Oxidative stress and impaired insulin secretion in type 2 diabetes

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Molecular mechanisms involving oxidative stress have been increasingly implicated in the pathogenesis of type 2 diabetes. These implications have arisen from reports that glucolipotoxicity of the pancreatic islet and non-islet tissues can lead to deterioration of islet function and insulin sensitivity, as well as structural abnormalities in tissues adversely affected by diabetes. Co-incident with these changes are profound alterations in insulin gene expression, which involve greatly diminished levels of two transcription factors, MafA and Pdx-1.

Introduction

This brief review provides a short historical retrospective on the concept that oxidative stress might adversely affect pancreatic islet function and insulin action, and focuses more intensely on recent studies suggesting molecular mechanisms by which excessive concentrations of reactive oxygen species (ROS) can cause pancreatic islet β cell dysfunction and impair insulin action. The rationale for examining oxidative stress in diabetes stems from the large number of reports documenting excess levels of biochemical markers in the blood, urine and pancreas of type 2 diabetic patients. The importance of a better understanding of these phenomena lies in the possibility that ancillary antioxidant therapy in such patients could provide a layer of protection against incomplete normalization of glycemia by conventional drugs, such as sulfonylureas, insulin sensitizers and exogenous insulin.

Section snippets

Pathogenesis of type 2 diabetes: β cell dysfunction and insulin resistance

Type 2 diabetes is usually the product of two distinct abnormalities: abnormal β cell function and decreased insulin sensitivity. It appears that type 2 diabetes is primarily a genetic disease, based on its strong familial association and high concordance rates in identical twins [1]. However, no single gene has been identified that is common to a general population of type 2 diabetic patients, leading to the conclusion that this must be a polygenic disease [2, 3, 4]. Most type 2 diabetic

Reactive oxygen species: physiology versus stress

Many forms of ROS exist, which in physiologic concentrations are thought to support physiologic functions such as gene transcription, mitochondrial function and leukocyte function. However, when concentrations of ROS reach excessive levels, they can cause structural and functional damage to proteins, lipids and DNA. With regard to the pancreatic islet, reports from studies of rodent islets have emphasized the low levels of intrinsic antioxidant enzyme mRNA, proteins and activities for

Glucolipotoxicity in the β cell and oxidative stress

The common findings of elevated glucose and lipid levels in the blood of diabetic patients led to the hypotheses of glucose toxicity [13] and lipotoxicity [14]. Relatively more information has been published about biochemical pathways through which elevated glucose concentrations can generate excessive levels of ROS (reviewed in [15]). These include glycolysis and oxidative phosphorylation; methylglyoxal formation and glycation; enediol and α-ketoaldehyde formation (glucoxidation);

Glucolipotoxicity in non-β cells, insulin resistance and oxidative stress

As this is a short review that centers primarily on the islet and the number of references is limited, only brief mention can be given to well-developed research areas involving interplay among oxidative stress, insulin resistance and the secondary complications of diabetes. Insulin resistance accompanies the development of obesity, pregnancy, excess growth hormone and glucocorticoid levels, and lack of exercise. Although clinical and laboratory methods for quantifying insulin resistance are

Antioxidant therapy and the islet

Mention has already been made of several antioxidants that have been used in clinical studies which protected against β cell dysfunction and insulin resistance associated with type 2 diabetes. A careful distinction must be made, however, between prevention of the disease and protection against its complications. There is little, if any, evidence that oxidative stress causes type 2 diabetes, which appears to be primarily a polygenic disease involving intrinsic defects in islet function. Rather,

Conclusions

Although ROS in small concentrations support physiologic functions, at abnormally high concentrations they cause both biochemical abnormalities and structural damage to tissue. Chronic hyperglycemia increases local concentrations of ROS, and thereby induces chronic oxidative stress. This sequence of events provides one explanation for many of the secondary complications of hyperglycemia, including ever-worsening abnormalities in the pancreatic β cell in type 2 diabetes. Other important defects

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Supported in part by NIH grant NIDDK RO-1 38325.

References (29)

  • N. Welsh et al.

    Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus

    Mol Med

    (1995)
  • N.T. Friesen et al.

    Generation of hydrogen peroxide and failure of antioxidative responses in pancreatic islets of male C57BL/6 mice are associated with diabetes induced by multiple low doses of streptozotocin

    Diabetologia

    (2004)
  • A.M. Roza et al.

    Pancreatic antioxidant enzyme activity in normoglycemic diabetic prone BB rats

    Pancreas

    (1995)
  • C. Le May et al.

    Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice

    Proc Natl Acad Sci USA

    (2006)
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