Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial
Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial
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DOI：
10.1016/s0140-6736(08)61309-4
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发表时间：
2008-11-15
期刊：
影响因子：
168.9
通讯作者：
Simell, Olli
中科院分区：
文献类型：
--
作者：
Nanto-Salonen, Kirsti;Kupila, Antti;Simell, Olli
背景 在糖尿病小鼠模型中，预防性施用胰岛素可降低疾病的发生率。我们调查了鼻用胰岛素是否可以降低 HLA 基因型和自身抗体增加疾病风险的儿童患 1 型糖尿病的发病率。方法 在图尔库、奥卢和坦佩雷（芬兰）的三所大学医院，我们分析了 116720 名连续出生的婴儿及其 3430 名兄弟姐妹的脐带血样本，以了解 1 型糖尿病的 HLA-DQB1 易感等位基因。 17 397名婴儿和1613名兄弟姐妹的遗传风险增加，其中分别有11225名和1574名同意每3-12个月筛查一次糖尿病相关自身抗体。在一项双盲试验中，我们在连续样本中随机分配 224 名婴儿和 40 名对两种或多种自身抗体呈阳性的兄弟姐妹，每天一次鼻内接受短效人胰岛素（1 单位/公斤；n=115 和 n=22）或安慰剂（n=109 和 n=18）。我们使用了限制性随机化，按位点分层，并使用大小为 2 的排列块。主要终点是糖尿病的诊断。分析是按意向治疗进行的。由于胰岛素没有任何有益作用，该研究提前终止。本研究已在 ClinicalTrials.gov 注册，编号为 NCT00223613。调查结果 干预持续时间中位数为 1.8 年（范围 0-9-7）。 49 名随机接受胰岛素治疗的儿童和 47 名随机接受安慰剂的儿童被诊断为糖尿病（风险比 [HRI 1.14；95% Cl 0.73-1-77）。其中 42 名和 38 名儿童分别继续接受治疗直至诊断，糖尿病的年发病率为 16.8% (95% Cl 11 . 7-21.9) 和 15.3% (10 . 5-20.2)。胰岛素组有 7 名兄弟姐妹被诊断患有糖尿病，而安慰剂组有 6 名兄弟姐妹被诊断患有糖尿病 (HR 1. 93; 0 - 56-6.77)。在所有随机儿童中，胰岛素组有 56 名儿童被诊断为糖尿病，安慰剂组有 53 名儿童被诊断为糖尿病（HR 0. 98；0. 67-1.43，p=0. 91）。 解释 在 HLA 赋予糖尿病易感性的儿童中，在检测到自身抗体后立即开始经鼻注射胰岛素，并不能证明可以预防或延缓 1 型糖尿病。国际资助：国际青少年糖尿病研究基金会；欧洲联盟;诺和诺德基金会。芬兰：芬兰科学院；芬兰TEKES国家技术局；芬兰大学医院特别研究基金；芬兰卫生技术评估办公室；糖尿病研究基金会，芬兰；西格丽德·朱塞留斯基金会；埃米尔·阿尔托宁基金会；贾马里和劳哈·阿霍卡斯基金会； Signe 和 Ane Gylenberg 基金会； Orion 公司研究基金会；儿科研究基金会； Pdivikki 和 Sakari Sohlberg 基金会。
Background In mouse models of diabetes, prophylactic administration of insulin reduced incidence of the disease. We investigated whether administration of nasal insulin decreased the incidence of type 1 diabetes, in children with HLA genotypes and autoantibodies increasing the risk of the disease.Methods At three university hospitals in Turku, Oulu, and Tampere (Finland), we analysed cord blood samples of 116720 consecutively born infants, and 3430 of their siblings, for the HLA-DQB1 susceptibility alleles for type 1 diabetes. 17 397 infants and 1613 siblings had increased genetic risk, of whom 11225 and 1574, respectively, consented to screening of diabetes-associated autoantibodies at every 3-12 months. in a double-blind trial, we randomly assigned 224 infants and 40 siblings positive for two or more autoantibodies, in consecutive samples, to receive short-acting human insulin (1 unit/kg; n=115 and n=22) or placebo (n=109 and n=18) once a day intranasally. We used a restricted randomisation, stratified by site, with permuted blocks of size two. Primary endpoint was diagnosis of diabetes. Analysis was by intention to treat. The study was terminated early because insulin had no beneficial effect. This study is registered with ClinicalTrials.gov, number NCT00223613.Findings Median duration of the intervention was 1.8 years (range 0-9-7). Diabetes was diagnosed in 49 index children randomised to receive insulin, and in 47 randomised to placebo (hazard ratio [HRI 1.14; 95% Cl 0.73-1-77). 42 and 38 of these children, respectively, continued treatment until diagnosis, with yearly rates of diabetes onset of 16.8% (95% Cl 11 . 7-21.9) and 15.3% (10 . 5-20.2). Seven siblings were diagnosed with diabetes in the insulin group, versus six in the placebo group (HR 1 . 93; 0 - 56-6.77). In all randomised children, diabetes was diagnosed in 56 in the insulin group, and 53 in the placebo group (HR 0 . 98; 0 . 67-1.43, p=0 . 91).Interpretation In children with HLA-conferred susceptibility to diabetes, administration of nasal insulin, started soon after detection of autoantibodies, could not be shown to prevent or delay type 1 diabetes. Funding International: juvenile Diabetes Research Foundation International; European Union; Novo Nordisk Foundation. Finland: Academy of Finland; TEKES National Technology Agency of Finland; Special Research Funds for University Hospitals in Finland; Finnish Office for Health Technology Assessment; Diabetes Research Foundation, Finland; Sigrid Juselius Foundation; Emil Aaltonen Foundation; Jalmari and Rauha Ahokas Foundation; Signe and Ane Gyllenberg Foundation; the Research Foundation of Orion Corporation; Foundation for Pediatric Research; Pdivikki and Sakari Sohlberg Foundation.