Hyperglycemia has been shown to be the main cause of microvascular complications in the DCCT (11) and UKPDS study (12). For cardiovascular complications, the contribution of hyperglycemia is probably also significant. Several biochemical mechanisms appear to explain the adverse effects of hyperglycemia on vascular cells (Table 3). This is not surprising because the metabolism of glucose and its metabolites can affect multiple cellular pathways. Glucose is transported into the vascular cells mostly by GLUT-1 transporters, which can be regulated by extracellular glucose concentration and other physiological stimulators, such as hypoxia (40). Once glucose is transported, it is metabolized to alter signal transduction pathways, such as the activation of diacylglycerol (DAG) and protein kinase C (PKC), or to increase flux through the mitochondria to change the redox potential (41-44). Lastly, another metabolic pathway (such as that of aldose reductase), which is normally inactive, can be used. In this review, we describe these theories and suggest that the common pathways for most of the adverse effects of hyperglycemia are mediated by alterations in signal transduction of such substances as DAG-PKC or other kinase and phosphatase.

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