The Finnish Pediatric Diabetes Register collected data and blood samples from children diagnosed with any type of diabetes in the pediatric unit, and their first-degree family members in 2002-2023. The holder of the register is Helsinki University Central Hospital, and it is led by Professor Mikael Knip.
The register covers more than 90% of children diagnosed with type 1 diabetes. By the end of 2023,11,411 children with type 1 diabetes and more than 32,000 family members were included in the Diabetes Register. The Diabetes Register collected data on the family history of diabetes and autoimmune diseases, and the clinical status and metabolic decompensation of newly diagnosed children at the time of diagnosis.
Newly diagnosed child or adolescent with any type of diabetes and her/his family members were asked to give blood sample for diabetes register collection. Data and samples are used for research of diabetes and its complications. If family wished, the results of genetic susceptibility to type 1 diabetes and diabetes associated autoantibodies were reported.
The results of the Pediatric Diabetes Register have been published in publications such as: Harsunen et al. Diabetologia 2023, Taka et al. Pediatr Diabetes 2022, Parviainen et al. Diabetes Care 2022. Link to the publication list of the Finnish Pediatric Diabetes Register is below. Analysis of the samples and data collected in the register is ongoing and new publications are forthcoming.
TRIGR study was the largest double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes ever aimed at primary prevention of type 1 diabetes. The study set out to determine whether delayed exposure to cow´s milk proteins being the first complex proteins that a baby is normally exposed to, will reduce the risk of developing type 1 diabetes later in life. The hypothesis was that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies and type 1 diabetes.
TRIGR subjects were recruited from May 2002 to January 2007 in 78 study centers in 15 countries (Finland, Sweden, Estonia, Germany, The Netherlands, Luxembourg, Switzerland, Poland, Hungary, Czech Republic, Spain, Italy, Australia, United States and Canada). The mothers were recommended to breastfeed as long as possible. Whenever breast milk was not available in sufficient amounts the mother was asked to give her baby the study formula being either an extensively hydrolyzed casein formula or a conventional cow's milk-based formula. The minimum duration of the study formula exposure was 60 days by 6.8 months of age.
The first end-point results in 2014 showed, there was no difference by the age of 7 years in the appearance of diabetes-associated autoantibodies between the casein formula and conventional cow´s milk formula groups (Knip et al 2014).The second end-point results, comparing the risk of type 1 diabetes between the study groups, were published in the first 2018 issue of the Journal of the American Medical Association (Writing Group for the TRIGR Study Group, JAMA 2018). Weaning to an extensively hydrolyzed casein formula during infancy did not result in a reduction in the incidence of type 1 diabetes compared to regular intact cow's milk-based formula after 11.5 years of follow up. Accordingly, there is no evidence to revise the current dietary recommendations for infants carrying high genetic risk for type 1 diabetes.
Link to the publication list of TRIGR is below. Analysis of the samples and data collected is ongoing and new publications are forthcoming.
The TRIGR study was coordinated by University of Helsinki and sponsored by the National Institute of Health (NIH), JDRF, European Union (EU), European Foundation for the Study of Diabetes (EFSD) and Academy of Finland.
The study yields important new information about the main environmental candidate risk factors in the pathogenesis of type 1 diabetes (T1D) utilizing the setup of TRIGR (dietary intervention). The aim is to evaluate associations and interactions between n-3 fatty acids, vitamin D, cow’s milk and viral infections with indicators of immune regulation and inflammation as well as induction of islet autoimmunity. In this project LID performs multiplexed Luminex analysis of concentrations of circulating cytokines, chemokines and growth factors in the serum samples collected in early childhood from the children that have participated the TRIGR study. Principal investigator of TRIGR-DIVIA is Professor Suvi Virtanen from the National Institute for Health and Welfare. The project is a collaboration between the National Institute for health and welfare, University of Helsinki, University of Tampere and University of South Florida.
The project was started in 2016. Analysis of the samples and data collected is ongoing and new publications are forthcoming.
To date, the results of the Divia study have been published in the following articles Hakola et al. Clin Nutr 2022, Niinistö et al. Front Immunol 2022, Hakola et al. Pediatr Diabetes 2021, Miettinen et al. Diabetologia 2020
The EDIA study is a clinical trial aimed at comparing the effects of weaning to two different formulas, i.e. an extensively hydrolyzed formula vs. a conventional formula on intestinal permeability, gut microbiota, Th17 immunity, as well as serum metabolome and proteome. The hypothesis was that and extensively hydrolyzed casein formula decreases intestinal permeability, down-regulates IL-17 immunity and proinflammatory lysophoshatidylcholines in serum, and stabilizes lactobacilli levels in the gut microbiota when compared to a conventional cow’s milk formula.
The parent of infants born in the area of Tampere University Hospital were invited during pregnancy to take part in the EDIA study. The recruitment was started in March 2013 and the last recruited infant was born in August 2015. The study population in the intervention trial comprised 82 newborn infants with HLA-conferred susceptibility to type 1 diabetes. The infants were followed until the age of 12 months, where after the families were offered continued follow-up within the DIPP study.
The mothers were encouraged to exclusively breastfeed their infants as long as possible. The timing of weaning and introduction of study formula was left to the mother. The infants were randomized to be weaned to one of the two study formulas: the extensively hydrolyzed casein formula or the conventional cow’s milk formula. Foods containing cow’s milk proteins, beef, and veal were excluded from the diet during the 9-month intervention period.
The first results were published in 2021 (Siljander et al. 2021) Other EDIA articles published to date are Lamichhane et al. Front Nutr 2022, Vatanen et al. Cell 2022, Koivusaari et al. J Pediatr Gastroenterol Nutr 2023, Bhosale et al. iScience 2023, Lalli et al. Am J Clin Nutr 2025. Analysis of the samples and data collected is ongoing and new publications are forthcoming.
EDIA Study was coordinated by University of Helsinki and sponsored by NIDDK; National Institute of Health as well as Finska Läkaresällskapet and Medicinska Understödsföreningen Liv och Hälsa r.f.
The DIABIMMUNE study aimed at assessing the role of environmental factors focusing on the role of hygiene in the development of allergies and immune-mediated diseases, type 1 diabetes in particular. The populations in Finland, Estonia and Russian Karelia have relatively similar distributions of HLA genotypes predispoising to autoimmunity but a marked difference in the incidence of type 1 diabetes and in the prevalence of allergies, asthma and celiac disease. This EU-sponsored study comprised 12 academic partners, including the University of Helsinki, which functioned as the coordinating center.
The DIABIMMUNE study started in 2008 in three centers: Espoo (Finland), Tartu (Estonia) and Petrozavodsk (Russian Karelia). The study comprises two cohorts: a birth cohort (BC) and a young children cohort (YCC). In the birth cohort, infants were followed from birth till the age of 3 years. The enrolment criteria in the BC cohort was a HLA genotype conferring increased risk for autoimmunity, while the participants in the YCC were from the general population, recruited at the age of 3 years and observed till the age of 5 years. Altogether there were more than 800 infants in the BC- and over 3600 young children in the YCC cohort. Samples were collected to analyze type 1 diabetes and celiac disease autoantibodies, allergies, function of regulatory T cell, infections and gut microbiome. In addition, information about diet, allergies, infections and use of drugs was collected.
The analysis of the intestinal microbiome showed a decrease in the microbial diversity after seroconversion to autoantibody positivity in those children who progressed to clinical diseases (Kostic et al. Cell Host & Microbe 2015). Predominance of Bacteroides species, which are weak immune stimulators, was common in Finnish and Estonian children, whereas LPS producing E.coli with a strong immunostimulatory potency was more abundant in Russian Karelian children than in Finnish and Estonian peers (Vatanen T et al. Cell 2016). Other key DIABIMMUNE publications include Vatanen et al. Nat Microbiol 2019, Yassour et al. Cell Host Microbe 2018, Yassour et al. Sci Transl Med 2016.
Below is a link to the list of DIABIMMUNE publications. Analysis of the samples and data collected is ongoing and new publications are forthcoming.
DIABIMMUNE was sponsored by EU FP7 program as well as Finska Läkaresällskapet and Medicinska Understödsföreningen Liv och Hälsa r.f.
TrialNet is an international network of leading academic institutions, physicians, scientists and healthcare teams dedicated to the prevention of type 1 diabetes. TrialNet offers risk screening for relatives of people with type 1 diabetes and innovative intervention studies to explore ways to prevent clinical disease.
Pathway to Prevention Screening (TN01) was the first step for all TrialNet prevention studies. Screening was offered free to relatives of people with type 1 diabetes to evaluate their risk of developing the disease. Those who were not family members and were known to have 1 or more islet antibodies were also eligible for screening. The screening can identify the early stages of type 1 diabetes years before any symptoms appear. It also helps researchers learn more about how type 1 diabetes develops and plan new studies exploring ways to prevent it.
Subjects who met the criteria for treatment trials were offered the opportunity to participate in studies that delay the onset of the type 1 diabetes. Of the preventive TrialNet treatment trials conducted in Finland, 1) the TN18 study aimed to find out whether Abatacept could delay or prevent progression of early stage type 1 diabetes to overt disease and the destruction of insulin-producing cells, and 2) the TN22 study aimed to determine the efficacy and safety of hydroxychloroquine in preventing abnormal glucose tolerance and clinical onset of type 1 diabetes in individuals at risk for type 1 diabetes.
In Finland, the TrialNet coordinating center at the University of Helsinki recruited relatives of patients with type 1 diabetes all around Finland together with the pediatric outpatient clinics.
In addition to the Finnish TrialNet center, clinical centers located in USA, Canada, Puerto Rico, Australia, New Zealand, Sweden, Germany, Italy and Great Britain. The international network is coordinated by the University of South Florida, Tampa, Florida, USA. The project is funded by JDRF and National Institute of Health (NIH).
The aim of INNODIA is to improve the understanding of how to predict and prevent the onset and progression of type 1 diabetes. Integral to this aim is clarifying the interaction between the environment and immune system, especially the beta cells. This study comprises 31 academic institutions and clinics, including the University of Helsinki, patient organizations and drug companies.
In the INNODIA study blood samples and data were collected from newly diagnosed patients with type 1 diabetes and from individuals aged 1 to 45 years who did not have diabetes themselves but were at increased risk of developing type 1 diabetes because they were either 1) first-degree relatives (parent, sibling or child) of a person with type 1 diabetes or 2) had been told by another study they were at increased risk of developing type 1 diabetes.
Patients with newly diagnosed type 1 diabetes were invited to come to a baseline study visit within 6 weeks from diagnosis and were observed for 2 years. Other participants were also screened for diabetes associated autoantibodies. Following the screening, the autoantibody positive participants were invited to follow-up study visits over the subsequent 2–4 years.
The recruitment started in February 2017 in Cambridge, UK. In Finland, the recruitment started in August 2017 and ended in October 2023. Thank you for all the study participants!
All diabetes autoantibody analyses within INNODIA are carried out in the PEDIA laboratory, University of Helsinki. INNODIA is coordinated by University of Leuven and University of Cambridge and funded by EU Horizon 2020 IMI2 Programme (Innovative Medicines Initiative), JDRF and Helmsley Charitable Trust.
The DIPP study was launched in 1994 in three Finnish university hospitals (Turku, Tampere, Oulu). The purpose of the DIPP project is to study the risk factors and pathomechanisms of type 1 diabetes in order to find new prevention and treatment methods. There are several ancillary studies clarifying potential environmental and gene-environmental factors contributing to the induction of beta-cell autoimmunity and overt diabetes.
In the DIPP study, newborn infants are screened for HLA-conferred susceptibility to type 1 diabetes, and those with increased genetic risk are asked to join the follow-up program with study center visits every 3 months until they are 2 years old, and then every 1–3 years until they are 15 years old. Diabetes-associated autoantibodies (ICA, IAA, GADA, IA-2A and ZnT8A) are analyzed from all samples. In addition to autoantibody analysis from serum samples, data on infections, diet, allergies, and vaccinations are collected at every visit.
Since 1994, over 250,000 have been screened, and over 20,000 families and their infants with increased HLA risk for type 1 diabetes have joined the follow-up study.
Results from the DIPP study suggest that viral infections and dietary factors may affect the development of type 1 diabetes. Enterovirus infections have been implicated as a definite risk factor for type 1 diabetes (Hyöty, Pediatr Diabetes 2016). Data indicate that Coxsackie B1 virus functions as a trigger of the disease process in a considerable proportion of children who progress to clinical type 1 diabetes. Gut microbiome studies have shown that bacterial diversity diminishes, and bacteria composition is dominated by non-butyrate-producing species in children that later present with clinical type diabetes (Giongo et al. ISME J. 2011). Results suggest that fatty acids, derived primarily from fish in maternal diet during pregnancy or lactation, may protect infants against pre-type 1 diabetes. Breastfeeding and fatty acids obtained from breast milk showed also a protective association (Niinistö et al. Diabetologia 2017). Early introduction of solid foods before the age 4 months was associated with increased risk to develop pre-diabetes before the age of 3 years (Hakola et al. Pediatr Obes 2017). High milk consumption in childhood has also been found to be associated with risk of developing prediabetes (Virtanen et al. Am J Clin Nutr 2012).