Are Oxidative Stress-Activated Signaling Pathways Mediators of Insulin Resistance and Beta-Cell Dysfunction?

Joseph L. Evans, Ira D. Goldfine, Betty A. Maddux, Gerold M. Grodsky

Disclosures

Diabetes. 2003;52(1) 

In This Article

Abstract and Introduction

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- B, p38 mitogen-activated protein kinase, NH2-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.

Both type 1 and type 2 diabetes possess a significant genetic component[1,2,3]. In the case of type 2 diabetes, additional environmental factors, including hormones, increased caloric intake, decreased physical inactivity, and adiposity[1,2], have a marked influence on the disease. Now there is evidence that elevated levels of metabolic substrates contribute to the diabetic phenotype.

There are considerable amounts of data indicating that the chronic elevation of plasma glucose causes many of the major complications of diabetes, including nephropathy, retinopathy, neuropathy, and macro- and microvascular damage[1,4]. A causative role for elevated free fatty acid (FFA) levels in the development of microvascular complications remains to be established, however. Increased levels of FFAs are positively correlated with both insulin resistance[5,6] and the deterioration of ß-cell function in the context of concomitant hyperglycemia[7,8]. These latter effects may result from oxidative stress.

There is evidence that oxidative stress, defined as a persistent imbalance between the production of highly reactive molecular species (chiefly oxygen and nitrogen) and antioxidant defenses, leads to tissue damage[9]. Oxidative stress results from increased content of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). Examples of ROS include charged species such as superoxide and the hydroxyl radical, and uncharged species such as hydrogen peroxide[9]. There are data indicating that ROS formation is a direct consequence of hyperglycemia[10]; more recent studies have suggested that increased FFA levels may also result in ROS formation (see below).

Because of their ability to directly oxidize and damage DNA, protein, and lipid, ROS are believed to play a key direct role in the pathogenesis of late diabetic complications[9,11]. In addition to their ability to directly inflict macromolecular damage, ROS can function as signaling molecules to activate a number of cellular stress-sensitive pathways that cause cellular damage, and are ultimately responsible for the late complications of diabetes. Furthermore, these same pathways are linked to insulin resistance and decreased insulin secretion. In this review, we propose that ROS and oxidative stress induced by elevations in glucose and possibly FFA levels play a key role in causing insulin resistance and ß-cell dysfunction by their ability to activate stress-sensitive signaling pathways (Fig. 1).

Figure 1.

Proposed general theory of how elevated glucose and possibly FFA levels contribute to the pathophysiology of diabetes via the generation of ROS and consequent activation of numerous stress-sensitive pathways. The causative link among hyperglycemia, mitochondrial ROS generation, oxidative stress, and the development of diabetic complications has been previously suggested[10,11,22]. ROS (and RNS), by inflicting macromolecular damage, may play a key direct role in the pathogenesis of diabetes. ROS also function as signaling molecules (analogous to second messengers) to activate several stress-sensitive pathways (indirect role). In addition, in type 2 diabetes, there is growing evidence that activation of stress-sensitive pathways, such as NF-kB, p38 MAPK, JNK/SAPK, and hexosamine, by elevations in glucose and possibly FFA levels leads to both insulin resistance and impaired insulin secretion. Thus ROS and oxidative stress, induced by elevations in glucose and possibly FFA levels, may play a key role in causing insulin resistance and ß-cell dysfunction by their ability to activate stress-sensitive signaling pathways. The proposed sequence of events may also include other stress pathways, such as the increased production of AGE, sorbitol, cytokines, and prostanoids along with PKC activation. DAG, diacylglycerol.

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