Glucose Toxicity in β-Cells: Type 2 Diabetes, Good Radicals Gone Bad, and the Glutathione Connection
TLDR
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 beta-cell function.Abstract:
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 β-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 β-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 β-cell function.read more
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Role of Oxidative Stress in Development of Complications in Diabetes
TL;DR: Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes.
superoxide production blocks three pathways of hyperglycaemic damage
Takeshi Nishikawa,Diane Edelstein,Xue Liang Du,Sho-ichi Yamagishi,Takeshi Matsumura,Yasufumi Kaneda,Mark A. Yorek,David Beebek,Peter J. Oatesk,Hans-Peter Hammes,Ida Giardino,Michael Brownlee +11 more
TL;DR: This paper showed that hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells and that this increase in reactive oxygen can be prevented by an inhibitor of electron transport chain complex II, an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase.
Journal ArticleDOI
Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
Takeshi Nishikawa,Diane Edelstein,Xue Liang Du,Sho-ichi Yamagishi,Takeshi Matsumura,Yasufumi Kaneda,Mark A. Yorek,David A. Beebe,Peter J. Oates,Hans-Peter Hammes,Ida Giardino,Michael Brownlee +11 more
TL;DR: This work shows that hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells and is prevented by an inhibitor of electron transport chain complex II, by an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase.
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β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes
Alexandra E. Butler,Juliette Janson,Susan Bonner-Weir,Robert A. Ritzel,Robert A. Rizza,Peter C. Butler +5 more
TL;DR: Since the major defect leading to a decrease in β-cell mass in type 2 diabetes is increased apoptosis, while new islet formation andβ-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 Diabetes.
Journal ArticleDOI
Reactive oxygen species, antioxidants, and the mammalian thioredoxin system.
Jonas Nordberg,Elias S.J. Arnér +1 more
TL;DR: The TrxR-catalyzed regeneration of several antioxidant compounds, including ascorbic acid (vitamin C), selenium-containing substances, lipoic acid, and ubiquinone are summarized.