Objective
DIPP Novum Study aims to identify genetic and environmental determinants of T1D. Several gene regions are known to affect the T1D risk and we aim to study whether a specific risk gene combination can be identified in Finland, where the incidence of T1D is the highest in the world. We also investigate the reasons why the children who have a father or sibling with T1D have a higher T1D risk than those with a mother with T1D.
Environment during the whole life span (pregnancy, childhood, adulthood) affects the function of our genes, which may be quiet or active depending on age and environmental factors. This epigenetic regulation will be studied in DIPP Novum in various types of cells collected from study children and their parents and grandparents. Epigenetic changes are transmitted over generations. Environmental factors to be studied in early life include living environment, comprehensive diet, microbes (bacteria, viruses, fungi), infections, chemical toxicants (persistent organic pollutants and chemicals used in every-day life), and food-derived toxins. We will explore factors that could explain why the disease process resulting in T1D so often starts during the first years of life. The first sign of the disease process is appearance of islet autoantibodies in the circulation. If these autoantibodies are found persistently the child has a very high risk to develop T1D, although the time to diagnosis may vary from weeks to several years. Immunological and other changes in initially autoantibody negative children developing islet autoimmunity will be explored applying modern technologies of cell and molecular biology. Frequency of abnormally high blood glucose values increases before diagnosis of T1D and we will investigate the fluctuations of glucose levels in detail by using continuous glucose monitoring (CGM).
We also aim to follow a special group of adolescents who are >15 years of age and have islet autoantibodies but have not developed T1D to learn more about the factors delaying the development of T1D in children who had autoantibodies since early childhood. In addition, we aim to characterize the disease pathway when islet autoantibodies have appeared late, during adolescence.
Background Rationale
The children born in families with the mother, father or sibling (first degree relative, FDR) affected by T1D are at an increased risk to develop T1D. The first sign of the disease process is the appearance of antibodies against the molecular structures of the insulin-producing cells in the pancreas (islet autoantibodies). Most previous studies have initiated follow-up of children at the age of 3 months or older, and therefore there is a gap in knowledge about possible determinant of disease before that age, i.e. during the first months of life, pregnancy and even before that. The Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study was launched already in 1994 and it continues active recruitment of newborn infants to the study. In the revised DIPP Novum protocol we will also follow up a prenatal cohort of babies who have at least one family member with T1D. Children from general population with increased genetic risk constitute a larger group of T1D patients than those with a family member with T1D. DIPP Novum study continues to follow up children from the prenatal cohort and also postnatally recruited children intensively during early childhood and collects new types of biological samples and data. There appears to be multiple pathways to T1D, and large studies, such as DIPP, are needed to be able to investigate distinct disease pathways effectively.
Determinants of islet autoimmunity and T1D are unknown, but epidemiological evidence strongly points to the role of environment. Due to the complex interactions between genes, immune system, and environmental and endogenous factors, the identification of the causative molecular pathways requires a multidisciplinary approach and the analysis of gene-environmental interactions in a dynamic way during different stages of the disease process. It also requires that children at increased genetic risk for T1D are followed from birth, and even during pregnancy. The prenatal and neonatal periods are very important to study, since during these periods the human immune system is under dynamic development. The multigenerational approach extends data and sample collection to the grandparents which creates new possibilities to investigate and understand the pathogenesis of T1D and the transgenerational effects on it.
Description of Project
Causes of type 1 diabetes (T1D) are still unknown, but the rapid increase in the number of new cases strongly points to the importance of environmental factors. On the other hand, the risk of T1D is increased in children who have a mother, father, or sibling with T1D, emphasizing also the role of genetics. More than 75 gene variants have been associated with the risk of T1D. The disease is most often diagnosed during childhood, and the number of new cases has increased particularly among very young children. The disease process resulting in T1D is characterized by appearance of islet autoantibodies in the circulation (i.e. antibodies against the structures of the pancreatic islets which produce insulin). These autoantibodies, if persistent, strongly predict progression to T1D but the time from islet autoantibody appearance to diagnosis may vary from months to several years or even decades. The DIPP study and other studies have discovered that islet autoantibodies most often appear at a very young age of 9-18 months. This suggests that early life events, even those during pregnancy, are important determinants of the disease.
The DIPP Novum study is investigating development of T1D starting from early pregnancy by following up babies whose mother, father or sibling has T1D. In addition, all children with an increased genetic risk for the disease, as defined from their cord blood sample, will be invited for follow-up from the age of 3 months. Data and biological samples from children, the family members and also from the grandparents will be collected. All DIPP children will be monitored intensively during the first three years of life and thereafter less frequently until 15 years of age. The role of genes, living environment, comprehensive diet, microbes, infections, and chemicals will be studied. Environment during the whole life span (pregnancy, childhood, adulthood) affects the function of our genes, which may be quiet or active depending on age and environmental factors. This epigenetic regulation will be studied in DIPP Novum in various types of cells collected from the study children and their parents and grandparents. It is possible that epigenetic changes are transmitted over generations. A special focus will be in the immune system to find out why it attacks against the insulin-producing cells in the pancreas.
We also aim to follow those adolescents who are >15 years of age and have islet autoantibodies but have not developed T1D. The aim is to learn more about factors that delay the development of T1D in children who have had autoantibodies since early childhood without progressing to T1D. In addition, we aim to characterize the disease pathway when islet autoantibodies have appeared late, during adolescence.
The participants who will develop T1D will benefit of the study because they will avoid ketoacidosis, a life-threatening condition at the time of the diagnosis. Furthermore, the study participants will be given a possibility to participate in clinical trials testing treatments to prevent or delay T1D.
Anticipated Outcome
The ultimate goal of the DIPP Novum Study is to understand specific mechanisms of the development of T1D, including different pathways to disease subtypes, and develop effective and safe prevention for T1D. By the prospective follow-up setting starting at early pregnancy and the continuous recruitment of newborns we have a possibility to understand the factors initiating islet autoimmunity and also the factors contributing to the progression from islet autoimmunity to clinical disease. A breakthrough in prevention is possible if the factors initiating autoimmunity can be identified and targeted by safe and effective intervention. The DIPP Novum cohort includes children of all ages from birth until young adulthood and gives them a possibility to participate in prevention trials at all stages of the disease process.
The DIPP Novum Study benefits the participating families and children by increasing the awareness of the increased disease risk and thereby facilitating early diagnosis and avoidance of diabetic ketoacidosis. When T1D is diagnosed early the required insulin doses are smaller, the remaining endogenous insulin secretion helps in maintaining near normal plasma glucose levels, and the families have more time to adapt to the daily routines required for the treatment. After the remission period, when the child is totally dependent on exogenous insulin and the plasma glucose levels become more variable, these skills together with a positive attitude towards the treatment are extremely important for the maintenance of good metabolic control and long-term health.
Relevance to T1D
This research proposal is in the core of human T1D research providing a unique opportunity to analyze crucial early life events leading first to islet autoimmunity and sooner or later to clinical disease. The new transgenerational approaches and prenatal screening will open new possibilities to find causes of T1D. The large data and sample series collected over the last 28 years give excellent possibilities to explore and make breakthroughs in understanding the disease process of T1D. Furthermore, the DIPP cohort gives an excellent possibility to test preventive treatments, since it provides a cost-effective infrastructure for the studies and a large group of subjects eligible for prevention trials.