Clin Chem Lab Med 2011;49(11):1773–1782  2011 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/CCLM.2011.250 2010/510 Article in press - uncorrected proof Review Oxidative stress and diabetes mellitus Hui Yang 1 , Xun Jin 1 , Christopher Wai Kei Lam 2 and Sheng-Kai Yan 1,3, * 1 Department of Laboratory Medicine, China-Japan Friendship Hospital, Ministry of Health, Beijing, P.R. China 2 Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, P.R. China 3 Guang Zhou Improve Medical Instruments Co., Ltd, Guangzhou, P.R. China Abstract Increasing evidences have suggested that oxidative stress plays a major role in the pathogenesis of diabetes mellitus (DM). Oxidative stress also appears to be the pathogenic factor in underlying diabetic complications. Reactive oxy- gen species (ROS) are generated by environmental factors, such as ionizing radiation and chemical carcinogens, and also by endogenous processes, including energy metabolism in mitochondria. ROS produced either endogenously or exo- genously can attack lipids, proteins and nucleic acids simul- taneously in living cells. There are many potential mecha- nisms whereby excess glucose metabolites traveling along these pathways might promote the development of DM com- plication and cause pancreatic b cell damage. However, all these pathways have in common the formation of ROS, that, in excess and over time, causes chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. Various methods for determining biomarkers of cellular oxidative stress have been developed, and some have been proposed for sensitive assessment of antioxidant defense and oxidative damage in diabetes and its complications. However, their clinical utility is limited by less than optimal standardization techniques and the lack of sufficient large-sized, multi- marker prospective trials. Keywords: advanced glycation endproducts; diabetes mel- litus; oxidative stress; reactive nitrogen species; reactive oxy- gen species. *Corresponding author: Dr. Sheng-Kai Yan, Department of Laboratory Medicine, China-Japan Friendship Hospital, Ministry of Health, No. 2 East Yinghua Road, Chaoyang District, Beijing 100029, P.R. China Phone: q86-10-84205213, Fax: q86-10-64288578, E-mail: yanshengkai@sina.com Received September 2, 2010; accepted June 1, 2011; previously published online August 3, 2011 Introduction Diabetes mellitus (DM) is a disease characterized by hyper- glycemia and is caused by absolute or relative insulin defi- ciency, frequently associated with insulin resistance. It has multiple etiologies and segregates into two major forms: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). DM affects more than 165 million individuals worldwide. T2DM represents over 80% of all diabetics and is increasing in incidence as a result of changes in human behavior and increased body mass index. However, it is T1DM that begins early in life and leads to long-term com- plications and represents only 5%–10% of all diabetics. Oxidative stress is a principal mechanism in the progres- sion of diabetes and actively leads to cellular injury that can precede the onset of many diabetic complications (1). Both diabetic cell injury and the development of insulin resistance are also closely related to the presence of cellular oxidative stress (2). Acute glucose fluctuations may promote oxidative stress (3). Elevated cellular glucose levels can also result in an increased production of reactive oxygen species (ROS) (4). In addition, oxidative stress may more directly promote the onset of DM by decreasing insulin sensitivity and destroying the insulin-producing cells within the pancreas. Free fatty acids (FFAs) can lead to formation of ROS besides contributing to mitochondrial DNA damage and impaired pancreatic b-cell function (5). The pathological conse- quences of these disorders are intimately linked through the pathways that mediate oxidative stress. In this review, we focus on the role of oxidative stress in the development and progression of DM and its complications. We also survey recent laboratory assessments of oxidative stress in DM and its complications. ROS and antioxidant systems Oxidative stress is defined in general as excess formation and/or insufficient removal of highly reactive molecules. ROS include free radicals, such as superoxide (ØO 2 – ), hydroxyl (ØOH), peroxyl (ØRO), hydroperoxyl (ØHRO 2 – ) as well as non-radical species, such as hydrogen peroxide (H 2 O 2 ) and hydrochlorous acid (HOCl). Reactive nitrogen species (RNS) include free radicals like nitric oxide (ØNO) and nitrogen dioxide (ØNO 2 – ), as well as non-radicals, such as peroxynitrite (ONOO – ), nitrous oxide (N 2 O) and alkyl peroxynitrites (RONOO – ) (1, 6, 7). Most superoxide radicals come from reaction catalyzed by xanthine oxidase, NADPH oxidase and cytochrome P450. Brought to you by | University of Illinois Chicago (University of Illinois Chicago) Authenticated | 172.16.1.226 Download Date | 6/8/12 4:40 PM