Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in type 2 diabetes

R. Robertson, Huarong Zhou, Tao Zhang, Jamie S. Harmon

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

Type 2 diabetes is characterized by a relentless decline in pancreatic islet beta cell function and worsening hyperglycemia despite optimal medical treatment. Our central hypothesis is that residual hyperglycemia, especially after meals, generates reactive oxygen species (ROS), which in turn causes chronic oxidative stress on the beta cell. This hypothesis is supported by several observations. Exposure of isolated islets to high glucose concentrations induces increases in intracellular peroxide levels. The beta cell has very low intrinsic levels of antioxidant proteins and activities and thus is very vulnerable to ROS. Treatment with antioxidants protects animal models of type 2 diabetes against complete development of phenotypic hyperglycemia. The molecular mechanisms responsible for the glucose toxic effect on beta cell function involves disappearance of two important regulators of insulin promoter activity, PDX-1 and MafA. Antioxidant treatment in vitro prevents disappearance of these two transcription factors and normalizes insulin gene expression. These observations suggest that the ancillary treatment with antioxidants may improve outcomes of standard therapy of type 2 diabetes in humans.

Original languageEnglish (US)
Pages (from-to)139-146
Number of pages8
JournalCell biochemistry and biophysics
Volume48
Issue number2-3
DOIs
StatePublished - Jun 2007
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgment This work is supported by NIH NIDDK RO1-38325.

Keywords

  • Beta cell
  • Glucose toxicity
  • Oxidative stress

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