Chronic Oxidative Stress as a Central Mechanism for Glucose Toxicity in Pancreatic Islet Beta Cells in Diabetes*

By R. Robertson. Journal of Biological Chemistry, 2004

1,126 citations recorded by the source corpus.

Glucose in chronic excess causes toxic effects on structure and function of organs, including the pancreatic islet. Multiple biochemical pathways and mechanisms of action for glucose toxicity have been suggested. These include glucose autoxidation, protein kinase C activation, methylglyoxal formation and glycation, hexosamine metabolism, sorbitol formation, and oxidative phosphorylation. There are many potential mechanisms whereby excess glucose metabolites traveling along these pathways might cause beta cell damage. However, all these pathways have in common the formation of reactive oxygen species that, in excess and over time, cause chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. This minireview provides an overview of these mechanisms, as well as a consideration of whether antioxidant strategies might be used to protect further deterioration of the beta cell after the onset of diabetes and hyperglycemia. Diabetes mellitus is a disease characterized by hyperglycemia and is caused by absolute or relative insulin deficiency, sometimes associated with insulin resistance. It has multiple etiologies and segregates into two major forms. Type 1 diabetes is an autoimmune disease in which the patient’s own immune system reacts against islet antigens and destroys the beta cell. Type 2 diabetes is a polygenic syndrome with multiple etiologies rather than a single specific disease. As the hyperglycemia of diabetes becomes chronic, the sugar that normally serves as substrate, fuel, and signal takes on the darker role of toxin. Chronic hyperglycemia is the proximate cause of retinopathy, kidney failure, neuropathies, and macrovascular disease in diabetes. The beta cell in type 2 diabetes is also adversely affected by chronic hyperglycemia and, in this sense, is also a target for secondary complications. As hyperglycemia worsens, the beta cell steadily undergoes deterioration, secretes less and less insulin, and becomes a participant in a downward spiral of loss of function. This relentless deterioration in cell function caused by constant exposure to supraphysiologic concentrations of glucose is termed glucose toxicity. Mechanisms of Hyperglycemia-induced Oxidative Stress In physiologic concentrations, endogenous reactive oxygen species (ROS) help to maintain homeostasis. However, when ROS accumulate in excess for prolonged periods of time, they cause chronic oxidative stress and adverse effects. This is particularly relevant and dangerous for the islet, which is among those tissues that have the lowest levels of intrinsic antioxidant defenses. Multiple biochemical pathways and mechanisms of action have been implicated in the deleterious effects of chronic hyperglycemia and oxidative stress on the function of vascular, retinal, and renal tissues. Considerably less work has been performed using islet tissue. At least six pathways are emphasized in the literature as being major contributors of ROS. Each will be considered briefly. Glyceraldehyde Autoxidation—Glyceraldehyde 3-phosphate is a phosphorylation product formed from glucose during anaerobic glycolysis. The partner product, dihydroxyacetone phosphate, also contributes to intracellular glyceraldehyde concentrations via enzymatic conversion by triose-phosphate isomerase. Thereafter, glyceraldehyde 3-phosphate is oxidized by glyceraldehyde-phosphate dehydrogenase (GAPDH). Continuance of glycolysis yields pyruvate, which enters the mitochondria where it is oxidized to acetyl-CoA, and the processes of the tricarboxylic acid cycle and oxidative phosphorylation begin. One alternative to this classic pathway of glucose metabolism is the less familiar route of glyceraldehyde autoxidation (Fig. 1, pathway 1). The potential relevance of this pathway to diabetes mellitus was pointed out by Wolff and Dean (1), who emphasized that autoxidation of -hydroxyaldehydes generates hydrogen peroxide (H2O2) and -ketoaldehydes. In the presence of redox active metals, H2O2 can form the highly toxic hydroxyl radical. This pathway, therefore, forms two potentially toxic substances, -ketoaldehydes, which contribute to glycosylation-related protein chromophore development, and the hydroxyl radical, a reactive oxygen species that can cause mutagenic alterations in DNA. Although glyceraldehyde is characteristically thought of as an insulin secretagogue, when present in excess it may also inhibit insulin secretion (2). Long term exposure to high glucose concentrations decreases GAPDH activity in islets (3), which favors excess glyceraldehyde accumulation. Exposure of endothelial cells to 30 mM glucose caused GAPDH inhibition (4) through the mechanism of ROS-activated poly(ADP-ribosyl)ation of GAPDH by poly(ADP-ribose) polymerase. This in turn was associated with intracellular advanced glycation end product (AGE) formation and activation of PKC, the hexosamine pathway, and NFB. PKC Activation—Dihydroxyacetone can undergo reduction to glycerol 3-phosphate and acylation and thereby increase de novo synthesis of diacylglycerol, which activates protein kinase C, of which there at least 11 isoforms (Fig. 1, pathway 2). Activation of PKC has many biochemical consequences that relate to microvascular disease in diabetes. PKC activation is associated with increases in TGF1, vascular endothelial

Subfields: Clinical Biochemistry, Genetics, Surgery

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In Clinical Biochemistry

1. M. Cerf
2. C. Palmeira
3. Lori Sussel
4. Hua V. Lin
5. A. Kappas
6. Nader G. Abraham
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In Genetics

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In Surgery

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2. C. Palmeira
3. Lori Sussel
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5. A. Kappas
6. Nader G. Abraham
7. Reem M. Sallam
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Citations in the corpus

• Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. (2006, background): “1) (Nishikawa et al., 2000a; Brownlee, 2001; Robertson, 2004): (1) increased polyol pathway flux; (2) increased advanced glycation end product (AGE) formation; (3) activation of protein kinase C (PKC) isoforms; and (4) increased hexosamine pathway flux.”
• Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. (2005, background): “Further, in the context of our proposed model of AGEs and RAGE triggering a vicious cycle of injury with multiple points of amplification, glucose, AGEs, and oxidative stress augment injury to islets and beta cells (El-Assaad et al., 2003; Robertson, 2004; Wu et al., 2004).”
• Pancreatic β-Cell Dedifferentiation As Mechanism Of Diabetic β-Cell Failure (2012, positive): “To distinguish between an intrinsic defect of insulin and glucagon secretion in multiparous IKO mice and secondary changes brought about by glucose toxicity (Robertson, 2004), we isolated islets and compared insulin secretion.”
• Beta Cell Dysfunction and Insulin Resistance (2013, background): “The limited glycolytic capacity of beta cells can generate ROS and the ensuing oxidative stress can uncouple glucose sensing from insulin secretion (Robertson, 2004).”
• Reactive Oxygen Species in Health and Disease (2012, background): “Excess glucose increases oxidative stress through several biochemical mechanisms, including glyceraldehydes autoxidation, protein kinase C activation, glycation, methyl glyoxal and sorbitol production, hexosamine pathway, and oxidative phosphorylation [50].”
• Pharmacological and Clinical Aspects of Heme Oxygenase (2008, positive): “The experimental basis for chronic oxidative stress as an underlying mechanism for glucose toxicity in -cells has been examined and shown to be a major problem in diabetes (Robertson et al., 1992; Robertson, 2004).”