1. Albert Einstein College of Medicine, Diabetes Research Centre, 1,300 Morris Park Ave, Bronx, New York 10461, USA
2. Division of Gene Therapy Science, Osaka University Medical School, Suita Osaka, 5650871 Japan
3. Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52246, USA
4. Department of Metabolic Diseases Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA
5. Justus-Liebig University III Medical Department, Giessen, D-35385, Germany
6. Present address: Kumamoto University School of Medicine, Department of Medicine, Kumamoto, Japan.

Correspondence to: Michael Brownlee¹ Correspondence and requests for reprints should be addressed to M.B. (e-mail: Email: brownlee@aecom.yu.edu).

Abstract

Diabetic hyperglycaemia causes a variety of pathological changes in small vessels, arteries and peripheral nerves¹. Vascular endothelial cells are an important target of hyperglycaemic damage, but the mechanisms underlying this damage are not fully understood. Three seemingly independent biochemical pathways are involved in the pathogenesis: glucose-induced activation of protein kinase C isoforms²; increased formation of glucose-derived advanced glycation end-products³; and increased glucose flux through the aldose reductase pathway⁴. The relevance of each of these pathways is supported by animal studies in which pathway-specific inhibitors prevent various hyperglycaemia-induced abnormalities^{3, 5, 6, 7}. Hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells⁸. Here we show that this increase in reactive oxygen species is prevented by an inhibitor of electron transport chain complex II, by an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase. Normalizing levels of mitochondrial reactive oxygen species with each of these agents prevents glucose-induced activation of protein kinase C, formation of advanced glycation end-products, sorbitol accumulation and NFB activation.