Genetic analysis of resistance to Type-1 Diabetes in ALR/Lt mice, a NOD-related strain with defenses against autoimmune-mediated diabetogenic stress

Mathews, Clayton E.; Graser, Robert T.; Bagley, Rebecca J.; Caldwell, John S.; Li, Renhua; Churchill, Gary A.; Serreze, David; Leiter, Edward H.

doi:10.1007/s00251-003-0603-8

Cited by 37 publications

(68 citation statements)

References 22 publications

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“…The 120 female progeny produced in the (NOD/ LtDvs×ALR/Lt)F1×NOD outcross are the same mice reported previously [20]; the diabetes frequency for this cross is reproduced here only for comparison to the diabetes frequency for 107 comparably aged [(ALR/Lt×NOD/Lt) F1×NOD/Lt] BC1 females generated from the reciprocal cross in the present study. Clinical diabetes was diagnosed after two sequential positive tests.…”

Section: Methodsmentioning

confidence: 58%

“…Diabetic females were euthanized by CO 2 asphyxiation. Non-glycosuric females were euthanized at the 40-week age point, and pancreata were removed and assessed for extent of insulitic damage to islets using a scoring system described elsewhere [20]. Segregants with clinical diabetes of at least 2-week duration typically exhibited mean 1insulitis scores of 3.5-4.0 (out of a maximally severe score of 4.0).…”

Section: Methodsmentioning

confidence: 99%

“…Segregants with clinical diabetes of at least 2-week duration typically exhibited mean 1insulitis scores of 3.5-4.0 (out of a maximally severe score of 4.0). Hence, segregants that were non-glycosuric at the time of euthanasia, but whose pancreata presented mean insulitis scores ≥3.8 were classified as incipient diabetics [20].…”

Section: Methodsmentioning

confidence: 99%

“…3) was mapped that suppressed neutrophil-generated superoxide burst following activation [19]. In outcross of NOD females with ALR males, and backcross of the T1D-resistant females to NOD males, three nuclear-encoded genes from the ALR genome were mapped that suppressed T1D development in BC1 females [20]. One resistance locus colocalized to the above-mentioned Chr.…”

Section: Introductionmentioning

confidence: 99%

“…17, and one mapped on Chr. 8 [20]. Because F1 mice from reciprocal ALR and ALS crosses were resistant to alloxan-induced diabetes, and F1 mice from reciprocal crosses of ALR and NOD mice were resistant to spontaneous T1D development, protective contributions from the ALR mitochondrial genome were not immediately indicated.…”

Section: Introductionmentioning

confidence: 99%

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mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

et al. 2005

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Aims/hypothesis: ALR/Lt, a mouse strain with strong resistance to type 1 diabetes, is closely related to autoimmune type 1 diabetes-prone NOD/Lt mice. ALR pancreatic beta cells are resistant to the beta cell toxin alloxan, combinations of cytotoxic cytokines, and diabetogenic NOD T-cell lines. Reciprocal F1 hybrids between either ALR and NOD or ALR and NON/Lt, showed that alloxan resistance was transmitted to F1 progeny only when ALR was the maternal parent. Here we show that the mitochondrial genome (mtDNA) of ALR mice contributes resistance to diabetes. Methods: When F1 progeny from reciprocal outcrosses between ALR and NOD were backcrossed to NOD, a four-fold lower frequency of spontaneous type 1 diabetes development occurred when ALR contributed the mtDNA. Because of the apparent interaction between nuclear and mtDNA, the mitochondrial genomes were sequenced. Results: An ALR-specific sequence variation in the mt-Nd2 gene producing a leucine to methionine substitution at amino acid residue 276 in the NADH dehydrogenase 2 was discovered. An isoleucine to valine mutation in the mt-Co3 gene encoding COX3 distinguished ALR and NOD from NON and ALS. All four strains were distinguished by variation in a mt-encoded arginyl tRNA polyadenine tract. Shared alleles of mt-Co3 and mt-Tr comparing NOD and ALR allowed for exclusion of these two genes as candidates, implicating the mt-Nd2 variation as a potential ALR-derived type 1 diabetes protective gene. Conclusions/interpretation: The unusual resistance of ALR mice to both ROS-mediated and autoimmune type 1 diabete stresses reflects an interaction between the nuclear and mt genomes. The latter contribution is most likely via a single nucleotide polymorphism in mt-Nd2.

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Section: Methodsmentioning

confidence: 58%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

et al. 2005

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Genetic and Pharmacologic Models for Type 1 Diabetes

Leiter

Schile

2013

CP Mouse Biology

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Type 1 diabetes (T1D) is characterized by a partial or total insufficiency of insulin. The premiere animal model of autoimmune T cell-mediated T1D is the NOD mouse. A dominant negative mutation in the mouse insulin 2 gene (Ins2Akita) produces a severe insulin deficiency syndrome without autoimmune involvement, as do a variety of transgenes overexpressed in beta cells. Pharmacologically-induced T1D (without autoimmunity) elicted by alloxan or streptozotocin at high doses can generate hyperglycemia in almost any strain of mouse by direct toxicity. Multiple low doses of streptozotocin combine direct beta cell toxicity with local inflammation to elicit T1D in a male sex-specific fashion. A summary of protocols relevant to the management of these different mouse models will be covered in this overview.

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