Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse.
It has been reported that an insulin 2 gene knockout, when bred onto nonobese diabetic (NOD) mice, accelerates diabetes. We produced insulin 1 gene knockout congenic NOD mice. In contrast to insulin 2, diabetes and insulitis were markedly reduced in insulin 1 knockout mice, with decreased and delayed diabetes in heterozygous females and no insulitis and diabetes in most homozygous female mice. Lack of insulitis was found for insulin 1 female homozygous knockout mice at 8, 12, and 37 weeks of age. Despite a lack of insulitis, insulin 1 homozygous knockout mice spontaneously expressed insulin autoantibodies. Administration of insulin peptide B:9-23 of both insulin 1 and 2 to NOD mice induced insulin autoantibodies. Insulin 1 is not the only lymphocytic target of NOD mice. Insulin 1 homozygous knockout islets, when transplanted into recently diabetic wild-type NOD mice, became infiltrated with lymphocytes and only transiently reversed diabetes. These observations indicate that loss of either insulin gene can influence progression to diabetes of NOD mice and suggest that the preproinsulin 1 gene is crucial for the spontaneous development of NOD insulitis and diabetes.
Moriyama
Hiroaki
H
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Abiru
Norio
N
Paronen
Johanna
J
Sikora
Kamila
K
Liu
Edwin
E
Miao
Dongmei
D
Devendra
Devasenan
D
Beilke
Joshua
J
Gianani
Roberto
R
Gill
Ron G
RG
Eisenbarth
George S
GS
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D005260:Female; D007328:Insulin; D007330:Insulin Antibodies / Q000097:blood; D007515:Islets of Langerhans / Q000473:pathology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011384:Proinsulin / Q000235:genetics / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology
D007328:Insulin; D007330:Insulin Antibodies; D011498:Protein Precursors; C013737:preproinsulin; D011384:Proinsulin