Cellular mechanisms and treatment of diabetes vascular complications converge on reactive oxygen species.
High glucose activates a myriad of signaling and gene expression pathways in non-insulin-dependent target cells causing diabetes complications. One of the earliest responses to high glucose by vascular cells is the generation of reactive oxygen species (ROS) that act directly on intracellular proteins and DNA, or indirectly as second messengers, transforming these cells into disease phenotypes. ROS are produced by mitochondria and/or NADPH oxidase in all target cells exposed to high glucose studied to date. Reports using cell cultures and diabetic animal models indicate that inhibition of ROS generation prevents the amplification of signaling and gene expression that are implicated in vascular complications. These models convincingly demonstrate that maneuvers preventing ROS production attenuate or completely abrogate early micro- and macrovascular end-organ damage of diabetes, including nephropathy, retinopathy, and large-vessel atherosclerosis. Attention now turns to the development of more effective antioxidants that could be used in clinical trials in the prevention and treatment of diabetes complications.
Whiteside
Catharine I
CI
Department of Medicine, University of Toronto, 1 King's College Circle, Room 2113, Toronto, ON M5S 1A8, Canada. catharine.whiteside@utoronto.ca
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D042541:Intracellular Space / Q000378:metabolism / Q000648:ultrastructure; D008301:Maleimides / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016896:Treatment Outcome
D007211:Indoles; D008301:Maleimides; D017382:Reactive Oxygen Species; C099154:ruboxistaurin; D004247:DNA; D011493:Protein Kinase C; D064546:Protein Kinase C beta