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Erschienen in:
01.06.2006 | Article
A new model of insulin-deficient diabetes: male NOD mice with a single copy of Ins1 and no Ins2
Erschienen in: Diabetologia | Ausgabe 6/2006
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Aims/hypothesis
We describe a novel model of insulin-deficient diabetes with a single copy of the gene encoding insulin 1 (Ins1) and no gene encoding insulin 2 (Ins2).
Materials and methods
We constructed five lines of mice: mice with two copies of Ins1 (NOD
Ins1+/+,Ins2−/−), mice with a single copy of Ins1 (NOD
Ins1+/−,Ins2−/−), mice with two copies of Ins2 (NOD
Ins1−/−,Ins2+/+), mice with a single copy of Ins2 (NOD
Ins1−/−,Ins2+/−) and NOD
Ins1+/−,Ins2−/− mice with a transgene encoding B16:Ala proinsulin.
Results
By 10 weeks of age, all male NOD
Ins1+/−,Ins2−/− mice were diabetic, whereas all female NOD
Ins1+/−,Ins2−/− were not diabetic (p<0.0001). In contrast, neither male nor female NOD
Ins1−/−,Ins2+/− with a single copy of Ins2 (rather than single copy of Ins1) developed early diabetes and no mice with two copies of either gene developed early diabetes. Islets of the diabetic male NOD
Ins1+/−,Ins2−/− at this early age had no lymphocyte infiltration. Instead there was heterogeneous (between islet cells) weak staining for insulin. Although only male NOD
Ins1+/−,Ins2−/− mice developed diabetes, both male and female NOD
Ins1+/−,Ins2−/− mice had markedly decreased insulin content. In NOD
Ins1+/+,Ins2−/−, there was also a significant decrease in insulin content, whereas NOD
Ins1−/−,Ins2+/+ mice, and even NOD
Ins1−/−,Ins2+/− mice, were normal. Male NOD
Ins1+/−,Ins2−/− mice were completely rescued from diabetes by introduction of a transgene encoding proinsulin. On i.p. insulin tolerance testing, male mice had insulin resistance compared with female mice.
Conclusions/interpretation
These results suggest that Ins1 is a ‘defective gene’ relative to Ins2, and that the mouse lines created provide a novel model of sex-dimorphic insulin-deficient diabetes.