Impact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: reduced insulin antibody titres and preserved beta cell function.
OBJECTIVE
The insulin-dependent diabetes mellitus 2 gene (IDDM2) is a type 1 diabetes susceptibility locus contributed to by the variable number of tandem repeats (VNTR) upstream of the insulin gene (INS). We investigated the association between INS VNTR class III alleles (-23HphIA/T) and both insulin antibody presentation and residual beta cell function during the first year after diagnosis in 257 children with type 1 diabetes.


METHODS
To estimate C-peptide levels and autoantibody presentation, patients underwent a meal-stimulated C-peptide test 1, 6, and 12 months after diagnosis. The insulin -23HphIA/T variant was used as a marker of class III alleles and genotyped by PCR-RFLP.


RESULTS
The insulin antibody titres at 1 and 6 months were significantly lower in the class III/III and class I/III genotype groups than in the class I/I genotype group (p = 0.01). Class III alleles were also associated with residual beta cell function 12 months after diagnosis and independently of age, sex, BMI, insulin antibody titres, and HLA-risk genotype group (p = 0.03). The C-peptide level was twice as high among class III/III genotypes as in class I/I and class I/III genotypes (319 vs 131 and 166 pmol/l, p=0.01). Furthermore, the class III/III genotype had a 1.1% reduction in HbA(1)c after adjustment for insulin dose (p = 0.04).


CONCLUSIONS
These findings suggest a direct connection in vivo between INS VNTR class III alleles, a decreased humoral immune response to insulin, and preservation of beta cell function in recent-onset type 1 diabetes.
Nielsen
L B
LB
Department of Paediatrics, Glostrup University Hospital, Ndr. Ringvej 57, D-2600 Glostrup, Denmark. lbn@dcb-glostrup.dk
Mortensen
H B
HB
Chiarelli
F
F
Holl
R
R
Swift
P
P
de Beaufort
C
C
Pociot
F
F
Hougaard
P
P
Gammeltoft
S
S
Knip
M
M
Hansen
L
L
D002096:C-Peptide / Q000097:blood; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007330:Insulin Antibodies / Q000097:blood*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D018598:Minisatellite Repeats / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013997:Time Factors
D002096:C-Peptide; D007328:Insulin; D007330:Insulin Antibodies