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Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction?
Joseph L Evans1, Ira D Goldfine, Betty A Maddux
1Medical Research Institute, San Francisco, California. University of California at San Francisco, San Francisco, California 94107, USA. jevansphd@earthlink.net
Abstract:
In both type 1 and type 2 diabetes, diabetic complications in target organs arise from chronic elevations of glucose. The pathogenic effect of high glucose, possibly in concert with fatty acids, is mediated to a significant extent via increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent oxidative stress. ROS and RNS directly oxidize and damage DNA, proteins, and lipids. In addition to their ability to directly inflict damage on macromolecules, ROS and RNS indirectly induce damage to tissues by activating a number of cellular stress-sensitive pathways. These pathways include nuclear factor-kappaB, p38 mitogen-activated protein kinase, NH(2)-terminal Jun kinases/stress-activated protein kinases, hexosamines, and others. In addition, there is evidence that in type 2 diabetes, the activation of these same pathways by elevations in glucose and free fatty acid (FFA) levels leads to both insulin resistance and impaired insulin secretion. Therefore, we propose here that the hyperglycemia-induced, and possibly FFA-induced, activation of stress pathways plays a key role in the development of not only the late complications in type 1 and type 2 diabetes, but also the insulin resistance and impaired insulin secretion seen in type 2 diabetes.
Insights
High glucose and fatty acids cause diabetic complications by increasing reactive oxygen species (ROS) and reactive nitrogen species (RNS). These activate stress pathways, leading to organ damage and insulin resistance in diabetes.
Area of Science:
- Biochemistry
- Cellular Biology
- Endocrinology
Background:
- Chronic hyperglycemia in diabetes mellitus (type 1 and type 2) leads to target organ complications.
- Elevated glucose and fatty acids contribute to oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS).
Purpose of the Study:
- To investigate the role of hyperglycemia- and free fatty acid (FFA)-induced stress pathway activation in diabetic complications.
- To explore the contribution of these pathways to insulin resistance and impaired insulin secretion in type 2 diabetes.
Main Methods:
- The study proposes a mechanism involving ROS/RNS generation and activation of stress-sensitive pathways.
- Key pathways discussed include nuclear factor-kappaB, p38 MAPK, JNK/SAPK, and hexosamine pathways.
Main Results:
- ROS and RNS directly damage DNA, proteins, and lipids.
- These reactive species also indirectly induce tissue damage by activating cellular stress pathways.
- Evidence suggests these pathways contribute to insulin resistance and impaired insulin secretion in type 2 diabetes.
Conclusions:
- Hyperglycemia-induced activation of stress pathways is crucial for diabetic complications in both type 1 and type 2 diabetes.
- FFA-induced activation of these pathways may also contribute to diabetic complications.
- These stress pathways are implicated in both the late-stage complications and metabolic dysfunction (insulin resistance/secretion) of type 2 diabetes.