DM is a complex metabolic state with hyperglycemia considered to be a key causal factor in the development of diabetic vascular complications by causing divergent cellular dysfunction . Hyperglycemia occurs as a result of an impaired glucose utilization by tissues due to either whole-body insulin resistance in DM type 2 or lack of sufficient availability of insulin in DM type 1 . Generally, lack of physiological effects of insulin on the cells and related hyperglycemia-induced cellular biochemical alterations are two major factors resulting in cellular dysfunction in DM. In the following, we are discussing major biochemical pathways through which elevated glucose levels can lead to cellular dysfunction: increased polyol pathway flux; increased advanced glycation end-product (AGE) formation; activation of protein kinase C (PKC) isoforms; and increased hexosamine pathway flux; increased formation of reactive oxygen species (ROS) and other products of abundant oxidative stress, e.g. LPO. The abovementioned mechanisms, their interaction and adverse effects on cellular physiology are summarized in Figure 2. The resulting cellular dysfunction involves unspecific cellular activation by oxidative stress and impaired gene and protein expression (growth factors, their receptors and ECM). This leads to an attenuation of the angiogenic stimulus and impairs and delays the angiogenic process.
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