Commonalities of genetic resistance to spontaneous autoimmune and free radical--mediated diabetes.
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.
Chen
Jing
J
Department of Pediatrics, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA.
Lu
Ying
Y
Lee
Chul-Ho
CH
Li
Renhua
R
Leiter
Edward H
EH
Mathews
Clayton E
CE
D000496:Alloxan / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity; D001786:Blood Glucose / Q000378:metabolism; D002875:Chromosomes / Q000648:ultrastructure; D003433:Crosses, Genetic; D004272:DNA, Mitochondrial / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D005609:Free Radicals; D008040:Genetic Linkage; D016678:Genome; D005838:Genotype; D051379:Mice; D016688:Mice, Inbred NOD; D008954:Models, Biological
D001786:Blood Glucose; D004272:DNA, Mitochondrial; D005609:Free Radicals; D000496:Alloxan