GAD Antibodies Seldom Disappear in Slowly Progressive IDDM
GAD Antibodies Seldom Disappear in Slowly Progressive IDDM
复制标题
在缓慢进展的 IDDM 中，GAD 抗体很少消失
作者：
Kobayashi Tetsuro;K. Nakanishi;M. Okubo;T. Murase;K. Kosáka
芬兰最近的一项研究报告了中年NIDDM患者中GAD抗体（Ab）的高发率(1)。然而，GAD抗体和胰岛细胞抗体（ICA）的时间过程尚未得到充分的研究。我们正在对伴有胰岛细胞自身抗体（慢进行性IDDM）的NIDDM患者的j8细胞功能进行前瞻性研究（2,3）。在这里，我们前瞻性地检查了GAD Ab和ICA的时间过程，并评估了抗体对NIDDM诊断后j3细胞功能障碍的预测价值。共有848名NIDDM患者从转诊人群中招募，并接受饮食或饮食和口服降糖药治疗，筛选GAD Ab和ICA。诊断后进行初筛血。在随访期间（95±31个月[范围36-126个月]），检测GAD Ab、ICA和c肽反应（CPR）对100 g口服葡萄糖耐量试验（OGTT）的纵向变化。胰岛素治疗的适应症包括空腹血糖水平达到> 12.2 mmol/1和/或HbA， >10%，最大日剂量格列本脲（15 mg）。用放射性结合法对库存样品进行GAD - Ab检测(4)。第二届GAD研讨会评估的GAD抗体检测质量如下：敏感性80%，特异性100%，正常范围< 5u（非糖尿病个体平均+ 3sd值）。间接免疫荧光法测定ICAs(2)。共有1.1% (10/848)NIDDM患者GAD Ab阳性，3.2% (27/848)NIDDM患者ICA阳性。根据GAD Ab和ICA的基线阳性，将NIDDM患者分为3组：ICA和GAD Ab f（组1:n = 10，男/女：5/5，发病年龄：46±11岁，持续时间：0.9±1.6年，mean±SD）；ICA和GAD”（第二组：n = 17，男/女：9/8，发病年龄：47±12岁，病程：0.8±1.2年）；（3组：n = 61，男/女：34/ 27，发病年龄：49±9岁，病程：1.4±3.2年）。第3组患者从821例初始GAD Ab和ICA均为阴性的NIDDM患者中选择。他们在年龄、性别和糖尿病病程方面与1组和2组患者相匹配。第三组患者是在研究开始时招募的。他们计划根据3比1的对照组：受试者组比例来匹配第一组和第二组。所有1组患者在4年内都需要胰岛素（图1）。在整个研究过程中，所有1组患者的GAD抗体持续呈高滴度阳性（基线滴度：687±388 U；研究结束时滴度[入组后80±35个月]:637±1346 U [NS与基线相比]）。1组患者血清c肽与OGTT的综合值（2次CPR，正常范围：7.9 ~ 13.6 nmol/1）由6.0±2.7变化为0.9±1.2 nmol/1，差异有统计学意义（P < 0.01）。在2组患者中，47%（8/17）患者需要胰岛素的频率低于1组患者（P < 0.01； Cox-Mantel试验，图1）。2组患者GAD抗体持续阴性。1组患者的ICA在整个研究过程中持续呈阳性，而2组患者在观察期间有53%（9/17）的ICA呈阴性。第2组患者的X CPR值在入组时为7.8±3.1 nmol/1，在研究结束时为7.0±3.9 nmol/1 （NS与基线比较）。在研究期间GAD Ab和ICA均为阴性的3组患者中，只有2%（1/61）需要胰岛素治疗（P < 0.01）
A recent Finnish study reported high prevalence of antibodies to GAD antibodies (Ab) in middle-aged patients with NIDDM (1). However, the time course of GAD Ab and islet cell antibody (ICA) has not been fully studied. We are conducting a prospective study on j8-cell function in NIDDM patients with islet cell autoantibodies (slowly progressive IDDM) (2,3). Here, we have prospectively examined the time course of GAD Ab and ICA and evaluated the predictive value of the antibodies for j3-cell dysfunction after diagnosis of NIDDM. A total of 848 NIDDM patients, who were recruited from referral-based population and treated with diet or diet and oral hypoglycemic agents, were screened for GAD Ab and ICA. Initial screening blood was obtained after diagnosis. Longitudinal changes of GAD Ab, ICA, and C-peptide response (CPR) to a 100-g oral glucose tolerance test (OGTT) were examined during follow-up period (95 ± 3 1 months [range 36-126 months]). The indication for insulin therapy included fasting blood glucose level becoming > 12.2 mmol/1 and/or HbA, >10% with the maximal daily dose of glibenclamide (15 mg). GAD Ab were assayed on stocked samples by radiobinding assay (4). The quality of GAD Ab assay evaluated in the 2nd GAD Workshop was as follows: sensitivity 80%, specificity 100% with a normal range <5 U (mean +3 SD value of nondiabetic individuals). ICAs were measured by indirect immunofluorescence method (2). A total of 1.1% (10/848) NIDDM patients were positive for GAD Ab, and 3.2% (27/848) were positive for ICA. Based on the baseline positivity of GAD Ab and ICA, the NIDDM patients were divided into three groups: ICA and GAD Ab f (group 1: n = 10, men/women: 5/5, age at onset: 46 ± 11 years, duration: 0.9 ± 1.6 years, mean ± SD); ICA and GAD " (group 2: n = 17, men/women: 9/8, age at onset: 47 ± 12 years, duration: 0.8 ± 1.2 years); and ICA" and GAD Ab (group 3: n = 61, men/women: 34/ 27, age at onset: 49 ± 9 years, duration: 1.4 ± 3.2 years). Group 3 patients were selected from 821 NIDDM patients, who were initially both negative for GAD Ab and ICA. They were matched to groups 1 and 2 patients with respect to age, sex, and duration of diabetes. Group 3 patients were recruited at the beginning of the study. They were planned to match groups 1 and 2 based on a 3-to-l control group:subject group ratio. All group 1 patients required insulin within 4 years (Fig. 1). GAD Abs in all group 1 patients were persistently positive with high titer throughout the study (titer at baseline: 687 ± 388 U; and titer at completion of the study [80 ± 35 months after entry]: 637 ± 1,346 U [NS vs. baseline]). The integrated value of serum C-peptide to OGTT (2 CPR, normal range: 7.9-13.6 nmol/1) in group 1 patients changed markedly from 6.0 ± 2.7 to 0.9 ± 1.2 nmol/1 (P < 0.01 vs. baseline). Of group 2 patients, 47% (8/17) required insulin less frequently than did group 1 patients (P < 0.01; Cox-Mantel test, Fig. 1). GAD Ab was persistently negative in group 2 patients. ICAs in group 1 patients were persistently positive throughout the study, while ICA became negative in 53% (9/17) of group 2 patients during the observation period. The values of X CPR in group 2 patients were 7.8 ± 3.1 nmol/1 at entry and 7.0 ± 3.9 nmol/1 at the completion of the study (NS vs. baseline). Only 2% (1/61) of group 3 patients, who were negative for both GAD Ab and ICA throughout the study period, required insulin (P < 0.01 vs. other groups; Cox-