A new model of insulin-deficient diabetes: Male NOD mice with a single copy of Ins1 and no Ins2

Abstract

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 (NODIns1+/+,Ins2-/-), mice with a single copy of Ins1 (NODIns1+/-,Ins2-/-), mice with two copies of Ins2 (NODIns1-/-,Ins2+/+), mice with a single copy of Ins2 (NOD Ins1-/-,Ins2+/-) and NODIns1+/-,Ins2-/- mice with a transgene encoding B16:Ala pro insulin. Results: By 10 weeks of age, all male NODIns1+/-,Ins2-/- mice were diabetic, whereas all female NOD Ins1+/-,Ins2-/- were not diabetic (p<0.0001). In contrast, neither male nor female NODIns1-/-,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 NODIns1+/-,Ins2-/- at this early age had no lymphocyte infiltration. Instead there was heterogeneous (between islet cells) weak staining for insulin. Although only male NODIns1+/-,Ins2-/- mice developed diabetes, both male and female NODIns1+/-,Ins2-/- mice had markedly decreased insulin content. In NODIns1+/+,Ins2-/-, there was also a significant decrease in insulin content, whereas NODIns1-/-,Ins2+/+ mice, and even NODIns1-/-,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. © Springer-Verlag 2006.