Oxidative stress, insulin signaling, and diabetes

doi:10.1016/j.freeradbiomed.2010.12.006

Free Radical Biology and Medicine

Volume 50, Issue 5, 1 March 2011, Pages 567-575

https://doi.org/10.1016/j.freeradbiomed.2010.12.006 Get rights and content

Abstract

Oxidative stress has been implicated as a contributor to both the onset and the progression of diabetes and its associated complications. Some of the consequences of an oxidative environment are the development of insulin resistance, β-cell dysfunction, impaired glucose tolerance, and mitochondrial dysfunction, which can lead ultimately to the diabetic disease state. Experimental and clinical data suggest an inverse association between insulin sensitivity and ROS levels. Oxidative stress can arise from a number of different sources, whether disease state or lifestyle, including episodes of ketosis, sleep restriction, and excessive nutrient intake. Oxidative stress activates a series of stress pathways involving a family of serine/threonine kinases, which in turn have a negative effect on insulin signaling. More experimental evidence is needed to pinpoint the mechanisms contributing to insulin resistance in both type 1 diabetics and nondiabetic individuals. Oxidative stress can be reduced by controlling hyperglycemia and calorie intake. Overall, this review outlines various mechanisms that lead to the development of oxidative stress. Intervention and therapy that alter or disrupt these mechanisms may serve to reduce the risk of insulin resistance and the development of diabetes.

Introduction

Diabetes is a complex metabolic disorder characterized by defects in the body's ability to control glucose and insulin homeostasis. Diabetes has become an epidemic and remains a major public health issue. In 2007, it was estimated that 23.6 million American people (7.8% of the U.S. population) had diabetes [1] and that diabetes would affect 210 million people worldwide by 2010 [2]. These numbers are expected to increase by 50% over the next 20 years, posing a tremendous economic burden on individuals and health care systems worldwide [2]. The total annual economic cost of diabetes in the United States in 2007 was estimated to be $174 billion [1]. With the rising cost and escalating incidence of diabetes, it is increasingly important to understand the mechanisms that lead to the disease. Diabetes is divided into two main types, type 1 and type 2. Type 1 diabetes occurs when the body stops making or makes only a tiny amount of insulin, whereas type 2 diabetes occurs when the body does not make enough or has trouble using the insulin. Type 1 diabetes has been linked mostly to genetics and the production of autoantibodies that destroy pancreatic β-cells [3]. Type 2 diabetes results primarily from insulin resistance and has been linked to factors such as obesity and age. Type 2 diabetes accounts for more than 90% of individuals diagnosed with diabetes [4].

Oxidative stress is thought to be a major risk factor in the onset and progression of diabetes. Many of the common risk factors, such as obesity, increased age, and unhealthy eating habits, all contribute to an oxidative environment that may alter insulin sensitivity either by increasing insulin resistance or impairing glucose tolerance. The mechanisms by which this occurs are often multifactorial and quite complex, involving many cell signaling pathways. A common result of both types of diabetes is hyperglycemia, which in turn contributes to the progression and maintenance of an overall oxidative environment. Macro- and microvascular complications are the leading cause of morbidity and mortality in diabetic patients, but the complications are tissue specific and result from similar mechanisms [5], with many being linked to oxidative stress. There is a large body of clinical evidence correlating diabetic complications with hyperglycemic levels and length of exposure to hyperglycemia [6]. This review discusses the current understanding of insulin signaling and the role of oxidative stress in the insulin signaling process. It also focuses on the many risk factors that alter insulin sensitivity through mechanisms linked to oxidative stress and potentially lead to insulin resistance and diabetes.

Section snippets

Insulin and normal insulin signaling

Insulin is a key hormone with an important role in the growth and development of tissues and the control of glucose homeostasis [7]. Insulin is secreted by pancreatic β-cells as an inactive single-chain precursor, preproinsulin, with a signal sequence that directs its passage into secretory vesicles. Proteolytic removal of this signal sequence results in the formation of proinsulin. In response to an increase in blood glucose or amino acid concentration, proinsulin is secreted and converted

Reactive oxygen species and redox state

Reactive oxygen species (ROS) and the cellular redox state are increasingly thought to be responsible for affecting different biological signaling pathways. ROS are formed from the reduction of molecular oxygen or by oxidation of water to yield products such as superoxide anion (O₂^•−), hydrogen peroxide (H₂O₂), and hydroxyl radical (^•OH). In a biological system, the mitochondria and NAD(PH) oxidase are the major sources of ROS production [15]. In moderate amounts, ROS are involved in a number

Hyperglycemia, oxidative stress, and diabetes

In the current literature there are numerous studies indicating that diabetic subjects tend to have more oxidative internal environments than healthy normal subjects [11], [24], [25]. From these studies it is clear that diabetic subjects show an increase in ROS generation and oxidative stress markers, with an accompanying decrease in antioxidant levels. Hyperglycemia can cause an increase in oxidative stress markers such as membrane lipid peroxidation. The degree of lipid peroxidation in

The influence of oxidative stress on insulin signaling

ROS and RNIs have been shown to affect the insulin signaling cascade; however, the disruption seems to be dose and time dependent. Millimolar ROS concentrations have been shown to play a physiological role in insulin signaling via an NAD(P)H oxidase-dependent mechanism. Upon insulin stimulation there is a burst of H₂O₂ production, creating a short-term and low-dose exposure to ROS. This enhances the insulin cascade by inhibiting tyrosine phosphatase activity, leading to an increase in the basal

Mitochondrial dysfunction and insulin signaling

Mitochondria are the main power supply for our cells and play a central role in cell life and death [50], [51]. They provide energy for almost all cellular processes, from muscle contraction to maintenance of ionic gradients for vesicle fusion, and the cycling necessary for secretion of hormones and neurotransmitters. The mitochondria also play an important role in how β cells release insulin in response to glucose levels and the sensing of oxygen tension in the carotid body and pulmonary

Ketosis and oxidative stress and insulin signaling

Ketosis is a state characterized by elevated serum levels of ketone bodies. In addition to hyperglycemia, type 1 diabetics frequently experience ketosis due to insulin deficiency. This condition is more common and severe in patients with type 1 versus type 2 diabetes, but it may exacerbate insulin resistance in type 2 diabetes. Several markers of vascular inflammation have been shown to be influenced by the presence of ketosis. It has been reported that acetoacetate, but not β-hydroxybutyrate,

Insulin sensitivity and nutrient availability

Both obesity and excessive intake of nutrients have long been risk factors for a variety of adverse health outcomes, such as high blood pressure, insulin resistance, oxidative stress, and type 2 diabetes. Furthermore, studies have shown that calorie overload in rodents results in rapidly induced skeletal muscle and liver insulin resistance, whereas calorie restriction enhances skeletal muscle, liver, and insulin sensitivity [72]. Several key modulators are thought to act as sensors to excessive

PTEN and insulin sensitivity

PTEN is a phosphoinositide phosphatase that regulates the PI3K/Akt signaling pathway. It was originally identified as a tumor suppressor gene and later determined to act as a negative regulator of the insulin signaling pathway [76], [77], [78]. Overexpression of PTEN in 3T3-L1 adipocytes results in inhibition of insulin-induced PtdIns(3,4)P₂ and PtdIns(3,4,5)P₃ production, Akt/PKB activation, GLUT4 translocation to the cell membrane, and glucose uptake [79], [80]. In contrast, attenuation of

Sleep restriction and insulin sensitivity

Sleep plays a vital role in the normal homeostasis of glucose metabolism and insulin sensitivity and sleep loss is now considered a novel risk factor for insulin resistance and type 2 diabetes. Sleep loss, whether voluntary or disease related, affects millions of individuals in our modern society. Over the past few decades, the average sleep duration of Americans has decreased by 1.5 to 2 hours [84]. Interestingly, the trends in increased obesity and diabetes seem to mirror the time period for

Therapy

Antioxidant therapy has been of great interest as a way to combat oxidative stress in diabetic patients over the past decade. Although a very logical approach, it may take more than simple dosing with an antioxidant. Classical antioxidants such as vitamins E and C do not always seem to be helpful among all diabetic patients [99]. Recent reports now show that patients with type 2 diabetes mellitus and the haptoglobin (Hp) 2-2 genotype benefit from vitamin E supplementation [100], [101]. The main

Conclusion

Oxidative stress seems to be an underlying cause of many diseases, in particular diabetes. Oxidative stress has been implicated as a contributor to both the onset and the progression of diabetes. Some of the consequences of an oxidative environment are development of insulin resistance, β-cell dysfunction, impaired glucose tolerance, and mitochondrial dysfunction, which can lead ultimately to the diabetic disease state. Experimental and clinical data suggest an inverse association between

Acknowledgments

The authors are supported by grants from the NIDDK and the Office of Dietary Supplements of the National Institutes of Health (RO1 DK072433) and the Malcolm Feist Endowed Chair in Diabetes. The authors thank Ms. Georgia Morgan for excellent editing of the manuscript.

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ReviewsOxidative stress, insulin signaling, and diabetes

Abstract

Introduction

Section snippets

Insulin and normal insulin signaling

Reactive oxygen species and redox state

Hyperglycemia, oxidative stress, and diabetes

The influence of oxidative stress on insulin signaling

Mitochondrial dysfunction and insulin signaling

Ketosis and oxidative stress and insulin signaling

Insulin sensitivity and nutrient availability

PTEN and insulin sensitivity

Sleep restriction and insulin sensitivity

Therapy

Conclusion

Acknowledgments

Best Pract. Res. Clin. Endocrinol. Metab.

J. Biol. Chem.

Int. J. Biochem. Cell Biol.

Metabolism

Free Radic. Biol. Med.

Free Radic. Biol. Med.

J. Theor. Biol.

Free Radic. Biol. Med.

Clin. Biochem.

J. Biol. Chem.

Metabolism

Free Radic. Biol. Med.

Metabolism

Free Radic. Biol. Med.

Int. J. Biochem. Cell Biol.

FEBS Lett.

Cell Metab.

Exp. Mol. Pathol.

Trends Endocrinol. Metab.

Free Radic. Biol. Med.

Ann. Hepatol.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Am. Coll. Cardiol.

Lancet

Domest. Anim. Endocrinol.

National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007

Diabetes e-Atlas

The genetic basis for type 1 diabetes

Br. Med. Bull.

Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia

Int. J. Clin. Pract.

Molecular targets of diabetic cardiovascular complications

Curr. Drug Targets

The Diabetes Control and Complications Trial—implications for policy and practice

N. Engl. J. Med.

Modulation of insulin action

Diabetologia

Regulation of insulin gene transcription

Diabetologia

Role of binding proteins to IRS-1 in insulin signalling

Mol. Cell. Biochem.

Proposed mechanisms for the induction of insulin resistance by oxidative stress

Antioxid. Redox Signaling

Insulin signalling and the regulation of glucose and lipid metabolism

Nature

Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1

Mol. Cell. Biol.

Redox-mediated bypass of restriction point via skipping of G1pm

Theor. Biol. Med. Model.

Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction?

Diabetes

Erythrocyte membrane lipid peroxidation and glycosylated hemoglobin in diabetes

Diabetes

Biochemistry and molecular cell biology of diabetic complications

Nature

Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options

Endocr. Rev.

Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes

Cardiovasc. Res.

TAGE (toxic AGEs) theory in diabetic complications

Curr. Mol. Med.

alpha-Tocopherol decreases superoxide anion release in human monocytes under hyperglycemic conditions via inhibition of protein kinase C-alpha

Reviews
Oxidative stress, insulin signaling, and diabetes