Etiology
The etiology of cardiovascular disease in diabetes is complex and multifactorial. It results from the interplay of a constellation of metabolic risk factors, excessive oxidation, endothelial dysfunction, inflammation, and imbalance in prothrombotic and antifibrinolytic processes.[31] The unifying metabolic factor is hyperglycemia, which results from both insulin deficiency and insulin resistance. Insulin resistance is associated with a variety of major metabolic risk factors including hyperinsulinemia, dyslipidemia, elevated blood pressure, and obesity.[32][33] Hyperglycemia leads to excessive oxidation and accumulation of advanced glycation end-products, while peroxidation of lipids leads to foam cell formation within the arterial wall.[34][35] Insulin resistance is an important precursor to endothelial dysfunction and associated with increased release of inflammatory proteins, including cytokines, C-reactive protein, and subsequent release of growth factors that stimulate smooth-muscle proliferation and platelet aggregation.[36][37] This cascade ultimately leads to arterial intimal thickening, increased plaque formation, and atherosclerosis.[37]
Pathophysiology
The underlying mechanism for cardiovascular disease (CVD) in diabetes is accelerated atherosclerosis.[38] Autopsy studies have shown that type 2 diabetes is associated with a global coronary disease burden and a prevalence of high-grade atherosclerosis similar to that observed in nondiabetic patients with an antemortem diagnosis of coronary artery disease (CAD); among deceased patients with diabetes who had no diagnosis of CAD, almost three quarters were found to have high-grade coronary atherosclerosis and more than half had multivessel disease.[39] Furthermore, angiographic data have shown that people with diabetes have more diffuse, extensive, multivessel (including left main), and distal disease than do people without diabetes.[40]
The clinical manifestations of atherosclerosis depend on the vascular bed involved. When atherosclerosis involves the coronary arteries it presents as angina pectoris and acute coronary syndromes. When it involves the cerebral or cerebellar arteries it presents as transient ischemic attacks and strokes. Involvement of the peripheral circulation presents as intermittent claudication or gangrene.
The process of atherosclerosis begins with damage to the endothelial cell layer.[38] Under physiologic conditions, the endothelial cell layer separates cells and circulating factors from the arterial intima and media and serves as an anticoagulant and fibrinolytic surface.[31] Circulating factors such as blood glucose, free fatty acids, and glycation end-products damage the endothelial layer, leading to adhesion and penetration of circulating monocytes and macrophages into the arterial intima. The endothelial cells and macrophages produce cytokines and growth factors that allow smooth-muscle migration and proliferation, leading to formation of the atherosclerotic plaque.[38] Continued exposure to circulating factors leads to cell death, and the combination of a large lipid core, necrotic tissue, macrophages, and a thin fibrous cap predisposes to plaque rupture.[31] Plaque rupture and thrombosis are responsible for the clinical events associated with CVD, including acute coronary syndromes and strokes. The development of atherosclerosis is usually a slow process, but in people with diabetes it is more rapid and aggressive and produces clinical disease at an earlier age.[38]
Aortic aneurysm is associated with atherosclerosis; however, current evidence suggests that patients with diabetes have a lower risk of developing abdominal aortic aneurysm compared with those without diabetes.[41][42] The protective mechanism is yet to be determined; however, possibilities include reduced extracellular matrix volume, altered inflammatory pathways, and the effects of oral antihyperglycemic drug.[42][43]
Due to the overlap in pathophysiology between diabetes, CVD, obesity, and chronic kidney disease, some groups argue that these conditions should be considered to be on a single spectrum known as cardiovascular-kidney-metabolic (CKM) syndrome. The American Heart Association, notably, has endorsed this terminology and proposed a four-stage model based on a patient’s number of risk factors and the presence of overt CVD.[44] It has also developed a series of risk prediction equations, known as PREVENT, for estimating 10- and 30-year CVD risks based on the CKM concept.[45] It is hoped that this new approach will improve screening, prevention, and treatment of CKM risk factors, particularly in people with adverse social determinants of health.[44]
Disruption of the gut microbiome has been postulated to play an important role in the development of various obesity-related metabolic abnormalities, among them type 2 diabetes and CVD. The intestinal microbiota therefore appears to be a promising target for the nutritional or therapeutic management of these diseases.[46]
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