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
Department of Paediatrics, Glostrup University Hospital, Ndr. Ringvej 57, D-2600 Glostrup, Denmark.
Diabetologia. 2006 Jan;49(1):71-4. doi: 10.1007/s00125-005-0042-1. Epub 2005 Nov 23.
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.
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.
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 recent-onset type 1 diabetes.
目的/假设：胰岛素依赖型糖尿病2基因（IDDM2）是1型糖尿病的一个易感位点，由胰岛素基因（INS）上游串联重复序列（VNTR）的可变数目所决定。我们调查了257例1型糖尿病患儿确诊后第一年中INS VNTR III类等位基因（-23HphIA/T）与胰岛素抗体呈现及残余β细胞功能之间的关联。
为评估C肽水平和自身抗体呈现情况，患者在确诊后1、6和12个月接受了餐刺激C肽试验。胰岛素-23HphIA/T变异用作III类等位基因的标志物，并通过PCR-RFLP进行基因分型。
III/III和I/III基因型组在1个月和6个月时的胰岛素抗体滴度显著低于I/I基因型组（p = 0.01）。III类等位基因还与确诊后12个月的残余β细胞功能相关，且独立于年龄、性别、BMI、胰岛素抗体滴度和HLA风险基因型组（p = 0.03）。III/III基因型的C肽水平是I/I和I/III基因型的两倍（319对131和166 pmol/l，p = 0.01）。此外，在调整胰岛素剂量后，III/III基因型的糖化血红蛋白（HbA1c）降低了1.1%（p = 0.04）。
结论/解读：这些发现提示，在新近发病的1型糖尿病中，INS VNTR III类等位基因、对胰岛素的体液免疫反应降低与β细胞功能的保留之间存在直接的体内联系。
