Serial Review: The Role of Oxidative Stress in Diabetes mellitus
Exercise training and the antioxidant α-lipoic acid in the treatment of insulin resistance and type 2 diabetes

https://doi.org/10.1016/j.freeradbiomed.2005.04.002Get rights and content

Abstract

One hallmark of the insulin-resistant state of prediabetes and overt type 2 diabetes is an impaired ability of insulin to activate glucose transport in skeletal muscle, due to defects in IRS-1-dependent signaling. An emerging body of evidence indicates that one potential factor in the multifactorial etiology of skeletal muscle insulin resistance is oxidative stress, an imbalance between the cellular exposure to an oxidant stress and the cellular antioxidant defenses. Exposure of skeletal muscle to an oxidant stress leads to impaired insulin signaling and subsequently to reduced glucose transport activity. Numerous studies have demonstrated that treatment of insulin-resistant animals and type 2 diabetic humans with antioxidants, including α-lipoic acid (ALA), is associated with improvements in skeletal muscle glucose transport activity and whole-body glucose tolerance. An additional intervention that is effective in ameliorating the skeletal muscle insulin resistance of prediabetes and type 2 diabetes is endurance exercise training. Recent investigations have demonstrated that the combination of exercise training and antioxidant treatment using ALA in an animal model of obesity-associated insulin resistance provides a unique interactive effect resulting in a greater improvement in insulin action on skeletal muscle glucose transport than either intervention individually. Moreover, this interactive effect of exercise training and ALA is due in part to improvements in IRS-1-dependent insulin signaling. These studies highlight the effectiveness of combining endurance exercise training and antioxidants in beneficially modulating the molecular defects in insulin action observed in insulin-resistant skeletal muscle.

Introduction

The long-term maintenance of plasma glucose concentrations under a variety of nutritional conditions and energetic demands is one of the most important and closely regulated processes in mammalian species. Whole-body glucose homeostasis is the product of input from three primary tissues: the liver, skeletal muscle, and β-cells of the pancreas. The liver functions as the primary source of endogenous glucose production in the body under conditions of increased peripheral glucose demand through the breakdown of glycogen stores (glycogenolysis) and the synthesis of new glucose (gluconeogenesis) from a variety of precursor molecules. The liver can also take up glucose from the circulation and store the glucose carbons as glycogen (glycogenesis). However, the most important site of glucose uptake is skeletal muscle, which makes up ∼40% of body mass in mammalian species. It is widely accepted that, following an oral or intravenous glucose load or in response to an acute exercise bout, skeletal muscle is a major site of glucose disposal [1], though evidence to the contrary has been published [2]. The most important hormone responsible for the stimulation of skeletal muscle glucose transport and metabolism is insulin, which is secreted by the pancreatic β-cells in response to appropriate stimuli. In addition, the muscle contractions associated with exercise have a powerful effect on the glucose transport process [3].

Important advances in our understanding of the molecular regulation by insulin and contractions of the glucose transport system in muscle have been made over the past two decades. In addition, it is clear that defects in this molecular regulation of glucose transport by insulin are a primary characteristic of insulin-resistant states, including prediabetes and overt type 2 diabetes [4]. An accumulating body of evidence indicates that one potential factor contributing to the multifactorial etiology of insulin resistance is oxidative stress, and that exercise training and antioxidant therapies can be effective interventions in treating insulin resistance associated with this oxidative stress [5], [6]. This review will briefly summarize our current understanding of the molecular defects associated with skeletal muscle insulin resistance, especially in the context of a state of oxidative stress. Moreover, this review will briefly cover current information on how exercise training and antioxidant therapy, both individually and in combination, can improve insulin action in insulin-resistant states.

Section snippets

Regulation of glucose transport activity in skeletal muscle

Glucose transport activity in skeletal muscle is acutely regulated by insulin through the activation of a series of intracellular proteins (for reviews, see Refs. [4], [7]). In brief, insulin binding enhances the tyrosine kinase activity of the insulin receptor (IR)1 β-subunits, and this activated IR then phosphorylates IR substrates (IRS; primarily IRS-1 in skeletal muscle) at conserved pYXXM sequences on tyrosine residues. Tyrosine-phosphorylated IRS-1 can interact with the SH2 domains of the

Role of oxidative stress in the etiology of insulin resistance

Oxidative stress-the imbalance between the cellular production of oxidants and the antioxidant defenses within cells-can play an important role in the multifactorial etiology of skeletal muscle insulin resistance (reviewed in Refs. [5], [6], [51], [52]). For example, plasma levels of hydroperoxides, one marker of oxidative stress, are higher in subjects with type 2 diabetic compared to nondiabetic controls and are inversely correlated with the degree of metabolic control [53]. More definitive

Interventions for improvement of insulin action in insulin-resistant states

Because of the critical role of skeletal muscle insulin resistance in the context of the “insulin resistance syndrome” and in the development of type 2 diabetes, interventions that can enhance insulin action in skeletal muscle are important components of treatment strategies in these insulin-resistant states. Effective nonpharmacological interventions include exercise training, especially endurance activities involving running, biking, or swimming, and specific dietary modifications leading to

Summary and perspectives

The interaction between exercise training and antioxidant treatment with R-ALA on the glucose transport system in insulin-resistant skeletal of the obese Zucker rat [36], [64] is summarized schematically in Fig. 1. In this figure, the number of down arrows reflects the magnitude of defects in these insulin-regulatable processes in muscle of obese Zucker rats compared to lean Zucker rats. Relative to skeletal muscle from the insulin-sensitive lean Zucker rat, this insulin-resistant obese

Acknowledgments

The work of the author cited in this article was supported in part by grants from the Pacific Mountain Affiliate of the American Heart Association and Viatris GmbH, Frankfurt, Germany.

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