Bingley P J, Gale E A M
Diabetes and Metabolism, Department of Clinical Science at North Bristol, University of Bristol, Southmead Hospital, UK.
Diabetologia. 2006 May;49(5):881-90. doi: 10.1007/s00125-006-0160-4. Epub 2006 Mar 3.
AIMS/HYPOTHESIS: To examine the role of additional immune, genetic and metabolic risk markers in determining risk of diabetes in islet cell antibody (ICA)-positive individuals with a family history of type 1 diabetes recruited into the European Nicotinamide Diabetes Intervention Trial.
Five hundred and forty-nine first-degree relatives with confirmed ICA levels > or =20 Juvenile Diabetes Foundation units (mean age 15.9 years; interquartile range 10.4-33.7 years) were recruited from 20 countries. OGTTs and IVGTTs were performed at baseline, antibodies to glutamate decarboxylase (GADA), protein tyrosine phosphatase (IA-2A) and insulin (IAA) were determined by RIA, and HLA class II genotyping was performed by PCR of sequence-specific oligonucleotides.
One hundred and fifty-nine participants developed diabetes within 5 years. Univariate analysis showed that the cumulative risk of development of diabetes within 5 years varied according to age, relationship to the proband, positivity for IAA, IA-2A and GADA, number and combination of islet antibodies, HLA class II genotype, baseline glucose tolerance, and first-phase insulin secretion, but not gender or incidence of childhood type 1 diabetes in the background population. Children aged < or =10 years had a 59% risk of diabetes within 5 years, compared with 11% in those > or =25 years (p<0.0001). Using multivariate analysis, independent determinants were age, first-phase insulin response, baseline glucose tolerance and number of additional antibody markers, but not antibody type or genotype. Individuals <25 years with two or more additional antibodies at baseline had a 62% risk of diabetes within 5 years and these combined criteria identified 81% of the cases in the whole cohort.
CONCLUSIONS/INTERPRETATION: We suggest that screening and recruitment for future intervention trials should be limited to family members aged <25 years, and should be based on islet autoantibodies alone.
目的/假设：在欧洲烟酰胺糖尿病干预试验招募的有1型糖尿病家族史的胰岛细胞抗体（ICA）阳性个体中，研究额外的免疫、遗传和代谢风险标志物在确定糖尿病风险中的作用。
从20个国家招募了549名确诊ICA水平≥20青少年糖尿病基金会单位的一级亲属（平均年龄15.9岁；四分位间距10.4 - 33.7岁）。在基线时进行口服葡萄糖耐量试验（OGTT）和静脉葡萄糖耐量试验（IVGTT），通过放射免疫分析法测定谷氨酸脱羧酶抗体（GADA）、蛋白酪氨酸磷酸酶抗体（IA - 2A）和胰岛素抗体（IAA），并通过序列特异性寡核苷酸的聚合酶链反应（PCR）进行HLA II类基因分型。
159名参与者在5年内患糖尿病。单因素分析显示，5年内糖尿病发生的累积风险因年龄、与先证者的关系、IAA、IA - 2A和GADA的阳性情况、胰岛抗体的数量和组合、HLA II类基因型、基线葡萄糖耐量和第一相胰岛素分泌而异，但与性别或背景人群中儿童1型糖尿病的发病率无关。年龄≤10岁的儿童5年内患糖尿病的风险为59%，而年龄≥25岁的儿童为11%（p<0.0001）。使用多因素分析，独立的决定因素是年龄、第一相胰岛素反应、基线葡萄糖耐量和额外抗体标志物的数量，而不是抗体类型或基因型。基线时有两种或更多额外抗体的25岁以下个体5年内患糖尿病的风险为62%，这些综合标准在整个队列中识别出81%的病例。
结论/解读：我们建议，未来干预试验的筛查和招募应限于25岁以下的家庭成员，并且应仅基于胰岛自身抗体。
