Thesis supervisors Professor Vallo Tillmann (Department of Paediatrics, University of Tartu) and Professor Mikael Knip (University of Helsinki).
Opponent Senior Research Fellow Lars Christian Stene, PhD (Norwegian Institute of Public Health, Norway).
The incidence of type 1 diabetes (T1D) is increasing by 3-4% annually all over the world. T1D is an autoimmune disease where immune system destroys the insulin-producing β-cells in pancreas. T1D has a genetic susceptibility conferred by specific HLA genes. However, only ca 5% of people with genetic susceptibility develops T1D. Therefore it has been suggested that the reasons for the increasing incidence of T1D are related to the changes in living environment.
An increased birth weight and early childhood growth have been found to be risk factors for T1D. According to acceleration hypothesis, in modern Western society the food overload and consecutive obesity increase the insulin demand already from early childhood. The over activity of β-cells leads to their targeting by immune system and facilitates the onset of autoimmunity.
The role of genetic factors conferring susceptibility to T1D in pre- and postnatal (i.e. before and after birth) growth is unclear. Also, the role of one of the most important growth factors in childhood – insulin-like growth factor I (IGF-I) and its binding protein (IGFBP-3), is not clear. Previous studies have shown that both can play role in the development of T1D.
As a part of large international study DIABIMMUNE, genetic risk by HLA genes was determined in ~9000 newborns born in three countries - Estonia, Finland and Russian Karelia. We investigated whether those genes affect the birth weight and postnatal growth. In ~500 children with increased genetic susceptibility to T1D we also studied whether IGF-I and IGFBP-3 influence childhood growth or are associated with β-cells autoimmunity.
We have found that generally there was no significant association between the HLA genes and birth weight. However, children with highest genetic risk for T1D grew slower during the first 24 months and they had lower plasma IGF-I and IGFBP-3 levels compared with others. The children with signs of autoimmunity had lower IGF-I and their IGFBP-3 showed a faster increment just before the emerge of autoimmunity compared to children without signs of autoimmunity.
We conclude that HLA genes associated with T1D risk influence early childhood growth, but not birth weight. IGF-I and IGFBP-3 may have both role in early growth as well as in the development of T1D autoimmunity.