Autoimmunity against INS-IGF2 protein expressed in human pancreatic islets.
Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain, and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine the expression of INS-IGF2 in human pancreatic islets and autoantibodies in newly diagnosed children with type 1 diabetes and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared with donors with either type 2 diabetes (p = 0.006) or high HbA1c levels (p < 0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed patients with type 1 diabetes (n = 304) compared with healthy controls (n = 355; p < 0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain, and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody-binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes.
From the Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Skåne University Hospital SUS, SE-205 02 Malmö, Sweden and.
Norio
N
Kanatsuna
Jalal
J
Taneera
Fariba
F
Vaziri-Sani
Nils
N
Wierup
Helena Elding
HE
Larsson
Ahmed
A
Delli
Hanna
H
Skärstrand
Alexander
A
Balhuizen
Hedvig
H
Bennet
Donald F
DF
Steiner
Carina
C
Törn
Malin
M
Fex
Åke
Å
Lernmark
D000293:Adolescent; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000276:immunology*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics / Q000276:immunology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D050506:Mutant Chimeric Proteins / Q000097:blood / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis; D011498:Protein Precursors / Q000097:blood / Q000276:immunology*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000378:metabolism; D014158:Transcription, Genetic
D001323:Autoantibodies; D018076:DNA, Complementary; C584675:INS-IGF2 protein, human; D007328:Insulin; D050506:Mutant Chimeric Proteins; D011498:Protein Precursors; C013737:preproinsulin; D007335:Insulin-Like Growth Factor II; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
Antibodies; Antigen; Beta Cell; Diabetes; Insulin; Insulin-like Growth Factor (IGF); Pancreatic Islets; Radioimmune Assays