Näntö-Salonen Kirsti, Kupila Antti, Simell Satu, Siljander Heli, Salonsaari Tiina, Hekkala Anne, Korhonen Sari, Erkkola Risto, Sipilä Jukka I, Haavisto Lotta, Siltala Marja, Tuominen Juhani, Hakalax Jari, Hyöty Heikki, Ilonen Jorma, Veijola Riitta, Simell Tuula, Knip Mikael, Simell Olli
Department of Paediatrics, University of Turku, Turku, Finland.
Lancet. 2008 Nov 15;372(9651):1746-55. doi: 10.1016/S0140-6736(08)61309-4. Epub 2008 Sep 22.
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.
At three university hospitals in Turku, Oulu, and Tampere (Finland), we analysed cord blood samples of 116 720 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 11 225 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.
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 [HR] 1.14; 95% CI 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% CI 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).
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.
在糖尿病小鼠模型中，预防性给予胰岛素可降低疾病发病率。我们调查了对于具有增加患1型糖尿病风险的HLA基因型和自身抗体的儿童，经鼻给予胰岛素是否会降低1型糖尿病的发病率。
在芬兰图尔库、奥卢和坦佩雷的三家大学医院，我们分析了116720例连续出生婴儿及其3430名兄弟姐妹的脐带血样本，检测其中1型糖尿病的HLA - DQB1易感等位基因。17397名婴儿和1613名兄弟姐妹具有增加的遗传风险，其中分别有11225名婴儿和1574名兄弟姐妹同意每3 - 12个月进行一次糖尿病相关自身抗体筛查。在一项双盲试验中，我们将连续样本中两种或更多种自身抗体呈阳性的224名婴儿和40名兄弟姐妹随机分为两组，分别每天经鼻给予短效人胰岛素（1单位/千克；n = 115和n = 22）或安慰剂（n = 109和n = 18）。我们采用受限随机化方法，按地点分层，使用大小为2的置换区组。主要终点是糖尿病的诊断。分析采用意向性分析。该研究因胰岛素无有益作用而提前终止。本研究已在ClinicalTrials.gov注册，注册号为NCT00223613。
干预的中位持续时间为1.8年（范围0 - 9.7年）。随机接受胰岛素治疗的49名受试儿童被诊断为糖尿病，随机接受安慰剂治疗的47名儿童被诊断为糖尿病（风险比[HR] 1.14；95%置信区间0.73 - 1.77）。这些儿童中分别有42名和38名持续治疗直至诊断，糖尿病年发病率分别为16.8%（95%置信区间11.7 - 21.9）和15.3%（10.5 - 20.2）。胰岛素组有7名兄弟姐妹被诊断为糖尿病，安慰剂组有6名（HR 1.93；0.56 - 6.77）。在所有随机分组的儿童中，胰岛素组有56名被诊断为糖尿病，安慰剂组有53名（HR 0.98；0.67 - 1.43，p = 0.91）。
对于具有HLA介导的糖尿病易感性的儿童，在检测到自身抗体后不久开始经鼻给予胰岛素，未能显示出可预防或延迟1型糖尿病。
