Serial Review: The role of oxidative stress in diabetes Serial Review Editor: Phyllis Dennery
Diabetes, glucose toxicity, and oxidative stress: A case of double jeopardy for the pancreatic islet β cell

https://doi.org/10.1016/j.freeradbiomed.2005.04.030Get rights and content

Abstract

Diabetes is commonly referred to in terms of type 1 and type 2. Both forms involve pancreatic islet β-cell abnormalities, characterized by death in type 1 and accelerated apoptosis in type 2. The resultant chronic hyperglycemia leads to chronic oxidative stress for all tissues because glucose in abnormally high concentrations forms reactive oxygen species. It has been repeatedly emphasized that this can lead to oxidative damage in the classical secondary targets of diabetes, such as eyes, kidneys, nerves, and blood vessels. However, it has been much less appreciated that the β cell itself is also a prime target, a case of double jeopardy. This situation is all the more pernicious because islets contain among the lowest levels of antioxidant enzyme activities compared to other tissues. This adverse effect of high glucose concentrations is referred to as glucose toxicity. A major manifestation of glucose toxicity in the β cell is defective insulin gene expression, diminished insulin content, and defective insulin secretion. The molecular mechanisms involve the development of decreased levels of two very important insulin promoter transcription factors, PDX-1 and MafA. Studies with animal models of type 2 diabetes have established that pharmacologic protection against oxidative stress ameliorates the severity of diabetes progression. Translational research with humans is now under way to ascertain whether this protection can be provided to patients experiencing inadequate glycemic control.

Introduction

Diabetes mellitus in humans is undergoing a remarkable upsurge in prevalence in the United States and elsewhere. In the United States this is particularly evident in several ethnic subsets, including Latino, American Indian, Japanese American, and African American people. Historically, the usual ratio for type 1 to type 2 diabetes has been 1:20. This is changing because of the marked increase in the incidence of type 2 diabetes now being seen in children. Type 1 diabetes is a case of β cell death, whereas type 2 diabetes is a syndrome of β cell dysfunction involving relative insulin deficiency and is usually associated with insulin resistance. Classically, type 1 diabetes is described as an autoimmune disease in which a foreign protein is incorporated into islet β cells, perhaps via viral infection. In response, the patient's lymphocytes attack the foreign protein and inadvertently destroy the patient's β cells as collateral damage. This leads to a state of absolute insulin deficiency. The pathogenesis of type 2 diabetes is less well defined. However, it is invariably associated with defective sensing of glucose signals by the β cell. It is often associated with a state of insulin resistance, which means insulin that is secreted by the β cell and bound to liver, muscle, and fat cells is subnormally efficacious in carrying out its metabolic actions. However, at the core of the pathogenesis of type 2 diabetes is defective β cell function. Many people, such as obese individuals, develop insulin resistance without developing type 2 diabetes. It seems that some individuals intrinsically have less β cell mass or less effective β cells, and it is these individuals who are particularly at risk for developing type 2 diabetes if they develop a state of insulin resistance.

Islets of Langerhans are microscopic organelles scattered diffusely throughout the pancreas. Each islet contains approximately 2000 cells, which include four types: α, β, δ, and PP cells. The major secretory products of these cells are glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively. The α cell secretes glucagon primarily in response to hypoglycemia, but also to amino acids. The β cell secretes insulin in response to elevated glucose levels and also responds to other substances such as glucagon and acetylcholine. Insulin responses to intravenous glucose are time-dependent and referred to as first- and second-phase responses. Islets in pancreas obtained from deceased type 2 diabetic patients are positive for insulin immunostaining. Functionally, patients with type 2 diabetes mellitus have intact insulin responses to all intravenous nonglucose secretagogues (such as isoproterenol, arginine, and secretin). These responses are both first and second phase in nature. In contrast, type 2 diabetic patients fail to have first-phase insulin responses to intravenous glucose and have impaired second-phase responses as well. The δ cell releases somatostatin in response to glucose. The PP cell releases pancreatic polypeptide in response to hypoglycemia and secretin. The functions of these hormones are distinctly different. Glucagon stimulates glycogenolysis in the liver to increase blood glucose levels. Insulin decreases hepatic glucose production and increases glucose entry into muscle and fat cells. Somatostatin inhibits the secretion of many hormones, including insulin and glucagon, and likely is an intraislet paracrine regulator of α and β cells. The function of pancreatic polypeptide in humans remains unclear.

Section snippets

Adverse effects of cytokines and hyperglycemia on β cells

Cytokines may be operative in the development of both types of diabetes. It has been appreciated for many years that cytokines are involved in the pathogenesis of type 1 diabetes. The three cytokines most often mentioned in descriptions of the pathogenesis of diabetes are interleukin 1β, tumor necrosis factor-α, and interferon-γ. Cytokines are associated with the generation of free radicals containing carbon, oxygen, and nitrogen. Recently, it has been reported that high glucose concentrations

Clinical evidence for glucose toxicity and oxidative stress in diabetes

The term glucose toxicity refers to the adverse effects that elevated blood glucose levels have on cellular function and structure in tissues throughout the body. The dimension of time is essential to the toxic effects of glucose; they are best understood in the context of chronic, time-related elevations of blood glucose over many months and years rather than days. Because blood glucose levels in nondiabetic people rise postprandially, it seems unlikely that short periods of elevated blood

Conclusion

Diabetes is due to β cells that are either dead or have defective function; the consequence is chronic hyperglycemia. Chronic exposure to high blood glucose levels over many years causes adverse structural and functional changes in tissues, a phenomenon termed glucose toxicity. This becomes a case of double jeopardy for any β cells that survive the disease. Diabetic patients have also been reported to have increased clinical markers for oxidative stress and damage, findings which raise the

Acknowledgment

This work was supported by NIH Grant DDK RO138325.

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    This article is part of a series of reviews on “The Role of Oxidative Stress in Diabetes.” The full list of papers may be found on the home page of the journal.

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