Molecular mechanisms involved in hyperglycemia-induced cellular damage

Long-term adverse outcomes of hyperglycemia are the major causes of disability, morbidity, and premature mortality in affected subjects. The underlying pathogenic mechanisms of hyperglycemia are the result of a complex intricate network of interactions of systemic metabolic changes that lead to local tissue responses to toxic metabolites derived from altered glucose metabolism and glucose autoxidation. Multiple molecular mechanisms drive hyperglycemia-derived cell damage, including an increased polyol pathway, activation of protein kinase C isoforms via de novo synthesis of the lipid second messenger diacylglycerol, overproduction of advanced glycation end-products, and induction of the hexosamine pathway. A growing body of evidence strongly suggests that excess glucose is also associated with impaired mitochondrial function. This chapter reviews the evidence on the main classical biochemical pathways activated by chronic hyperglycemia. This review further deepens our understanding of the contribution of mitochondrial dysfunction.