ALR mice are closely related to type-1 diabetes mellitus (T1DM)-prone NOD mice. The ALR genome confers systemically elevated free radical defenses, dominantly protecting their pancreatic islets from free radical generating toxins, cytotoxic cytokines, and diabetogenic T cells. The ALR major histocompatibility complex (MHC) ( H2(gx) haplotype) is largely, but not completely identical with the NOD H2(g7) haplotype, sharing alleles from H2-K through the class II and distally into the class III region. This same H2(gx) haplotype in the related CTS strain was linked to the Idd16 resistance locus. In the present study, ALR was outcrossed to NOD to fine map the Idd16 locus and establish chromosomal regions carrying other ALR non-MHC-linked resistance loci. To this end, 120 (NODxALR)xNOD backcross progeny females were monitored for T1DM and genetic linkage analysis was performed on all progeny using 88 markers covering all chromosomes. Glucosuria or end-stage insulitis developed in 32 females, while 88 remained both aglucosuria and insulitis free. Three ALR-derived resistance loci segregated. As expected, one mapped to Chromosome 17, with peak linkage mapping just proximal to H2-K. A novel resistance locus mapped to Chr 8. A pairwise scan for interactions detected a significant interaction between the loci on Chr 8 and Chr 17. On Chr 3, resistance segregated with a marker between previously described Idd loci and coinciding with an independently mapped locus conferring a suppressed superoxide burst by ALR neutrophils (Susp). These results indicate that the Idd16 resistance allele, defined originally by linkage to the H2(gx) haplotype of CTS, is immediately proximal to H2-K. Two additional ALR-contributed resistance loci may be ALR-specific and contribute to this strain's ability to dissipate free-radical stress.

The diabetogenic major histocompatibility complex (MHC) (H2

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 ␤-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. Diabetes 53 (Suppl. 1):S125-S129, 2004 O utbred CD-1 mice (a commercial stock of ICR mice) carry a spectrum of genetic susceptibilities for obesity and impaired glucose tolerance (IGT), both risk factors for the development of type 2 diabetes. Homozygous fixation of potential type 2 diabetes susceptibility genes is reflected in male mice of two ICR-derived inbred strains: NSY and NON (1,2). Both of these inbred strains develop IGT, but neither makes the transition into chronic nonfasting hyperglycemia. ALS (alloxan [AL]-susceptible) mice were derived from outbred CD-1 mice by selection for sensitivity to AL-induced diabetes, with concomitant selection for an AL-resistant (ALR) line (3). Alloxan, a chemical with structural similarities to glucose and a potent generator of free radicals, is a selective ␤-cell toxin because of the high affinity of AL for GLUT2 transporters. Interestingly, the differential AL sensitivity of the ALS/Lt and ALR/Lt strains correlated with differential ability to dissipate free radical stress (4). The ALS/Lt strain has significantly decreased global free radical defenses compared with the ALR/Lt strain, which reciprocally shows a constitutive elevation in systemic antioxidative capacity (4,5). Although ALS mice were selected for high susceptibility to AL-induced insulinrequiring diabetes, this selection has in fact produced a mouse strain with high type 2 diabetes predisposition (6).Initially, the type 2 diabetes predisposition of ALS was recognized by congenic analysis of the yellow mutation (A y ) at the agouti locus on chromosome 2 (6). The incidence of diabetes...