Role of Oxidative Stress and Targeted Antioxidant Therapies in Experimental Models of Diabetic Complications

  • Judy B. de Haan
  • Karin A. Jandeleit-Dahm
  • Terri J. AllenEmail author
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Diabetic patients, whether of type 1 or type 2 origin, are at greater risk of developing complications of the vasculature than non-diabetic patients. Macrovascular complications such as diabetes-associated atherosclerosis lead to accelerated and often more advanced lesions than seen in the general population. Microvascular complications such as nephropathy, retinopathy and neuropathy as well as diabetic cardiomyopathy are further complications associated with the diabetic milieu. Understanding the mechanisms leading to and accelerating these complications is a major research initiative of many laboratories. To facilitate these studies, the design and use of appropriate animal models has been central to the study of these diabetic complications. A new and emerging concept underpinning many of these end-organ complications is oxidative stress, particularly of mitochondrial origin, which is understood to play a critical role in the initiation and progression of these diabetic complications. Thus the development of experimental models that specifically delineate the cause and role of ROS in diabetic complications is now becoming a major research area. This chapter focuses on some of the latest oxidative stress-driven experimental models of diabetic complications. Use of the ApoE/GPx1 double-knockout mouse has revealed the importance of antioxidant defense in limiting accelerated diabetes-associated atherosclerosis and diabetic nephropathy, while RAGE knockout mice have shown that oxidative stress is inextricably linked with pathophysiological cell signaling, particularly through RAGE. The use of NOX knockout mice is shedding light on the contribution of the NADPH oxidases to the ROS milieu as well as the contribution of the various isoforms (NOX 1, 2 and 4) to the individual diabetic complications. Furthermore, these models are helping to understand the types of ROS involved and their cellular location, which may help in the specific targeting of these ROS to reduce ROS-mediated pathogenesis. For example, antioxidants that target mitochondrial ROS (location) or ROS such as hydrogen peroxide (specificity) may offer an alternate approach to reduce diabetes-driven oxidative stress. It is only via manipulation of experimental models of diabetes-driven oxidative stress that the contribution of the various ROS will be revealed, and only then that effective treatment regimens can be designed to lessen the effect of oxidative stress on diabetic complications.


Antioxidant defense Diabetic complications Ebselen Experimental models Glutathione peroxidase Oxidative stress 



T.J.A. and K.J-D. are supported by an Australian National Health and Medical Research Council (NH&MRC) Senior Research Fellowship. All three authors acknowledge support from the Australian NH&MRC and the Australian National Heart Foundation.


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Judy B. de Haan
  • Karin A. Jandeleit-Dahm
  • Terri J. Allen
    • 1
    Email author
  1. 1.Diabetic Complications Laboratory, JDRF Diabetes DivisionBaker IDI Heart and Diabetes InstituteMelbourneAustralia

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