Selection of Mouse Strains Showing High and Low Incidences of Alloxan-induced Diabetes

Ino, Takayoshi; Kawamoto, Yasuo; Sato, Katsunori; Nishikawa, Kumi; Yamada, Akihisa; Ishibashi, Keiichiro; Sekiguchi, Fujio

doi:10.1538/expanim1978.40.1_61

Cited by 19 publications

(18 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ALR and ALS inbred strains were initially developed from outbred CD-1 (ICR) mice with successive generations selected for resistance or for increased sensitivity to the diabetogenic effects of alloxan, which imposes oxidant stress on β-cells [16]. Tracking gene polymorphisms that distinguish B6 from the ALR or ALS genotypes allowed us to insert the Ncb5or −/− allele into ALR or ALS genetic backgrounds more rapidly.…”

Section: Methodsmentioning

confidence: 99%

Development of diabetes in lean Ncb5or-null mice is associated with manifestations of endoplasmic reticulum and oxidative stress in beta cells

Wang

Guo

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

NADH-cytochrome b5 oxidoreductase (Ncb5or) is an endoplasmic reticulum (ER)-associated redox enzyme involved in fatty acid metabolism, and phenotypic abnormalities of Ncb5or−/− mice include diabetes and lipoatrophy. These mice are lean and insulin-sensitive but become hyperglycemic at age 7 weeks as a result of β-cell dysfunction and loss. Here we examine early cellular and molecular events associated with manifestations of β-cell defects in Ncb5or−/− mice. We observe lower islet β-cell content in pancreata at age 4 weeks and prominent ER distention in β-cells by age 5 weeks. Ultrastructural changes progress rapidly in severity from age 5 to 6 weeks, and their frequency rises from 10% of β-cells at 5 weeks to 33% at 6 weeks. These changes correlate temporally with the onset of diabetes. ER stress responses and lipid load in Ncb5or−/− β-cells were assessed with isolated islets from mice at age 5 weeks. Expression levels of the stress marker protein Grp78/BiP and of phosphorylated eIF2α protein were found to be reduced, although their transcript levels did not decline. This pattern stands in contrast to the canonical unfolded protein response. Ncb5or−/− β-cells also accumulated higher intracellular levels of palmitate and other free fatty acids and exhibited greater reactive oxygen species production than wild-type cells. An alloxan-susceptible genetic background was found to confer accelerated onset of diabetes in Ncb5or−/− mice. These findings provide the first direct evidence that manifestations of diabetes in lean Ncb5or−/− mice involve saturated free fatty acid overload of β-cells and ER and oxidative stress responses.

show abstract

Section: Methodsmentioning

confidence: 99%

Development of diabetes in lean Ncb5or-null mice is associated with manifestations of endoplasmic reticulum and oxidative stress in beta cells

Wang

Guo

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

show abstract

“…ALR/Lt mice and NOD/Lt mice have a common ancestry and a high degree of gene sharing, including an extensive region of the MHC (3)(4)(5). ALR mice were originally selected for ␤ cell resistance to chemical diabetes produced by alloxan, a potent generator of hydroxyl radicals (6). However, subsequent studies showed that resistance was systemic, entailing increased activities of antioxidant enzyme activities in multiple tissues and higher tissue ratios of reduced to oxidized glutathione (7).…”

mentioning

confidence: 99%

Mechanisms Underlying Resistance of Pancreatic Islets from ALR/Lt Mice to Cytokine-Induced Destruction

Mathews

Suarez-Pinzon²,

Baust

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

Nuclear and mitochondrial genomes combine in ALR/Lt mice to produce systemically elevated defenses against free radical damage, rendering these mice resistant to immune-mediated pancreatic islet destruction. We analyzed the mechanism whereby isolated islets from ALR mice resisted proinflammatory stress mediated by combined cytokines (IL-1β, TNF-α, and IFN-γ) in vitro. Such damage entails both superoxide and NO radical generation, as well as peroxynitrite, resulting from their combination. In contrast to islets from other mouse strains, ALR islets expressed constitutively higher glutathione reductase, glutathione peroxidase, and higher ratios of reduced to oxidized glutathione. Following incubation with combined cytokines, islets from control strains produced significantly higher levels of hydrogen peroxide and NO than islets from ALR mice. Nitrotyrosine was generated in NOD and C3H/HeJ islets but not by ALR islets. Western blot analysis showed that combined cytokines up-regulated the NF-κB inducible NO synthase in NOD-Rag and C3H/HeJ islets but not in ALR islets. This inability of cytokine-treated ALR islets to up-regulate inducible NO synthase and produce NO correlated both with reduced kinetics of IκB degradation and with markedly suppressed NF-κB p65 nuclear translocation. Hence, ALR/Lt islets resist cytokine-induced diabetogenic stress through enhanced dissipation and/or suppressed formation of reactive oxygen and nitrogen species, impaired IκB degradation, and blunted NF-κB activation. Nitrotyrosylation of β cell proteins may generate neoantigens; therefore, resistance of ALR islets to nitrotyrosine formation may, in part, explain why ALR mice are resistant to type 1 diabetes when reconstituted with a NOD immune system.

show abstract

“…The ALR mouse was derived from the same outbred population as the NOD strain (1, 31) and shares significant genomic similarity: 85% genetic identity at SNPs typed genome-wide (32). However, unlike the NOD, ALR mice are extremely resistant against the development of both spontaneous and induced T1D.…”

Section: Discussionmentioning

confidence: 99%

The Type 1 Diabetes–Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice

Whitener

Knight

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

Type 1 Diabetes (T1D) has a strong genetic component. The Insulin dependent diabetes 22 (Idd22) locus was identified in crosses of T1D-susceptible NOD mice with the strongly T1D-resistant ALR strain. The NOD-Idd22 recombinant congenic mouse strain was generated where NOD mice carry the full Idd22 confidence interval. NOD-Idd22 mice exhibit almost complete protection from spontaneous T1D and a significant reduction in insulitis. Our goal was to unravel the mode of Idd22 based protection using in vivo and in vitro models. We determined that Idd22 did not impact immune cell diabetogenicity or β-cell resistance to cytoxicity in vitro. However, NOD-Idd22 mice were highly protected against adoptive transfer of T1D. Transferred CTL trafficked to the pancreatic lymph node (PLN) and proliferated to the same extent in NOD and NOD-Idd22 mice yet, the accumulation of pathogenic CTL in the islets was significantly reduced in NOD-Idd22 mice, correlating with disease resistance. Pancreatic endothelial cells from NOD-Idd22 animals expressed lower levels of adhesion molecules, even in response to inflammatory stimuli. Lower adhesion molecule expression resulted in weaker adherence of T cells to NOD-Idd22 endothelium as compared to NOD derived endothelium. Taken together, these results provide evidence that Idd22 regulates the ability of β-cell autoreactive T cells to traffic into the pancreatic islets and may represent a new target for pharmaceutical intervention to potentially prevent T1D.

show abstract

Selection of Mouse Strains Showing High and Low Incidences of Alloxan-induced Diabetes

Cited by 19 publications

References 7 publications

Development of diabetes in lean Ncb5or-null mice is associated with manifestations of endoplasmic reticulum and oxidative stress in beta cells

Development of diabetes in lean Ncb5or-null mice is associated with manifestations of endoplasmic reticulum and oxidative stress in beta cells

Mechanisms Underlying Resistance of Pancreatic Islets from ALR/Lt Mice to Cytokine-Induced Destruction

The Type 1 Diabetes–Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice

Contact Info

Product

Resources

About