The earliest prediction of islet autoimmunity and Type 1 Diabetes (T1D) in the Norwegian MIDIA Study

The PhD-student spent the first year at VTT Technical Research Center in Espoo, Finland, where she was trained in metabolomics and lipidomics methodology, and analyzed the plasma samples from the MIDIA study on a quadrupole/time-of-flight mass spectrometer, for analysis of small, polar metabolites. She has analyzed the data from this study, and presented the results in a manuscript called "Longitudinal plasma metabolic profiles, infant feeding and islet autoimmunity in the MIDIA study", which has been published in the journal Pediatric Diabetes (January 2016). It was found that during early childhood plasma levels of several small, polar metabolites changed with age, independent of sex and later autoimmunity status, and that breastfeeding was associated with higher levels of branched-chain amino acids, and lower levels of methionine and 3,4-dihydroxybutyric acid. Co-authors on this article are Lars Christian Stene, German Tapia, Håkon Bøås, Kjersti Skjold Rønningen, Milaim Pepaj, Per M. Thorsby, Jens Petter Berg, Matej Oresic and Tuulia Hyötyläinen. In addition, the student performed experiments at VTT Technical Research Center to investigate the stability of metabolites and lipids in serum and different types of plasma. The student has written about the results in an article «The influence of sample collection methodology and and sample preprocessing on the blood metabolic profile", published in Bioanalysis (7(8) 2015). It was found that the profiles of polar metabolites were dependent on the type of sample, while lipid profiles were similar in serum and plasma. It was also found that extended storage of plasma in room temperature resulted in degradation of lipids already after one day. Co-authors on this article are Sirkku Jäntti, Ismo Mattila, Tuulikki Seppänen-Laakso, Kjersti Skjold-Rønningen, Hannele Yki-Järvinen, Matej Oresic and Tuulia Hyötyläinen. The student has also presented the results of a study about metabolomics and lipidomics in hypertrophic cardiomyopathy (HCM) in an article, where she analyzed plasma samples from Finnish HCM-patients carrying a mutation in the cardiac myosin-binding protein C gene (MYBPC3-Q1061X), mutation carriers without HCM and healthy controls. This was done in co-operation with cardiologists at the University of Kuopio, Finland. The title of this article is «The metabolome in Finnish carriers of the MYBPC3-Q1061X mutation for hypertrophic cardiomyopathy», and published in PLOS ONE (10(8) 2015), with co-authors Mikko Jalanko, Tiina Heliö, Pertti Jääskeläinen, Mika Laine, Mika Hilvo, Markku S Nieminen, Markku Laakso, Tuulia Hyötyläinen, Matej Oresic and Johanna Kuusisto. It was found that concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic left ventricular hypertrophy and signs of systolic and diastolic dysfunction in subjects with the MYBPC3-Q1061X mutation. The student participated at the Chromatography Symposium in Montreux, November 6th-8th 2012, with a poster about the methodology used in the MIDIA study. She also participated at the Chromatography Symposium in Sandefjord January 12th-14th 2014, and on a Research Seminar for Oslo Diabetes Center on March 20th-21th 2014, where she had a lecture about the MIDIA metabolomics study. She participated on a Chromatography Seminar in Salzburg, Austria September 14th to 18th 2014, and on a seminar for Medical Biochemistry, Oslo University Hospital, where she had a lecture about the MIDIA metabolomics study. She has also had lectures about metabolomcis and the MIDIA-study on the Norwegian Institute of Public health and at the Hormone Laboratory, Aker Hospital, during 2013. She has also had a lecture about the results from the Finnish hypertrophic cardiomyopathy study at the seminar for Medical Biochemistry, Oslo University Hospital, May 6th 2015. In addition, the student has finnished all courses for her degree; Introduction course I and II, "Introduction to statistics", and "Bioanalytical Chemistry: Advanced separation techniques and bioanalysis".

Type 1 Diabetes (T1D) is one of the most prevalent chronic diseases with childhood onset, and Norway is among the countries with the highest incidence in the world. Recently it was interprented that if present trend continues, the prevalence of children w ith the disease in Europe will increase with 50% within year 2020. The disease has a multifactorial aetiology and appears after a preclinical period of varying length (months to years) where the immune system destroys the insulin producing beta-cells in t he pancreas and islet autoantibodies can be detected in the circulation. However, we still do not know what starts the disease process, and it is not possible to prevent the disease. Identification of novel markers with increased specificity/sensitivity i s urgently needed, and longitudinal studies are necessary in this endeavour. Recently Finish children with genetic risk for T1D, participating in The Diabetes Prediction and Prevention Study, were studied by new markers (proteomics and lipidomics). It was shown dysregulation of lipid and amino acid metabolism proceeding islet autoimmunity in children who later progressed to T1D. This exciting new finding is, however, needed to be studied in another prospective birth cohort. In the MIDIA study, babies with the high-risk HLA genotype have been identified and are followed with blood and stool samples as well as questionnaires. What makes the MIDIA project unique is the access to samples from pregnancy as well as cord blood. In the MoBa study, 100,000 pregnan cies are followed prospectively, and children who develop T1D can therefore also be identified through the Norwegian Childhood Diabetes Registry, by registry linkage via the personal identification number. In collaboration with The Quantitative Biology an d Information group, VVT, Technical Research Centre of Finland, we will study metabolic dysregulation and search for new markers. The aim is to offer new opportunities for disease prediction and early prevention.