Truyen I, De Pauw P, Jørgensen P N, Van Schravendijk C, Ubani O, Decochez K, Vandemeulebroucke E, Weets I, Mao R, Pipeleers D G, Gorus F K
Diabetes Research Center, Brussels Free University-VUB, Brussels, Belgium.
Diabetologia. 2005 Nov;48(11):2322-9. doi: 10.1007/s00125-005-1959-0. Epub 2005 Oct 7.
AIMS/HYPOTHESIS: We investigated whether random proinsulin levels and proinsulin:C-peptide ratio (PI:C) complement immune and genetic markers for identifying relatives at high risk of type 1 diabetes.
During an initial sampling, random glycaemia, proinsulin, PI:C and HLA DQ genotype were determined in 561 non-diabetic first-degree relatives who had been positive for islet autoantibodies on one or more occasions and in 561 age- and sex-matched persistently antibody-negative relatives.
During follow-up (median 62 months), 46 relatives with antibodies at entry developed type 1 diabetes. At baseline, antibody-positive relatives (n=338) had higher PI:C values (p<0.001) than antibody-negative subjects with (n=223) or subjects without (n=561) later seroconversion. Proinsulin and PI:C were graded according to risk of diabetes as expressed by positivity for (multiple) antibodies or IA-2 antibodies, especially in persons carrying the high-risk HLA DQ2/DQ8 genotype and in prediabetic relatives. In the presence of multiple or IA-2 antibodies, a PI:C ratio exceeding percentile 66 of all antibody-negative relatives at entry (n=784) conferred a 5-year diabetes risk of 50% and 68%, respectively (p<0.001 vs 13% for same antibody status with PI:C<percentile 66). Cox regression analysis confirmed random PI:C as an independent predictor of the risk of diabetes (p< or =0.001).
CONCLUSIONS/INTERPRETATION: Random proinsulin and PI:C represent dynamic markers of the state of beta cell function that complement immune markers in identifying relatives who are at homogeneously high risk of contracting type 1 diabetes and are therefore eligible for secondary prevention trials.
目的/假设：我们研究了随机胰岛素原水平和胰岛素原与C肽比值（PI:C）是否可补充免疫和遗传标志物，用于识别1型糖尿病高危亲属。
在初次采样时，测定了561名非糖尿病一级亲属的随机血糖、胰岛素原、PI:C和HLA DQ基因型，这些亲属曾一次或多次胰岛自身抗体检测呈阳性，同时测定了561名年龄和性别匹配的持续抗体阴性亲属。
在随访期间（中位时间62个月），46名入组时抗体阳性的亲属发生了1型糖尿病。基线时，抗体阳性亲属（n = 338）的PI:C值高于抗体阴性且后来血清转化的亲属（n = 223）以及抗体阴性且未发生血清转化的亲属（n = 561）（p < 0.001）。胰岛素原和PI:C根据糖尿病风险进行分级，以（多种）抗体或IA - 2抗体阳性表示，特别是在携带高危HLA DQ2/DQ8基因型的人群和糖尿病前期亲属中。在存在多种或IA - 2抗体的情况下，PI:C比值超过所有入组时抗体阴性亲属（n = 784）的第66百分位数，5年糖尿病风险分别为50%和68%（与PI:C低于第66百分位数且抗体状态相同者的13%相比，p < 0.001）。Cox回归分析证实随机PI:C是糖尿病风险的独立预测指标（p ≤ 0.001）。
结论/解读：随机胰岛素原和PI:C代表β细胞功能状态的动态标志物，可补充免疫标志物，用于识别1型糖尿病均一性高危亲属，因此适合进行二级预防试验。
