Table 1.13 Risk factors of atherosclerosis and diabetic macroangiopathy
| Classical risk factors of atherosclerosis | Additional specific risk factors of diabetic macroangiopathy |
|---|---|
| Hypertension, systolic and diastolic | Hyperglycemia |
| Dyslipidemia | Abnormal lipoproteins |
| Obesity | Platelet activation |
| Smoking | Endothelial dysfunction |
| Stress | Hypercoagulation (increased fibrinogen and PAI-1) |
| Physical inactivity | Albuminuria |
| Family history of atherosclerosis | Hyperhomocystinemia |
| Age | Insulin? |
| Previous myocardial infarction | Duration of diabetes? |
Platelet activation, which is well documented [259–261], is in part constitutional and results from the priming of megakaryocytes [262,263]. However, it may also be induced reactively by LDL [264] and by endothelial injury through thromboxane A2 which is increased in diabetes [265]. Platelet activation goes along with increased expression of adhesion molecules. It favors thrombogenesis and the formation of circulating aggregates of platelets and platelets with leukocytes that are large enough to occlude small vessels [266]. This process is promoted by dyslipoproteinemia [267]. The expression of adhesion molecules contributes to the unfavorable rheological properties of the blood.
After interaction of activated platelets with injured endothelial cells, various growth factors are released which are known to be involved in atherogenesis, such as platelet-derived growth factor (PDGF), TGF-β, endothelium-derived relaxing factor (EDRF), endothelial, and others [268]. Thus, platelet activation may favor thrombogenesis, atherogenesis, capillary occlusion, and microvascular proliferation.
Endothelial dysfunction is another key factor in the pathogenesis of diabetic angiopathies [140,269]. The balanced interaction between blood and vessel wall, which regulates blood flow, hemostasis and vessel wall metabolism, is disturbed in diabetes. Loss of normal endothelial function and activation of abnormal reactions [270] may initially be caused by endothelial injury, and this may finally result in loss of cellular integrity and in cell death.
Endothelial dysfunction is a ubiquitous defect which is not limited to the regions of clinical angiopathy. Its early clinical marker seems to be microalbuminuria.
Blood flow is mainly regulated by vasodilatory EDRF (EDRF = nitric oxide) and the prostaglandin derivative prostacyclin, while endothelin-1, angiotensin II and the platelet factors thromboxane and serotonin are vasoconstrictive. In diabetes the balance of this system is disturbed. The main cause seems to be nitric oxide quenching by AGE [150] and other oxidative stress [271,272].
Lipids and lipoproteins are predictors of coronary artery disease [273]. Discussions of their role in the pathogenesis of atherosclerosis usually emphasize high triglycerides and cholesterol and low HDL-cholesterol levels. These abnormalities are frequently observed in diabetes, and their impact on risk of coronary artery disease is at least as high as in the nondiabetic population [274–278]. The significance of postprandial hypertriglyceridemia in diabetes may have been underestimated in the past [279–281]. Insulin substitution favors an antiatherogenic lipoprotein pattern [282]. In well-controlled type 1 diabetes, lipids tend to be fairly normal. By contrast, dyslipidemia is usually observed as a part of the metabolic syndrome in obese subjects with impaired glucose tolerance and type 2 diabetes [276]. It also develops in poorly controlled type 1 diabetes and in subjects with nephropathy [283,284] (Table 1.14). Lipid abnormalities seem to be more pronounced in women than in men [285,286].
In the presence of insulin and under the influence of high serum glucose, free fatty acids, and amino acids, VLDL synthesis is increased in the liver. Peripheral triglyceride uptake is delayed because of low lipoprotein lipase activity, resulting in hypertriglyceridemia. Hypertriglyceridemia correlates with PAI-1 activity and is associated with low HDL-cholesterol and alterations in the metabolism of other lipoproteins.
In addition to these quantitative alterations, the generation of abnormal lipoproteins seems to be very important [287,288]. The dyslipoproteinemia of diabetes is characterized by the formation of triglyceriderich particles (VLDLI) and abnormal LDL [274,289,290], Small, dense LDL (LDL III) are susceptible to lipid oxidation and strongly related to cardiovascular risk [291–295]. Another effect is the lowering of cardioprotective HDL2, usually measured as low HDL-cholesterol [290,296–298].
Lipoproteins are also subject to glycation of their apoproteins and phospholipids [227]. Glycation promotes lipid oxidation and markedly changes the functional properties of lipoproteins. They become immunogenic and bind to specific scavenger receptors. This excludes them from the regulated