Review Article
Oxidative stress and the etiology of insulin resistance and type 2 diabetes

https://doi.org/10.1016/j.freeradbiomed.2010.12.005Get rights and content

Abstract

The condition of oxidative stress arises when oxidant production exceeds antioxidant activity in cells and plasma. The overabundance of oxidants is mechanistically connected to the multifactorial etiology of insulin resistance, primarily in skeletal muscle tissue, and the subsequent development of type 2 diabetes. Two important mechanisms for this oxidant excess are (1) the mitochondrial overproduction of hydrogen peroxide and superoxide ion under conditions of energy surplus and (2) the enhanced activation of cellular NADPH oxidase via angiotensin II receptors. Several recent studies are reviewed that support the concept that direct exposure of mammalian skeletal muscle to an oxidant stress (including hydrogen peroxide) results in stimulation of the serine kinase p38 mitogen-activated protein kinase (p38 MAPK), and that the engagement of this stress-activated p38 MAPK signaling is mechanistically associated with diminished insulin-dependent stimulation of insulin signaling elements and glucose transport activity. The beneficial interactions between the antioxidant α-lipoic acid and the advanced glycation end-product inhibitor pyridoxamine that ameliorate oxidant stress-associated defects in whole-body and skeletal-muscle insulin action in the obese Zucker rat, a model of prediabetes, are also addressed. Overall, this review highlights the importance of oxidative stress in the development of insulin resistance in mammalian skeletal muscle tissue, at least in part via a p38-MAPK-dependent mechanism, and indicates that interventions that reduce this oxidative stress and oxidative damage can improve insulin action in insulin-resistant animal models. Strategies to prevent and ameliorate oxidative stress remain important in the overall treatment of insulin resistance and type 2 diabetes.

Introduction

The long-term maintenance of blood glucose levels within a normal range is a key physiological function in mammalian species. One criterion for normal glucose homeostasis in humans is the maintenance of blood glucose levels below 100 mg/dl after an overnight fast. If fasting blood glucose rises above 100 mg/dl, but does not surpass 126 mg/dl, these individual are considered to be “prediabetic.” Moreover, if glucoregulation deteriorates further, and fasting blood glucose exceeds 126 mg/dl, these individuals can be diagnosed with frank diabetes [1]. The vast majority (90–95%) of diabetic cases are classified as type 2 diabetes, a condition characterized by both reduced action of the hormone insulin in activating the glucose transport system in skeletal muscle (referred to as “insulin resistance”) and an inadequate compensatory hyperinsulinemia to overcome this insulin resistance [1]. This insulin resistance in skeletal muscle is a critical, early defect leading to the initial development of impaired glucose tolerance (reduced ability to dispose of an oral glucose load) in prediabetes and subsequently to the conversion from prediabetes to overt type 2 diabetes. Therefore, insulin resistance is a common metabolic impairment affecting individuals with either prediabetes (> 57 million people in the United States) or overt type 2 diabetes, estimated to afflict ~ 24 million Americans and increasing [2].

The foregoing observations underscore the need for understanding how normal glucose homeostasis is achieved in humans and what specific defects can lead to impairments in the cellular and systemic mechanisms required for this homeostatic process. In this context, this review briefly covers how insulin action at the level of skeletal muscle contributes to the maintenance of normal blood glucose levels and subsequently focuses on the role of one important factor, oxidative stress, involved in the multifactorial etiology of insulin resistance of glucose transport activity in skeletal muscle. The discussion of oxidative stress in this review is limited to a few selected cellular factors engaged by oxidants (including glycogen synthase kinase-3β (GSK-3β)1 and p38 mitogen-activated protein kinase (p38 MAPK)) or that themselves are involved in the production of oxidants (angiotensin II (ANG II)) and are mechanistically linked to the development of insulin resistance in skeletal muscle.

Section snippets

Brief overview of normal glucoregulation in mammalian species

Systemic glucose homeostasis is achieved by the coordinated functions of several organ systems, including skeletal muscle, the liver, the endocrine pancreas, adipose tissue, and specific hypothalamic neurons [3]. The liver contributes to glucoregulation primarily via appropriate alterations in hepatic glucose production. The adipose tissue is a site of insulin-dependent glucose disposal and also acts as an endocrine organ releasing adipokines. The pancreatic α- and β-cells are the sites of the

Select mechanisms for overproduction of oxidants: mitochondrial dysfunction and overactivation of NADPH oxidase

Oxidative stress develops from an imbalance between oxidant production and antioxidant activity in cells and in the plasma. This overabundance of oxidants is associated with the multifactorial etiology of insulin resistance, primarily in skeletal muscle tissue [14], [15], [16], [17], [18]. Correlative evidence in humans indicates an association between plasma markers of oxidative stress and damage and the degree of insulin resistance [19], [20]. Although many possible cellular sites exist for

In vitro oxidant production: experimental approach to investigating oxidant-induced insulin resistance

Over the past 5 years, we have utilized an in vitro approach, based on previous studies in cultured 3T3L1 adipocytes [34], [35] and L6 myotubes [36], to investigate the potential cellular mechanisms underlying the deleterious effects of the oxidant H2O2 on insulin signaling and glucose transport activity in mammalian skeletal muscle. This approach involves preparation of rat soleus muscle into strips that are suitable for in vitro incubations [37]. Subsequently, the enzyme glucose oxidase is

Role of oxidative stress in diabetic complications

In addition to its documented contributions to the etiology of insulin resistance and type 2 diabetes, oxidative stress has been implicated in the development of diabetic complications, including diabetic retinopathy, nephropathy, peripheral neuropathy, and cardiovascular disease. Specific cell types, including endothelial cells, in tissues susceptible to diabetic complications are unable to regulate intracellular glucose levels [80], and hyperglycemia-induced overproduction of superoxide by

Conclusions and perspectives

The results reviewed herein support the contribution of oxidative stress to the multifactorial etiology of insulin resistance in the whole body and specifically to the insulin-dependent glucose transport system in skeletal muscle. An overall mechanism for this oxidant-associated deterioration of insulin action in skeletal muscle is depicted in Fig. 1. In this schema, oxidant overproduction can ensue from either enhanced engagement of NADPH oxidase through an AT1R-mediated event or excessive

Acknowledgments

The work of the authors cited in this article was supported in part by Grants DK063967 and T32 HL07249 from the National Institutes of Health and a grant from BASF AG (Ludwigshafen, Germany).

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