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Nrf2 and Antioxidant Response in Animal Models of Type 2 Diabetes
1Division of Metabolism, Endocrinology and Nutrition, Department of Internal Medicine, University of Washington, Seattle, WA 98105, USA.
Abstract:
This perspective examines the proposition that chronically elevated blood glucose levels caused by type 2 diabetes (T2D) harm body tissues by locally generating reactive oxygen species (ROS). A feed-forward scenario is described in which the initial onset of defective beta cell function T2D becomes sustained and causes chronic elevations in blood glucose, which flood metabolic pathways throughout the body, giving rise to abnormally high local levels of ROS. Most cells can defend themselves via a full complement of antioxidant enzymes that are activated by ROS. However, the beta cell itself does not contain catalase or glutathione peroxidases and thereby runs a greater risk of ROS-induced damage. In this review, previously published experiments are revisited to examine the concept that chronic hyperglycemia can lead to oxidative stress in the beta cell, how this relates to the absence of beta cell glutathione peroxidase (GPx) activity, and whether this deficiency might be ameliorated by genetic enrichment of beta cell GPx and by oral antioxidants, including ebselen, a GPx mimetic.
Insights
Type 2 diabetes (T2D) causes high blood glucose, leading to reactive oxygen species (ROS) that damage tissues. Beta cells lack antioxidants, increasing vulnerability to ROS, but genetic and oral antioxidant therapies may help.
Area of Science:
- Endocrinology
- Molecular Biology
- Biochemistry
Background:
- Type 2 diabetes (T2D) is characterized by chronically elevated blood glucose (hyperglycemia).
- Hyperglycemia can lead to increased production of reactive oxygen species (ROS), causing cellular damage.
- Beta cells, crucial for insulin production, are particularly vulnerable to ROS due to a limited antioxidant defense system.
Approach:
- This perspective reviews existing experimental data on T2D, hyperglycemia, and oxidative stress.
- It examines the specific role of glutathione peroxidase (GPx) deficiency in beta cell damage.
- The potential of therapeutic interventions, including genetic enrichment of beta cell GPx and oral antioxidants like ebselen, is explored.
Key Points:
- Chronic hyperglycemia in T2D promotes ROS generation, leading to oxidative stress.
- Beta cells lack key antioxidant enzymes like catalase and glutathione peroxidases, making them susceptible to ROS-induced damage.
- The absence of GPx activity in beta cells is a critical factor in T2D-related beta cell dysfunction.
Conclusions:
- Targeting ROS and enhancing antioxidant defenses in beta cells may offer a therapeutic strategy for T2D.
- Genetic augmentation of beta cell GPx or administration of GPx mimetics like ebselen could protect against hyperglycemia-induced oxidative stress.
- Further research is warranted to validate these approaches for T2D management.
