Verge C F, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson R A, Chase H P, Eisenbarth G S
Barbara Davis Center for Childhood Diabetes, Denver, Colorado, USA.
Diabetes. 1996 Jul;45(7):926-33. doi: 10.2337/diab.45.7.926.
Islet cell antibodies (ICAs) are predictive of type I diabetes in first-degree relatives, but this immunohistochemical assay has proven difficult to standardize. As an alternative, we assessed the use of radioassays for antibodies against three molecularly characterized islet autoantigens, including ICA512bdc (amino acid residues 256-979 of the IA-2 molecule, incorporating the intracellular domain). We measured insulin autoantibodies (IAAs), GAD autoantibodies (GAAs), and ICA512bdc autoantibodies (ICA512bdcAAs) by radioassay, in addition to ICAs, in 882 first-degree relatives of patients with type I diabetes, 50 of whom later developed diabetes with a median follow-up of 2.0 years (maximum 11.3 years). The cutoff for each radioassay was determined by testing >200 control subjects. When autoantibody frequencies among the relatives were analyzed according to relationship to the proband, the offspring of diabetic fathers had a higher frequency of ICA5I2bdcAAs (P = 0.008), IAAs (P = 0.0001) and GAAs (P = 0.0001) than the offspring of diabetic mothers. ICA512bdcAAs and IAAs both showed a significant association with HLA-DR4-DQ8 (P = 0.0005). Among relatives developing diabetes, 98% had one or more of IAAs, GAAs, or ICA512bdcAAs, and 80% had two or more of these autoantibodies, compared with none of the control subjects. Using survival analysis to allow for different lengths of follow-up, there was a significant increase in the risk of diabetes with the number of these autoantibodies present, comparing zero, one, two, and three autoantibodies (P < 0.0001, log-rank test), and by Cox regression analysis, this was independent of ICAs and age. For relatives with two or more of these autoantibodies, the risk of diabetes within 3 years was 39% (95% CI, 27-52) and the risk within 5 years was 68% (95% CI, 52-84). Relatives with all three autoantibodies had a risk within 5 years estimated to be 100%. The presence of low first-phase insulin release further increased the risk for relatives with one or two autoantibodies. We conclude that the presence of two or more autoantibodies (out of IAAs, GAAs, and ICA512bdcAAs) is highly predictive of the development of type I diabetes among relatives.
胰岛细胞抗体（ICAs）可预测一级亲属患I型糖尿病的风险，但这种免疫组织化学检测方法难以标准化。作为替代方法，我们评估了针对三种分子特征明确的胰岛自身抗原的抗体放射免疫测定法的应用，其中包括ICA512bdc（IA-2分子的氨基酸残基256 - 979，包含细胞内结构域）。我们通过放射免疫测定法测量了882名I型糖尿病患者一级亲属的胰岛素自身抗体（IAAs）、谷氨酸脱羧酶自身抗体（GAAs）和ICA512bdc自身抗体（ICA512bdcAAs），此外还测量了ICAs。其中50名亲属后来患糖尿病，中位随访时间为2.0年（最长11.3年）。每种放射免疫测定法的临界值通过检测200多名对照受试者来确定。当根据与先证者的关系分析亲属中的自身抗体频率时，糖尿病父亲的后代中ICA5I2bdcAAs（P = 0.008）、IAAs（P = 0.0001）和GAAs（P = 0.0001）的频率高于糖尿病母亲的后代。ICA512bdcAAs和IAAs均与HLA - DR4 - DQ8显著相关（P = 0.0005）。在患糖尿病的亲属中，98%有IAAs、GAAs或ICA512bdcAAs中的一种或多种，80%有两种或更多种这些自身抗体，而对照受试者中无一例有这些情况。使用生存分析来考虑不同的随访时间长度，与存在零种、一种、两种和三种自身抗体相比，随着这些自身抗体数量的增加，患糖尿病的风险显著增加（P < 0.0001，对数秩检验），并且通过Cox回归分析，这与ICAs和年龄无关。对于有两种或更多种这些自身抗体的亲属，3年内患糖尿病的风险为39%（95%可信区间，27 - 52），5年内患糖尿病的风险为68%（95%可信区间，52 - 84）。有所有三种自身抗体的亲属5年内患糖尿病的风险估计为100%。低第一相胰岛素释放的存在进一步增加了有一种或两种自身抗体的亲属患糖尿病的风险。我们得出结论：（IAAs、GAAs和ICA512bdcAAs中）存在两种或更多种自身抗体高度预测亲属中I型糖尿病的发生。
