Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA.

Maria Månsson Martinez, Lampros Spiliopoulos, Falastin Salami, Daniel Agardh, Jorma Toppari, Åke Lernmark, Jukka Kero, Riitta Veijola, Päivi Tossavainen, Sauli Palmu, Markus Lundgren, Henrik Borg, Anastasia Katsarou, Helena Elding Larsson, Mikael Knip, Marlena Maziarz, Carina Törn
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引用次数: 0

Abstract

Background: Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.

Methods: Subjects (n = 57) at 2-50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24).

Results: Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2-4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was - 1.88 (- 2.71, - 1.05) p = 3.49 × 10-5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (- 0.80 (- 1.58, - 0.02), p = 0.046).

Conclusions: The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account.

Trial registration: ClinicalTrials.gov identifier: NCT02605148 , November 16, 2015.

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TEDDY家族预防研究--TEFA中多种胰岛自身抗体受试者β细胞功能的异质性。
背景:有多种胰岛自身抗体的人患临床 1 型糖尿病的风险会增加,而且可能会从一个阶段逐渐发展到另一个阶段,从而使二级预防研究的招募工作变得复杂。我们在一项临床试验中对多个胰岛自身抗体呈阳性的受试者进行了随机化评估,评估内容包括β细胞功能、葡萄糖代谢和连续血糖监测(CGM),时间间隔为一个月。我们假设,胰岛自身抗体的数量和类型与不同的糖代谢指标(包括空腹血糖、HbA1c、口服葡萄糖耐量试验(OGTT)、静脉内葡萄糖耐量试验(IvGTT)和 CGM)相结合,能比单独的胰岛自身抗体数量更精确地对自身免疫性 1 型糖尿病进行分期:方法:对 2-50 岁、两种或两种以上胰岛自身抗体阳性的受试者(n = 57)进行空腹血浆胰岛素、血糖、HbA1c 和 IvGTT 第一阶段胰岛素反应(FPIR)评估,1 个月后进行 OGTT 和 1 周 CGM(n = 24):结果:2-4种自身抗体的9种不同组合中存在针对GAD65(GADA;n = 52)、ZnT8(ZnT8A;n = 40)、IA-2(IA-2A;n = 38)和胰岛素(IAA;n = 28)的自身抗体。两次检查的空腹血糖和 HbA1c 没有差异。将对数2转换的FPIR作为结果,将对数2转换的OGTT血糖曲线下面积(AUC)作为预测因子,调整年龄和性别后,两者之间的线性关系估计值为- 1.88 (- 2.71, - 1.05) p = 3.49 × 10-5。除 FPIR 为负值外,所有葡萄糖代谢指标的估计值方向均为正值。FPIR 与血糖升高有关。CGM 血糖数据的中位数和差值都与基于 OGTT 的较高血糖值、较高 HbA1c 和较低 FPIR 显著相关。葡萄糖代谢、自身抗体数量和类型之间没有关联,但有迹象表明,至少存在一种 ZnT8(Q/R/W) A 与较低的对数2转换 FPIR 相关(- 0.80 (- 1.58, - 0.02), p = 0.046):结论:在预防试验中,仅将两种或两种以上胰岛自身抗体作为1期糖尿病的纳入标准并不令人满意。对1型糖尿病进行分期需要考虑到β细胞功能和糖代谢的异质性:试验注册:ClinicalTrials.gov identifier:NCT02605148 , 2015年11月16日。
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来源期刊
自引率
0.00%
发文量
7
审稿时长
8 weeks
期刊介绍: Clinical Diabetes and Endocrinology is an open access journal publishing within the field of diabetes and endocrine disease. The journal aims to provide a widely available resource for people working within the field of diabetes and endocrinology, in order to improve the care of people affected by these conditions. The audience includes, but is not limited to, physicians, researchers, nurses, nutritionists, pharmacists, podiatrists, psychologists, epidemiologists, exercise physiologists and health care researchers. Research articles include patient-based research (clinical trials, clinical studies, and others), translational research (translation of basic science to clinical practice, translation of clinical practice to policy and others), as well as epidemiology and health care research. Clinical articles include case reports, case seminars, consensus statements, clinical practice guidelines and evidence-based medicine. Only articles considered to contribute new knowledge to the field will be considered for publication.
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