Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children
Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children
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DOI：
10.1111/j.1399-5448.2010.00681.x
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发表时间：
2011-05-01
影响因子：
3.4
通讯作者：
Verge, Charles F.
中科院分区：
文献类型：
--
作者：
Hameed, Shihab;Ellard, Sian;Verge, Charles F.
背景：自身抗体阴性诊断为1型糖尿病的儿童可能患有未被识别的单基因或2型糖尿病。研究设计和方法：在诊断为1型糖尿病时（年龄在0.5 ~ 16.3岁之间，n = 470），自身抗体[谷氨酸脱羧酶（GAD）、胰岛素瘤相关蛋白2 （IA2）、胰岛素自身抗体（IAA）和/或胰岛细胞抗体（ICA）]阳性330例，阴性37例（103例未知）。自身抗体阴性的患者在糖尿病病程中位数为3.2年（范围0.9-16.2）时重新检测自身抗体（GAD、IA2、ZnT8）、人白细胞抗原（HLA）分型、非空腹c肽，以及HNF4A、HNF1A、KCNJ11和INS的测序。结果：367例患者中有19例（5%）持续自身抗体阴性（PAN）， 17例（PORT）阳性，1例拒绝复检。PORT未发现突变。一个PAN是HNF1A中P112L突变的杂合，并从胰岛素转移到口服格列齐特。另一个PAN转移到二甲双胍，诊断修改为2型糖尿病。其余17例PAN与ab+组的临床特征难以区分。HLA基因型在剩余PAN和PORT中分别有82%和100%的1型糖尿病高危。在排除糖尿病病程< 1年的患者后，剩余PAN（7/16）和PORT（6/17）的c肽检测频率高于随机选择ab+ (3/28, p = 0.03)。结论：PAN患者中有一部分患有单基因或2型糖尿病，因此应重新评估1型糖尿病的诊断。与ab+相比，剩余的PAN具有相对保存的c肽，提示β细胞破坏较慢，但糖尿病源性HLA的频率非常高，提示1B型（特发性）糖尿病罕见。
Background: Autoantibody-negative children diagnosed with type 1 diabetes might have unrecognized monogenic or type 2 diabetes.Research design and methods: At diagnosis of type 1 diabetes (between ages 0.5 and 16.3 yr, n = 470), autoantibodies [glutamic acid decarboxylase (GAD), insulinoma-associated protein 2 (IA2), insulin autoantibodies (IAA), and/or islet cell antibody (ICA)] were positive (ab+) in 330 and negative in 37 (unknown in 103). Autoantibody-negative patients were retested at median diabetes duration of 3.2 yr (range 0.9-16.2) for autoantibodies (GAD, IA2, ZnT8), human leukocyte antigen (HLA) typing, non-fasting C-peptide, and sequencing of HNF4A, HNF1A, KCNJ11, and INS.Results: Nineteen (5% of 367) remained persistently autoantibody negative (PAN), 17 were positive on repeat testing (PORT), and 1 refused retesting. No mutations were found in PORT. One PAN was heterozygous for P112L mutation in HNF1A and transferred from insulin to oral gliclazide. Another PAN transferred to metformin and the diagnosis was revised to type 2 diabetes. The remaining 17 PAN were indistinguishable from the ab+ group by clinical characteristics. HLA genotype was at high risk for type 1 diabetes in 82% of remaining PAN and 100% of PORT. After excluding patients with diabetes duration < 1 yr, C-peptide was detectable more frequently in the remaining PAN (7/16) and PORT (6/17) than in a random selection of ab+ (3/28, p = 0.03).Conclusions: The diagnosis of type 1 diabetes should be reevaluated in PAN patients, because a subset has monogenic or type 2 diabetes. The remaining PAN have relatively preserved C-peptide compared with ab+, suggesting slower beta-cell destruction, but a very high frequency of diabetogenic HLA, implying that type 1B (idiopathic) diabetes is rare.