Lernmark Åke, Agardh Daniel, Akolkar Beena, Gesualdo Patricia, Hagopian William A, Haller Michael J, Hyöty Heikki, Johnson Suzanne Bennett, Elding Larsson Helena, Liu Edwin, Lynch Kristian F, McKinney Eoin F, McIndoe Richard, Melin Jessica, Norris Jill M, Rewers Marian, Rich Stephen S, Toppari Jorma, Triplett Eric, Vehik Kendra, Virtanen Suvi M, Ziegler Anette-G, Schatz Desmond A, Krischer Jeffrey
Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden.
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Nat Rev Endocrinol. 2025 Mar;21(3):154-165. doi: 10.1038/s41574-024-01045-0. Epub 2024 Nov 4.
The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years) of 8,667 children showed high retention and compliance. End points of the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of insulin autoantibodies (1-3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2-4 years). Genetic and environmental factors, including enterovirus infection and gastroenteritis, support mechanistic differences underlying one phenotype of autoimmunity against insulin and another against GAD65. Infant growth and both probiotics and high protein intake affect the two phenotypes differently, as do serious life events during pregnancy. As the end of the TEDDY sampling phase is approaching, major omics approaches are in progress to further dissect the mechanisms that might explain the two possible endotypes of T1DM.
TEDDY（青少年糖尿病环境决定因素）研究的目标是阐明导致胰岛自身免疫启动的因素（首要主要结局）以及与进展为1型糖尿病（T1DM；次要主要结局）相关的因素。本综述概述了迄今为止的主要发现，特别是与首要主要结局相关的发现。文中讨论了该研究的背景、历史和组织情况。对8667名儿童进行的招募及随访（从4个月大至15岁）显示，保留率和依从性都很高。针对胰岛素、GAD65、IA-2和ZnT8的自身抗体的终点显示，HLA相关的胰岛素自身抗体早期出现（1至3岁），而GAD65自身抗体出现较晚。针对组织转谷氨酰胺酶的竞争性自身抗体（标志着乳糜泻自身免疫）也较早出现（2至4岁）。遗传和环境因素，包括肠道病毒感染和肠胃炎，支持了针对胰岛素的一种自身免疫表型与针对GAD65的另一种自身免疫表型背后的机制差异。婴儿生长以及益生菌和高蛋白摄入对这两种表型的影响不同，孕期的重大生活事件也是如此。随着TEDDY采样阶段接近尾声，正在采用主要的组学方法进一步剖析可能解释T1DM两种可能终末型的机制。
