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

Free Radic Biol Med. 2008 Nov 1;45(9):1263-70. doi: 10.1016/j.freeradbiomed.2008.07.020. Epub 2008 Jul 31.

Abstract

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-Nd2(a) 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-Nd2(c) allele and NOD mice congenic for the protective Chr. 8 locus supported our mapping results. Alloxan sensitivity was increased in ALR.mt(NOD) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alloxan / metabolism
  • Animals
  • Autoimmunity*
  • Blood Glucose / metabolism
  • Chromosomes / ultrastructure
  • Crosses, Genetic
  • DNA, Mitochondrial / metabolism
  • Diabetes Mellitus / metabolism*
  • Free Radicals*
  • Genetic Linkage
  • Genome
  • Genotype
  • Mice
  • Mice, Inbred NOD
  • Models, Biological

Substances

  • Blood Glucose
  • DNA, Mitochondrial
  • Free Radicals
  • Alloxan