Perspectives in Diabetes Glucose Toxicity in -Cells: Type 2 Diabetes, Good Radicals Gone Bad, and the Glutathione Connection

Chronic exposure to hyperglycemia can lead to cellular dysfunction that may become irreversible over time, a process that is termed glucose toxicity. Our perspective about glucose toxicity as it pertains to the pancreatic -cell is that the characteristic decreases in insulin synthesis and secretion are caused by decreased insulin gene expression. The responsible metabolic lesion appears to involve a posttranscriptional defect in pancreas duodenum homeobox-1 (PDX-1) mRNA maturation. PDX-1 is a critically important transcription factor for the insulin promoter, is absent in glucotoxic islets, and, when transfected into glucotoxic -cells, improves insulin promoter activity. Because reactive oxygen species are produced via oxidative phosphorylation during anaerobic glycolysis, via the Schiff reaction during glycation, via glucose autoxidation, and via hexosamine metabolism under supraphysiological glucose concentrations, we hypothesize that chronic oxidative stress is an important mechanism for glucose toxicity. Support for this hypothesis is found in the observations that high glucose concentrations increase intraislet peroxide levels, that islets contain very low levels of antioxidant enzyme activities, and that adenoviral overexpression of antioxidant enzymes in vitro in islets, as well as exogenous treatment with antioxidants in vivo in animals, protect the islet from the toxic effects of excessive glucose levels. Clinically, consideration of antioxidants as adjunct therapy in type 2 diabetes is warranted because of the many reports of elevated markers of oxidative stress in patients with this disease, which is characterized by imperfect management of glycemia, consequent chronic hyperglycemia, and relentless deterioration of -cell function. Diabetes 52: 581–587, 2003 A fter type 2 diabetes patients initially respond to diet and oral hypoglycemic agents, why do they usually relapse into hyperglycemia, despite dietary compliance and maximal drug dosages? Is this a case of -cell desensitization to the drugs, or is it something more sinister happening to the -cell over time? Is there ongoing apoptosis of -cells, and, if so, is this caused by aberrant genetic programming or something bad that invades the -cell’s microenvironment? Type 2 diabetes is characterized as a polygenic disorder and generally thought of as a syndrome, rather than a single specific entity. This suggests that a common adverse force is exerted on -cells in all patients, regardless of the initial specific pathogenesis. One such force all patients experience in common is the chronic tendency toward developing abnormally high glucose levels on a daily basis. Even though fasting glucose and HbA1c levels might be within the normal range, postprandial levels of glucose are often abnormal. The glucose toxicity theory proposes that continual exposure to modest increases in blood glucose over a long period of time could have adverse effects on -cells. In essence, the consequence of type 2 diabetes, hyperglycemia, is proposed as a secondary cause of continued -cell deterioration. Definition of glucose toxicity. For the purposes of this article, glucose toxicity of the islet is defined as nonphysiological and potentially irreversible -cell damage caused by chronic exposure to supraphysiological glucose concentrations. In its initial stages, this damage is characterized by defective insulin gene expression (1,2). Desensitization refers to a temporary physiological state of cellular refractoriness to glucose stimulation induced by repeated or prolonged exposure to high glucose concentrations. Desensitization is reversed in a time-dependent manner, usually minutes after restoration of normal glucose concentrations, and implies involvement of an intrinsic and reversible alteration in stimulus-secretion coupling. -Cell exhaustion refers to a physical depletion of -cell insulin stores secondary to prolonged, chronic stimulation with glucose or nonglucose secretatgogues, so that insulin secretion is not possible, even if the -cell were to become resensitized to glucose. An important distinction between -cell exhaustion and glucose toxicity is that the exhausted islet has no defects in insulin synthesis, and therefore cell function fully recovers as it rests. Glucose toxicity, on the other hand, implies the gradual, timeFrom the Pacific Northwest Research Institute, Seattle, Washington. Address correspondence and reprint requests to R. Paul Robertson, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122. Received for publication 5 September 2002 and accepted in revised form 11 November 2002. DN, dominant-negative; GCL, -glutamylcysteine ligase; GSH, glutathione; GSSG, oxidized GSH; GPx, GSH peroxidase; JNK; c-Jun NH2-terminal kinase; PDX-1, pancreas duodenum homeobox-1; ROS, reactive oxygen species; SOD, superoxide dismutase.