Commonalities of genetic resistance to spontaneous autoimmune and free radical-mediated diabetes

Jing Chen, Ying Lu, Chul Ho Lee, Renhua Li, Edward H. Leiter, Clayton E. Mathews*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


ALR/Lt, a NOD-related mouse strain, was selected for resistance to alloxan free radical-mediated diabetes (ALD). Despite extensive genomic identity with NOD (> 70%), ALR mice display strong resistance to autoimmune type 1 diabetes (T1D) due to both an unusual elevation in systemic antioxidant defenses and a reduction in cellular ROS production that extends to the beta cell level. Reciprocal backcross to NOD previously linked the ALR-derived T1D resistance to Chr. 3, 8, and 17 as well as to the ALR mt-Nd2a allele encoded by the mitochondrial genome (mtDNA). To determine whether any of the ALR-derived loci protecting against T1D also protected against ALD, 296 six-week-old F2 mice from reciprocal outcrosses were alloxan-treated and assessed for diabetes onset, and a genome-wide scan (GWS) was conducted. GWS linked mt-Nd2 as well as three nuclear loci with alloxan-induced diabetes. A dominant ALR-derived ALD resistance locus on Chr. 8 colocalized with the ALR-derived T1D resistance locus identified in the previous backcross analysis. In contrast, whereas ALR contributed a novel T1D resistance locus on Chr. 3 marked by Susp, a more proximal ALR-derived region marked by Il-2 contributed ALD susceptibility, not resistance. In addition, a locus was mapped on Chr. 2, where heterozygosity provided heightened susceptibility. Tests for alloxan sensitivity in ALR conplastic mice encoding the NOD mt-Nd2c allele and NOD mice congenic for the protective Chr. 8 locus supported our mapping results. Alloxan sensitivity was increased in ALR.mtNOD mice, whereas it was decreased by congenic introduction of ALR genome on Chr. 8 into NOD. These data demonstrate both similarities and differences in the genetic control of T1D versus ROS-induced diabetes.

Original languageEnglish
Pages (from-to)1263-1270
Number of pages8
JournalFree Radical Biology and Medicine
Issue number9
StatePublished - 1 Nov 2008
Externally publishedYes


  • Autoimmunity
  • Diabetes
  • Free radicals
  • Genetics
  • Mice


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