Molecular and Pathophysiological Mechanisms Leading to Ischemic Heart Disease in Patients with Diabetes Mellitus

Abstract

Coronary atherosclerosis in patients with diabetes mellitus is the most significant pathophysiological mechanism responsible for ischemic heart disease. Atherosclerosis in diabetes is premature, more diffuse, and more progressive, and it affects more coronary blood vessels compared to non-diabetics. Atherosclerosis begins with endothelial dysfunction, continues with the formation of fatty streaks in the intima of coronary arteries, and ends with the appearance of an atherosclerotic plaque that expands centrifugally and remodels the coronary artery. If the atherosclerotic plaque is injured, a thrombus forms at the site of the damage, which can lead to vessel occlusion and potentially fatal consequences. Diabetes mellitus and atherosclerosis are connected through several pathological pathways. Among the most significant factors that lead to atherosclerosis in diabetics are hyperglycemia, insulin resistance, oxidative stress, dyslipidemia, and chronic inflammation. Chronic inflammation is currently considered one of the most important factors in the development of atherosclerosis. However, to date, no adequate anti-inflammatory therapeutic measures have been found to prevent the progression of the atherosclerotic process, and they remain a subject of ongoing research. In this review, we summarize the most significant pathophysiological mechanisms that link atherosclerosis and diabetes mellitus.

Keywords: atherosclerosis; chronic inflammation; diabetes mellitus; dyslipidemia; hyperglycemia; oxidative stress.

Figure 1

Schematic representation of the pathophysiological connection between diabetes mellitus and atherosclerosis. Hyperglycemia, dyslipidemia, oxidative stress, and chronic inflammation in patients with diabetes cause a spectrum of physiological changes in the endothelium of blood vessels, primarily leading to its damage. A damaged endothelium in the presence of pro-inflammatory cytokines increases leukocyte adhesion through the help of adhesion molecules (ICAM-1, VCAM-1, E-selectin, and P-selectin). Leukocytes, predominantly monocytes and T lymphocytes, more easily adhere and pass through the intimal layer of the blood vessel, where they differentiate into macrophages. Macrophages phagocytize LDL, becoming foam cells. Foam cells secrete growth factors (such as PDGF), which stimulate the proliferation of fibroblasts and smooth muscle cells. The figure also shows how neutrophils in a hyperglycemic state activate the process of NETosis, which helps in pathogen elimination but also contributes to further tissue damage. VCAM 1, Vascular Cell Adhesion Molecule; ICAM 1, Intercellular Adhesion Molecule; PDGF, Platelet-Derived Growth Factor; VSCMs, Vascular Smooth Muscle Cells; LDL, Low-Density Lipoprotein; oxLDL, oxidized LDL; ROS, Reactive Oxygen Species.

Figure 2

Schematic representation of the activation of the polyol pathway contributing to the development of oxidative stress and chronic inflammation. Final products of the activation are marked on the figure (marked in orange color), while all of them represent complications of diabetes (marked in red color). In conditions of hyperglycemia, excess glucose is converted to sorbitol with the help of the enzyme aldose reductase, which is then further converted to fructose with the help of the en-zyme sorbitol dehydrogenase. Fructose, as the end product of this metabolic pathway, contributes to the increased synthesis of (AGEs). In the polyol pathway, the conversion of glucose to sorbitol and fructose, along with the increase in NADH levels, leads to a reduction in NADPH levels, which lowers the production of glutathione, a key antioxidant, thereby increasing oxidative stress. Addi-tionally, the activity of sorbitol dehydrogenase leads to an increase in NADH levels, which, through glycerol-3-phosphate, results in the activation of protein kinase C (PKC). NADPH, nico-tinamide adenine dinucleotide phosphate; NADH, nicotinamide adenine dinucleotide; AGEs, ad-vanced glycation end-products; PKC, protein kinase C.