Proinsulin 2 knockout NOD mice: a model for genetic variation of insulin gene expression in type 1 diabetes.
Insulin is a major disease determinant in type 1 diabetes, type 2 diabetes, and related disorders. The role of variations in the expression of the insulin gene has been proposed in genetic susceptibility to the three pathological conditions in humans. In contrast to humans, rodents express two proinsulin isoforms. One isoform, proinsulin 1, is expressed exclusively in islets. The second, proinsulin 2, is expressed in islets and in other tissues, especially the thymus. We took advantage of the expression of these two isoforms to introduce a null proinsulin 2 allele in NOD mice and to evaluate the consequence of a variation of proinsulin 2 gene expression on the development of type 1 diabetes on the NOD genetic background. Heterozygote NOD mutant mice carrying a null proinsulin 2 mutation showed an increased incidence of type 1 diabetes at successive backcross generations. Plasma glucose and insulin levels were identical in prediabetic mutant and in wild-type mice at 4 weeks of age. Variation in insulin gene expression is hypothesized to interfere with diabetes development at both the islet and the thymus level.
Dubois-Lafforgue
Danièle
D
Institut National de la Santé et de la Recherche Médicale (INSERM) U561, Hôpital Saint Vincent de Paul, Paris, France.
Mogenet
Laurent
L
Thébault
Karine
K
Jami
Jacques
J
Krief
Patricia
P
Boitard
Christian
C
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D007328:Insulin / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics / Q000502:physiology*; D018345:Mice, Knockout / Q000235:genetics; D011384:Proinsulin / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology
D007328:Insulin; D020033:Protein Isoforms; D011384:Proinsulin