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

• Published in: Diabetologia 2006, Vol.49 (1), p.71-74
• Main Authors: Nielsen, L. B, Mortensen, H. B, Chiarelli, F, Holl, R, Swift, P, de Beaufort, C, Pociot, F, Hougaard, P, Gammeltoft, S, Knip, M, Hansen, L
• Format: Article
• Language: English
• Subjects: Beta cell function; Biological and medical sciences; C-Peptide - blood; Child; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Follow-Up Studies; Genetic Predisposition to Disease; Humans; IDDM2; Insulin - genetics; Insulin antibodies; Insulin Antibodies - blood; insulin-dependent diabetes mellitus; Insulin-Secreting Cells - secretion; Medical sciences; Minisatellite Repeats - genetics; Polymorphism, Single Nucleotide; Time Factors
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-005-0042-1

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 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 HbA₁c 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 recent-onset type 1 diabetes.