Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstrase 1, Neuherberg, Germany 85764.
JAMA. 2013 Jun 19;309(23):2473-9. doi: 10.1001/jama.2013.6285.
Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain.
To determine the rate of progression to diabetes after islet autoantibody seroconversion.
DESIGN, SETTING, AND PARTICIPANTS: Data were pooled from prospective cohort studies performed in Colorado (recruitment, 1993-2006), Finland (recruitment, 1994-2009), and Germany (recruitment, 1989-2006) examining children genetically at risk for type 1 diabetes for the development of insulin autoantibodies, glutamic acid decarboxylase 65 (GAD65) autoantibodies, insulinoma antigen 2 (IA2) autoantibodies, and diabetes. Participants were all children recruited and followed up in the 3 studies (Colorado, 1962; Finland, 8597; Germany, 2818). Follow-up assessment in each study was concluded by July 2012.
The primary analysis was the diagnosis of type 1 diabetes in children with 2 or more autoantibodies. The secondary analysis was the diagnosis of type 1 diabetes in children with 1 autoantibody or no autoantibodies.
Progression to type 1 diabetes at 10-year follow-up after islet autoantibody seroconversion in 585 children with multiple islet autoantibodies was 69.7% (95% CI, 65.1%-74.3%), and in 474 children with a single islet autoantibody was 14.5% (95% CI, 10.3%-18.7%). Risk of diabetes in children who had no islet autoantibodies was 0.4% (95% CI, 0.2%-0.6%) by the age of 15 years. Progression to type 1 diabetes in the children with multiple islet autoantibodies was faster for children who had islet autoantibody seroconversion younger than age 3 years (hazard ratio [HR], 1.65 [95% CI, 1.30-2.09; P < .001]; 10-year risk, 74.9% [95% CI, 69.7%-80.1%]) vs children 3 years or older (60.9% [95% CI, 51.5%-70.3%]); for children with the human leukocyte antigen (HLA) genotype DR3/DR4-DQ8 (HR, 1.35 [95% CI, 1.09-1.68; P = .007]; 10-year risk, 76.6% [95% CI, 69.2%-84%]) vs other HLA genotypes (66.2% [95% CI, 60.2%-72.2%]); and for girls (HR, 1.28 [95% CI, 1.04-1.58; P = .02];10-year risk, 74.8% [95% CI, 68.0%-81.6%]) vs boys (65.7% [95% CI, 59.3%-72.1%]).
The majority of children at risk of type 1 diabetes who had multiple islet autoantibody seroconversion progressed to diabetes over the next 15 years. Future prevention studies should focus on this high-risk population.
1 型糖尿病通常有一个可通过循环胰岛自身抗体识别的临床前期阶段，但自身抗体转阳后进展为糖尿病的速度尚不确定。
确定胰岛自身抗体转阳后进展为糖尿病的速度。
设计、地点和参与者：数据来自科罗拉多州（招募，1993-2006 年）、芬兰（招募，1994-2009 年）和德国（招募，1989-2006 年）的前瞻性队列研究，这些研究在遗传上对 1 型糖尿病有风险的儿童中检查了胰岛素自身抗体、谷氨酸脱羧酶 65（GAD65）自身抗体、胰岛抗原 2（IA2）自身抗体和糖尿病的发展。所有参与者均为这 3 项研究（科罗拉多州，1962 年；芬兰，8597 年；德国，2818 年）招募并随访的儿童。每个研究的随访评估均于 2012 年 7 月结束。
主要分析是在胰岛自身抗体转阳的儿童中诊断为 1 型糖尿病，有 2 种或更多自身抗体。次要分析是在有 1 种自身抗体或无自身抗体的儿童中诊断为 1 型糖尿病。
在 585 名有多种胰岛自身抗体的儿童中，胰岛自身抗体转阳后 10 年的随访中，有 69.7%（95%CI，65.1%-74.3%）进展为 1 型糖尿病，在 474 名有单一胰岛自身抗体的儿童中为 14.5%（95%CI，10.3%-18.7%）。在没有胰岛自身抗体的儿童中，到 15 岁时，糖尿病的风险为 0.4%（95%CI，0.2%-0.6%）。在胰岛自身抗体转阳的儿童中，自身抗体转阳年龄小于 3 岁的儿童（HR，1.65 [95%CI，1.30-2.09；P<0.001]；10 年风险，74.9% [95%CI，69.7%-80.1%]）比 3 岁或以上的儿童（60.9% [95%CI，51.5%-70.3%]）进展为 1 型糖尿病的速度更快；对于 HLA 基因型为 DR3/DR4-DQ8 的儿童（HR，1.35 [95%CI，1.09-1.68；P=0.007]；10 年风险，76.6% [95%CI，69.2%-84%]）比其他 HLA 基因型（66.2% [95%CI，60.2%-72.2%]）的儿童更快；对于女孩（HR，1.28 [95%CI，1.04-1.58；P=0.02]；10 年风险，74.8% [95%CI，68.0%-81.6%]）比男孩（65.7% [95%CI，59.3%-72.1%]）更快。
大多数有多种胰岛自身抗体转阳风险的儿童在未来 15 年内进展为糖尿病。未来的预防研究应集中在这一高危人群。
