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Abstract
Oxidative stress plays a pivotal role in the development of diabetes complications,
both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause
mitochondrial superoxide overproduction in endothelial cells of both large and small
vessels, as well as in the myocardium. This increased superoxide production causes
the activation of 5 major pathways involved in the pathogenesis of complications:
polyol pathway flux, increased formation of AGEs (advanced glycation end products),
increased expression of the receptor for AGEs and its activating ligands, activation
of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also
directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide
synthase and prostacyclin synthase. Through these pathways, increased intracellular
reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia,
activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes
that drive persistent expression of proinflammatory genes after glycemia is normalized
("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are
caused in part by pathway-selective insulin resistance, which increases mitochondrial
ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes
by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents
diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to
highlight advances in understanding the role of metabolite-generated ROS in the development
of diabetic complications.
[1
]From the Diabetes Research Center, Departments of Medicine/Endocrinology, Albert Einstein
College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461-1602.