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Glucose Toxicity in Beta-Cells: Type 2 Diabetes, Good
Radicals Gone Bad, and the Glutathione Connection
R. Paul Robertson, Jamie Harmon, Phuong Oanh Tran, Yoshito Tanaka, and
Hiroki Takahashi
Diabetes 52:581–587, 2003
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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
beta-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 beta-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 beta-cell function.
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