A new model of insulin-deficient diabetes: male NOD mice with a single copy of Ins1 and no Ins2.
OBJECTIVE
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).


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
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.
Babaya
N
N
Barbara Davis Center for Childhood Diabetes, University of Colorado, 1775 N. Ursula St., Aurora, CO 80045-6511, USA.
Nakayama
M
M
Moriyama
H
H
Gianani
R
R
Still
T
T
Miao
D
D
Yu
L
L
Hutton
J C
JC
Eisenbarth
G S
GS
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005951:Glucose Tolerance Test; D007328:Insulin / Q000032:analysis / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000737:chemistry; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics*; D018345:Mice, Knockout; D012727:Sex Characteristics
C514817:Ins1 protein, mouse; D007328:Insulin