ALS/Lt: A New Type 2 Diabetes Mouse Model Associated With Low Free Radical Scavenging Potential

  1. Clayton E. Mathews1,
  2. Rebecca Bagley2 and
  3. Edward H. Leiter2
  1. 1Department of Pediatrics, the University of Pittsburgh, Pittsburgh, Pennsylvania
  2. 2The Jackson Laboratory, Bar Harbor, Maine
  1. Address correspondence and reprint requests to Dr. Clayton E. Mathews, Diabetes Institute, 3460 5th Ave./Rangos Research Center, the University of Pittsburgh, Pittsburgh, PA 15213. E-mail: cem65{at}pitt.edu

Abstract

Outbred CD-1 mice carry a spectrum of genetic susceptibilities for obesity and type 2 diabetes. ALS is an inbred strain with low antioxidant defenses produced by inbreeding CD-1 mice, with selection for susceptibility to alloxan, a generator of highly reactive oxygen free radicals and a potent β-cell toxin. The objective of this study was to determine if the low ability to diffuse free radical stress would contribute to spontaneous type 2 diabetes development in alloxan-untreated males. Indeed, both hyperinsulinemia and impaired glucose tolerance developed spontaneously between 6 and 8 weeks of age in alloxan-untreated males. Further aging was accompanied by increases in body mass, progressively more severe hyperinsulinemia, and development of overt hyperglycemia. Transition from impaired glucose tolerance to overt hyperglycemia correlated with a decreased ratio of reduced to oxidized glutathione. Evidence that the increased oxidative burden elicited the type 2 diabetes syndrome was obtained by the systemic elevation of the antioxidative capacity through daily administration of R-lipoic acid. R-lipoic acid (30 mg/kg) prevented hyperglycemia, reduced insulin levels, and increased free radical scavenging potential. This mouse model with reduced ability to diffuse free radical stress is of obvious interest because free radical-mediated damage is implicated in the pathogenesis and complications of both type 1 and type 2 diabetes.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Les Laboratoires Servier.

    • Accepted April 7, 2003.
    • Received March 27, 2003.
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