relationship between diabetes and atherosclerosis.

Graphical Abstract

Initiation and progression of diabetic atherosclerosis. Insulin resistance with hyperinsulinemia, hyperglycemia and lipotoxicity contribute to multiple processes including AGEs production, increased FFA and ox-LDL, which together lead to endothelial dysfunction, macrophages-derived foam cell formation, and VSMCs phenotypic switch. In the early stages of diabetic atherosclerosis, circulating monocytes bind to adhesion factors expressed by activated endothelial cell, while endothelial cells release chemokines that promote migration of the bound monocytes into the arterial wall. After entering the intima, monocytes mature into macrophages, including pro-inflammatory M1 and anti-inflammatory M2 types, macrophages engulf retained ox-LDL and transform into lipidloaded macrophage. At the same time, DCs increased local inflammation of endothelial cells and activated VSMCs. VSMCs in the media proliferate and migrate to the intima, forming a fibrous cap to cover the necrotic core. VSMCs and macrophages can undergo cell death, including apoptosis, pyroptosis, ferroptosis, necroptosis, cell fragments gathered and formed lipid-rich necrotic cores. Fiber caps became thinner, plaque vulnerability increased and rupture, platelet activation led to the formation of thrombosis, and NETosis promoted the formation of thrombosis.