Oxidative stress and impaired insulin secretion in type 2 diabetes
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.
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