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

Abstract

Aims/hypothesis: 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. Materials and methods: To estimate C-peptide levels and autoantibody presentation, patients underwent a mealstimulated 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/interpretation: 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 recentonset type 1 diabetes.

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

“…Recently, a more preserved beta cell function in recent-onset cases was found in individuals with the INS VNTR class III allele compared with those carrying class I alleles [37]. These data are in line with the hypothesis proposing that the INS-VNTR has a role in the regulation of insulin gene transcription in the thymus and modulation of insulin-specific self tolerance [38,39].…”

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

“…The sensitivity was below 1pmol/l, the intra-assay coefficient of variation were below 6% at 20pmol/l, and recovery of the standard, added to plasma before extraction, was about 100% when corrected for losses inherent in the plasma extraction procedure [12].…”

“…The design and characteristics of the Hvidøre Study has been explained elsewhere, [11,12]. In brief, prospective clinical and biochemical data of one year from diagnosis were available for 256 children and adolescents (134 girls and 122 boys, median age 9.6years, range 3months to 16.8years) out of 275 initially investigated patients at baseline (response rate 93.1%).…”

“…Blood was drawn 90min after ingestion of the standardized liquid meal by venipuncture according to a standard protocol [12]. Thereby, an influence of catheterization on possible local production of inflammatory mediators during the 90min boost test could be excluded [18].…”

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

“…15,16 Allelic variation at INS-VNTR confers differential susceptibility to T1D. Subjects with the VNTR III genotype have a lower frequency of anti-insulin autoantibodies, 17 more preserved b-cell function 18 and a lower concordance rate of diabetes among twins 19 when compared with subjects having the VNTR I/I genotype. Overall, the INS-VNTR genotype is associated with an odds ratio for T1D susceptibility of 2.2, 20 and the presence of the VNTR III genotype can moderate disease risk, even in populations that carry high-risk HLA genotypes.…”