Intrauterine and postnatal growth in children with HLA-conferred susceptibility to type 1 diabetes
Date
2015-10-22
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Abstract
Üle kogu maailma tõuseb insuliinisõltuva ehk 1.tüüpi diabeedi (T1D) esinemissagedus keskmiselt 3-4% aastas. Tegemist on autoimmuunhaigusega, kus organismi enda immuunsüsteem hakkab hävitama kõhunäärmes asuvaid insuliini tootvaid β-rakke. Kuigi tegemist on geneetilise eelsoodumusega haigusega, kus pärilikku riski määravad eeskätt HLA geenid, haigestub vaid ca 5% geneetilise eelsoodumusega inimestest. Seetõttu arvatakse, et T1D haigestumuse tõusu põhjuseks on eeskätt muutuv elukeskkond.
Suurem sünnikaal ja kiirem lapseea kasv suurendavad riski haigestuda T1D. Aktseleratsiooni hüpoteesi kohaselt tänapäeva Lääne ühiskonnas, kus esineb pidev toidu üleküllus ja sellest tingitud rasvumine, on insuliini vajadus tõusnud juba varasest lapsepõlvest alates. Ülekoormatud β-rakud võivad aga muutuda immuunsüsteemile sihtmärgiks, põhjustades nii nende rakkude autoimmuunse kahjustuse.
T1D eelsoodumust põhjustavate geenide roll kiirenenud pre- ja postnataalses (ehk sünnieelses ja -järgses) kasvus ei ole selge. Samuti pole täpselt teada ka lapseea kasvu reguleeriva väga olulise faktori, insuliini sarnase kasvufaktori I (IGF-I) ja seda veres kandva valgu IGFBP-3, roll haiguse kujunemises. Varasemad uuringud on näidanud, et mõlemad võivad olla olulised T1D väljakujunemises.
Rahvusvahelise projekti DIABIMMUNE raames määrati T1D geneetiline risk kolmes riigis (Eestis, Soomes ja Karjalas Venemaal) ca 9000 vastsündinul. Uurisime, kas laste sünnikaal ja sünnijärgne kasv sõltuvad HLA geeni tüüpidest. Lisaks uurisime geneetilise eelsoodumusega lastel (ca 500 last) veel seda, kas IGF-I või IGFBP-3 võiksid mõjutada laste kasvu või β-rakkude vastase autoimmuunsuse tekkimist.
Leidsime, et T1D riski kandvad HLA geenid üldiselt ei mõjuta sünnikaalu. Samas kasvavad lapsed kõrge geneetilise riskiga kahel esimesel eluaastal aeglasemalt ja nende IGF-I ja IGFBP-3 tase veres on oluliselt madalam võrreldes lastega, kel suurenenud geneetiline risk haigestuda T1D puudub. Juba käimasoleva autoimmuunse protsessiga lastel on IGF-I sisaldus veres madalam võrreldes teiste lastega. Samuti esines neil lastel oluliselt suurem IGFBP-3 taseme tõus vahetult enne autoimmuunsuse teket.
Kokkuvõttes leidsime, et T1D riski kandvad HLA geenid ei mõjuta sünnikaalu, küll aga varajast lapseea kasvu, kus olulist rolli võivad mängida ka IGF-I ja IGFBP-3. Viimastel võib olla oma osa β-rakkude vastase autoimmuunsuse väljakujunemises.
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.
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.
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Keywords
sünnikaal, 1. tüüpi diabeet, riskitegurid, füüsiline areng, genotüüp, lapsed, HL-antigeenid, birth weight, diabetes mellitus, type 1, risk factors, physical development, genotype, children, HLA antigens