Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies
Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies
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DOI：
10.1186/1472-6823-10-16
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发表时间：
2010-09-23
影响因子：
2.7
通讯作者：
Njolstad, Pal R.
中科院分区：
文献类型：
--
作者：
Porksen, Sven;Laborie, Lene Bjerke;Njolstad, Pal R.
背景资料：研究胰腺自身抗体[胰岛细胞自身抗体（伊卡）、谷氨酸脱羧酶抗体（GADA）和胰岛素瘤相关抗原-2抗体（IA-2A）]阴性（AAB阴性）的1型糖尿病儿童诊断后前12个月的疾病进展。此外，本研究旨在确定是否在KCNJ 11，ABCC 8，HNF 1A，HNF 4A或INS突变是常见的AAB阴性diabetes.Materials和方法：在261例新诊断的儿童1型糖尿病，我们测量残余β细胞功能，伊卡，GADA，IA-2A在1，6和12个月后诊断。对确诊时AAB阴性的受试者进行KCNJ 11、ABCC 8、HNF 1A、HNF 4A和INS基因测序。我们在非洲爪蟾卵母细胞中表达重组K-ATP通道，以分析ABCC 8突变的功能效应。结果：24例患者（9.1%）在一个月后检测AAB阴性。在12个月期间AAB阴性的患者在诊断后12个月具有较高的残余β细胞功能（P = 0.002），较低的血糖（P = 0.004），接受较少的胰岛素（P = 0.05）和较低的HbA（1c）（P = 0.02）。1例患者存在杂合突变，导致SUR 1（ABCC 8）残基1530处精氨酸被半胱氨酸取代。重组K-ATP通道的功能分析表明，R1530 C显着降低K-ATP通道的敏感性，抑制MgATP。该通道对磺脲类药物高度敏感。然而，有没有影响磺脲类药物治疗四周后，1.0-1.2毫克/公斤/24小时glibenclamide.Conclusion：GAD，IA-2A，伊卡阴性儿童新发1型糖尿病有缓慢的疾病进展评估残留β细胞功能和改善血糖控制12个月后诊断。24例中有1例发生ABCC 8突变，提示在AAB阴性的1型糖尿病患者中应考虑筛查ABCC 8。
Background: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes.Materials and methods: In 261 newly diagnosed children with type 1 diabetes, we measured residual beta-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation.Results: Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual beta-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA(1c) (P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide.Conclusion: GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.