Genetic resistance to chemically-induced diabetes in mice linked to elevated antioxidant levels

August 10, 1999

Research at The Jackson Laboratory comparing mice bred for resistance or susceptibility to chemically-induced insulin-dependent (Type 1) diabetes suggests that the major difference is in the genetic control of antioxidant enzymes. These enzymes help protect against pancreatic beta-cell destruction caused by free radical-mediated stress in both mice and humans.

The results add a new dimension in understanding why some humans with "high-risk" genes for developing Type 1 diabetes remain free of this disease. Identification of the gene or genes conferring such remarkable resistance could lead to therapies to boost natural defenses against diabetes and improve survival of pancreatic islet transplants.

"These studies in model systems suggest that the extent to which an individual can detoxify free radicals as they form in pancreatic beta cells may be an important component of genetically inherited susceptibility or resistance to diabetes," said Clayton E. Mathews, a Postdoctoral Associate at The Jackson Laboratory.

The research is published in the August 1999 issue of Free Radical Biology & Medicine by Dr. Mathews and Senior Staff Scientist Dr. Edward H. Leiter. Their paper is entitled, "Constitutive Differences in Antioxidant Defense Status Distinguish Alloxan-Resistant and Alloxan-Susceptible Mice."

The scientists focused on ALR (alloxan-resistant) and ALS (alloxan-susceptible) inbred mice, developed by F. Sekiguchi and colleagues in Japan as a model animal system for diabetes induced by an environmental toxin known as alloxan. This potent chemical generates free radicals, or reactive oxygen species, which contribute to beta cell destruction in Type 1 diabetes and damage to eyes, kidney, heart, and nerves associated with both Type 1 and Type 2 (non-insulin dependent) diabetes.

Past research has shown that the beta-cell death induced by alloxan can be inhibited by the use of antioxidants. Dietary supplementation of vitamin E, selenium, or zinc is protective against experimentally induced diabetes, while their depletion enhances the development of diabetes.

In their experiment, Drs. Mathews and Leiter found upregulation of a diverse group of antioxidant enzymes in the resistant mice as compared to the susceptible mice, including elevated superoxide dismutase, glutathione reductase, and glutathione peroxidase in the pancreas and other tissues systemwide.

A controlled cross between the ALS and ALR strains resulted in all F1 offspring of both sexes exhibiting resistance to alloxan-induced diabetes, suggesting that the unusually high free radical defense trait in ALR may provide protection when transferred into the susceptible strain. A subsequent F1 backcross to ALS strongly supports the hypothesis that the trait is attributable to a single gene.

Drs. Mathews and Leiter have proposed that the genetic resistance of ALR mice to diabetogenic stress may be attributed to differences in expression of a transcription factor that activates a battery of stress-response genes. Transcription factors are molecules that turn on or off the process of protein synthesis in which genes are copied for activation in the cell.

The research was supported by individual grants from the American Diabetes Association, the Juvenile Diabetes Federation International, and the National Institutes of Health, as well as an institutional grant from the National Cancer Institute.
-end-


Jackson Laboratory

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