Åke Lernmark

Aims: To study the associations of dietary intake of A and E vitamins, as well as plasma retinols, carotenoids, and tocopherols in relation to development of islet autoimmunity and progression to T1D. Materials and Methods: The Environmental Determinants of Diabetes in the Young (TEDDY) Study followed 7659 newborns with genetic susceptibility to T1D for 6 years in the USA, Finland, Germany, and Sweden. Dietary vitamin intake was assessed repeatedly with 3‐day food‐records in full cohort at ages 6 months to 6 years. Plasma retinols, carotenoids, and tocopherols were analysed in a nested case‐control setting with 359 children with islet autoimmunity and 1033 matched controls. Results: In the full cohort analyses, dietary intake of retinol, β ‐carotene, and vitamin E was not associated with the risk of islet autoimmunity or progression to T1D. Further, none of the plasma retinol, carotenoid, and tocopherol biomarkers were associated with islet autoimmunity or T1D in the full nested case‐control analyses. We observed effect modification by country, breastfeeding, sex, and follow‐up time for both intake and biomarkers of vitamins on the risk of islet autoimmunity or T1D, and some subgroup associations. Finally, a plasma carotenoid metabolite (likely zeinoxanthin) (OR 0.61, 95% CI 0.39, 0.95, p = 0.03) and γ ‐carotene at 6 months (OR 0.65, 95% CI 0.45, 0.94, p = 0.02) were inversely associated with the odds of developing GADA‐first. Conclusions: Retinol, carotenoids and tocopherols were not consistently associated with islet autoimmunity. This study adds to the understanding of factors and their interactions related to T1D development.

Introduction: Autoantibodies against insulin (IAA) are early appearing markers of autoimmunity against the pancreatic islet beta cells and predict progression to type 1 diabetes if additional islet autoantibodies also develop. It is still controversial if proinsulin rather than insulin is the primary autoantibody. Methods: The aim of the present study was to compare the half-maximal concentration (IC50) between insulin and proinsulin to displace the binding of insulin to insulin autoantibodies (IAA) in the Antibody Detection by Agglutination PCR (ADAP) assay. Results: IC50 as a measure of potency to displace insulin binding to IAA was determined in 36 newly diagnosed type 1 diabetes children. The ability of either insulin or proinsulin to displace IAA was heterogenous. Proinsulin curves were consistently right-shifted relative to insulin as median IC50 was 21.0 nM (IQR 14.9–25.1) for insulin and 26.1 nM (IQR 12.3–37.5) for proinsulin. A significant age × sex interaction was observed (F (1,31) = 14.3, p < 0.001), indicating that IC50 for both insulin and proinsulin increased with age in boys but decreased in girls. It may reflect whether autoantibodies to insulin or proinsulin was first appearing or of variable maturation from the time of initiation through progression to clinical onset. Conclusion: It was concluded that the IC50 of insulin and proinsulin for IAA was comparable in children with newly diagnosed type 1 diabetes. The ADAP IAA assay should prove useful to determine whether insulin or proinsulin is the primary target at the time of seroconversion to IAA.

Polymorphisms in genes in the human leukocyte antigen (HLA) class II region comprise the most important inherited risk factors for many autoimmune diseases, including type 1 diabetes (T1D) and celiac disease (CD): both diseases are positively associated with the HLA-DR3 haplotype ( DRB1*03:01-DQA1*05:01-DQB1*02:01 ). Studies of two different populations have recently documented that T1D susceptibility in HLA-DR3 homozygous individuals is stratified by a haplotype consisting of three single nucleotide polymorphisms (‘tri-SNP’) in intron 1 of the HLA-DRA gene. In this study, we use a large cohort from the longitudinal ‘The Environmental Determinants of Diabetes in the Young’ (TEDDY) study to further refine the tri-SNP association with T1D and with autoantibody-defined T1D endotypes. We found that the tri-SNP association is primarily in subjects whose first-appearing T1D autoantibody is to insulin. In addition, we discovered that the tri-SNP is also associated with CD, and that the particular tri-SNP haplotype (‘101’) that is negatively associated with T1D risk is positively associated with risk for CD. The opposite effect of the tri-SNP haplotype on two DR3-associated diseases can enhance and refine current models of disease prediction based on genetic risk. Finally, we investigated possible functional differences between the individuals carrying high and low-risk tri-SNP haplotypes and found that differences in complement system genes C4A and C4B may underlie the observed divergence in disease risk.

We aimed to determine if thyroid autoimmunity is associated with a child’s risk for subsequent development of islet or celiac autoantibodies. Children at high genetic risk of type 1 diabetes were followed for thyroid autoimmunity (thyroid peroxidase antibodies [TPOAb] and thyroglobulin antibodies [TGAb]), islet autoimmunity (IA), and celiac disease autoimmunity (CDA) in The Environmental Determinants of Diabetes in the Young study. Out of 5482 children tested for thyroid autoimmunity, IA, and CDA, 39% developed at least one autoantibody. At age 14 years, thyroid autoimmunity co-occurred with IA in 59 children (15 more cases than expected by chance alone, P = 0.02) and with CDA in 125 children (26 cases above expected, P = 0.01). The risk of developing IA or CDA after thyroid autoimmunity varied by which thyroid autoantibody appeared first: TPOAb-first was associated with both IA (HR 1.92, 95% CI, 1.09-3.40) and CDA (1.69, 95% CI, 1.03-2.76), whereas TGAb-first was not associated with the risk of either. Islet autoimmunity and CDA are frequently found in connection to thyroid autoimmunity in children and young adolescents. The relationships of thyroid autoimmunity with IA and CDA depend on which thyroid autoantibody appears first.

Summary: This paper presents a joint model of multivariate longitudinal data and multistate data with application to modeling and predicting autoantibody development in The Environmental Determinants of Diabetes in the Young (TEDDY) study. The model quantifies the risks of state transitions based on observed time-varying and non-time-varying risk factors. Based on the estimated model, a dynamic prediction approach is suggested to predict future state occupation probabilities using historical data. The proposed method can handle uncertainties in the observed data, due to measurement errors in the observed longitudinal data and interval censoring or missing information in the observed multistate data. For evaluating the predictions by the proposed approach, some performance metrics and their estimation are discussed. The proposed method is evaluated by some simulation studies. It is discussed in detail how this method can be used in analyzing the TEDDY data by properly handling the missing information and predicting future disease status using the proposed dynamic prediction algorithm.

The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two completed clinical trials (DPT-1 and TN07), we applied next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1,214 individuals and assessed LRI associations with disease progression. A Cox regression model was used to quantify LRI associations. IGHG or FCGR alone was found to have weak and sporadic associations with progression. Multiple LRIs between IGHG and FCGR gene products were found to be associated with progression, especially LRIs of IGHG2 with multiple FCGR receptors that accelerate progression and those of IGHG4 with multiple FCGR receptors (some overlapping) that delay progression. Furthermore, as several crystal structures of FcγRs complexed with distinct IgG molecules are known, application of this knowledge here was hampered by the absence of any information on the subclass distribution of each of the several T1D-related autoantibodies. It cannot be excluded that their respective state of glycosylation may influence binding affinity to various FcγRs and the function of thus-formed complexes. Our findings suggest that LRIs of the IGHG and FCGR gene products probably influence progression, shedding new insights into some of the immunological mechanisms involved in progression to T1D. Our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression. Article Highlights: This study investigated ligand-receptor interactions (LRIs) between IGHG and FCGR gene products in type 1 diabetes progression. Genes of 1,214 participants from the DPT-1 and TN07 trials were sequenced using next-generation targeted sequencing technology, and LRI associations with the progression time to type 1 diabetes were analyzed using Cox regression modeling. Weak associations were found for IGHG or FCGR variants individually, but multiple LRIs significantly impacted progression. Several IGHG2-FCGR interactions accelerated progression, while a few other IGHG4-FCGR interactions delayed it. The results may provide insights into certain immunogenetic mechanisms of T1D and suggest therapeutic potential of targeting specific LRIs.

Objective and design: The objective was to determine the association between serum IgE levels and the infiltration order of T lymphocytes and macrophages in pancreatic islets in relation to the loss of insulin and glucagon cells in presymptomatic congenic BB Gimap5-DP (Diabetes Prone) rats. Material: Congenic prediabetes BB Gimap5-DP and control Gimap5-DR (Diabetes Resistant) rats were followed every other day from 29 to 32 days of age until peak serum IgE (≤ 55 days of age). Methods: Serum IgE was measured using ELISA. The HALO™ platform facilitated quantitative image analysis of infiltrating T lymphocytes, macrophages, and target organ insulin and glucagon cells. Whole genome sequencing (WGS) was employed to identify candidate type 1 diabetes genes. Results: Serum IgE levels increased with age in normoglycemic BB Gimap5-DP rats. Quantification of infiltrating cells per mm ² in and around the islets indicated that T lymphocytes are the initial infiltrators, followed by macrophages. Elevated serum IgE levels inversely correlated with beta-cell mass (total mg insulin/mg pancreas). WGS refined the risk segment for islet inflammation to 1.02 Mbp, leaving 10 candidate genes, including Gimap4 and Gimap5 . Conclusions: Elevated IgE levels herald T lymphocyte and macrophage infiltration. Pancreatic islet inflammation was linked to Gimap4 , Gimap5, and other potential candidate genes on rat chromosome 4.