Assessment of Risk for Type 1 Diabetes in Children of Affected Families and in the General Population : Role of Immunological and Metabolic Markers

Background and aims. Type 1 diabetes (T1D), an autoimmune disease in which the insulin producing beta cells are gradually destroyed, is preceded by a prodromal phase characterized by appearance of diabetes-associated autoantibodies in circulation. Both the timing of the appearance of autoantibodies and their quality have been used in the prediction of T1D among first-degree relatives of diabetic patients (FDRs). So far, no general strategies for identifying individuals at increased disease risk in the general population have been established, although the majority of new cases originate in this population. The current work aimed at assessing the predictive role of diabetes-associated immunologic and metabolic risk factors in the general population, and comparing these factors with data obtained from studies on FDRs. Subjects and methods. Study subjects in the current work were subcohorts of participants of the Childhood Diabetes in Finland Study (DiMe; n=755), the Cardiovascular Risk in Young Finns Study (LASERI; n=3475), and the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP) Study subjects (n=7410). These children were observed for signs of beta-cell autoimmunity and progression to T1D, and the results obtained were compared between the FDRs and the general population cohorts. --- Results and conclusions. By combining HLA and autoantibody screening, T1D risks similar to those reported for autoantibody-positive FDRs are observed in the pediatric general population. Progression rate to T1D is high in genetically susceptible children with persistent multipositivity. Measurement of IAA affinity failed in stratifying the risk assessment in young IAA-positive children with HLA-conferred disease susceptibility, among whom affinity of IAA did not increase during the prediabetic period. Young age at seroconversion, increased weight-for-height, decreased early insulin response, and increased IAA and IA-2A levels predict T1D in young children with genetic disease susceptibility and signs of advanced beta-cell autoimmunity. Since the incidence of T1D continues to increase, efforts aimed at preventing T1D are important, and reliable disease prediction is needed both for intervention trials and for effective and safe preventive therapies in the future. Our observations confirmed that combined HLA-based screening and regular autoantibody measurements reveal similar disease risks in pediatric general population as those seen in prediabetic FDRs, and that risk assessment can be stratified further by studying glucose metabolism of prediabetic subjects. As these screening efforts are feasible in practice, the knowledge now obtained can be exploited while designing intervention trials aimed at secondary prevention of T1D.Tausta ja tavoitteet. Tyypin 1 (T1) diabetes on autoimmuunisairaus, jossa insuliinia tuottavat beetasolut vähitellen tuhoutuvat. Kliinistä tautia edeltää esidiabetes, jolle on tyypillistä diabeettisten vasta-aineiden ilmaantuminen verenkiertoon. Tautiriskiä on diabeetikkojen perheenjäsenillä arvioitu vasta-aineiden luonteen ja ilmaantumisajankohdan perusteella, mutta normaaliväestössä, josta suurin osa T1 diabetekseen sairastuvista ilmenee, näiden riski-indikaattorien luonnetta ei vielä tunneta. Tämän väitöskirjatyön tavoitteena oli tutkia diabetekseen liittyvien immunologisten ja aineenvaihdunnallisten tekijöiden ennusarvoa normaaliväestössä ja verrata saatuja arvoja diabeetikkojen perheenjäsenillä havaittuihin tuloksiin. Tutkittavat ja tutkimusmetodit. Tämän työn tutkittavat olivat Lasten diabetes Suomessa -tutkimuksen (DiMe; n=755), Lasten sepelvaltimotaudin riskitekijät -tutkimuksen (LASERI; n=3475) ja Tyypin 1 diabeteksen ennustamiseen ja ehkäisyyn tähtäävän tutkimuksen (DIPP; n=7410), osallistujia. Tutkittavia seurattiin diabetekseen liittyvien immunologisten ja aineenvaihduntaan liittyvien riskitekijöiden sekä T1 diabeteksen kehittymisen suhteen. Tulokset ja päätelmät. Yhdistämällä geneettisen, HLA-määrityksiin perustuvan, ja säännöllisen vasta-aineseurannan, normaalista lapsiväestöstä voidaan tunnistaa yksilöt, joilla on kohonnut riski sairastua T1 diabetekseen. Nämä riskiarviot ovat pitkälti samankaltaisia kuin diabeetikkojen perheenjäsenillä aiemmin julkaistut tulokset. Erityisen suuri sairastumisriski on pysyvästi useammalle kuin yhdelle vasta-aineelle positiivisilla yksilöillä sekä niillä, joilla on vasta-aineita insuliinia kohtaan. Nuori esidiabeteksen ilmaantumisikä, koholla oleva suhteellinen paino, vähentynyt varhainen insuliinieritys ja koholla olevat insuliini- ja saarekesoluvasta-aine 2 (IA-2A) -tasot ennustavat sairastumista lapsilla, joilla on perinnöllinen T1 diabetesalttius ja merkkejä esidiabeteksesta. Koska T1 diabetes yleistyy maailmanlaajuisesti, strategiat, joilla sairastumista voitaisiin ehkäistä, ovat tärkeitä. Luotettavat riskiarviot ovat edellytys ehkäisevien tutkimusten suunnittelemiseksi, ja koska tässä työssä kuvatut menetelmät sairastumisriskin arvioimiseksi ovat toteuttamiskelpoisia myös käytännössä, tämän työn tuloksena käytössämme on jatkossa mahdollisuudet luoda laajempia normaaliväestöä koskevia suunnitelmia T1 diabeteksen ennustamiseksi ja ehkäisemiseksi

Diabetes ja mikrobiota

Mikrobiotatutkimukset avaavat ikkunan monimutkaisiin säätelyjärjestelmiin

Reclassification of asymptomatic beta cell autoimmunity : a critical perspective

Type 1 diabetes is an immune-mediated disease leading to almost total beta cell destruction and permanent exogenous insulin dependency. The appearance of clinical symptoms is preceded by an asymptomatic preclinical period, the duration of which is highly individual. The emergence of diabetes-associated autoantibodies into the peripheral circulation is the first detectable sign of beta cell autoimmunity. If type 1 diabetes is diagnosed in childhood the preclinical period lasts for an average of 2.5-3 years, but clinical symptoms may in some cases appear within a few months or be delayed for more than 20 years. In this issue of Diabetologia, Bonifacio and colleagues (doi:) suggest that asymptomatic beta cell autoimmunity should be considered as a pathological and diagnostic entity. Although such a strategy may have some positive consequences, it might also have serious drawbacks. To label an asymptomatic child that may have 10-20 years of a healthy life ahead of him/her as a patient will most likely affect both the life of the family and the child. Therefore, we think that one should not adapt the new diagnosis before the psychological consequences of such a strategy have been assessed. Instead, since metabolic abnormalities precede the appearance of clinical symptoms of type 1 diabetes, analysis of a combination of immunological and metabolic markers will provide better insight into the likelihood of progression to clinical disease, with a shorter 'sickness' period.Peer reviewe

Lipidomics of human umbilical cord serum : identification of unique sterol sulfates

Aim: There are currently limited lipidomics data for human umbilical cord blood. Therefore, the lipidomes of cord sera from six newborns and sera from six nonpregnant females were compared. Materials & methods: Sera lipidomics analyses were conducted using a high-resolution mass spectrometry analytical platform. Results: Cord serum contained a diverse array of glycerophospholipids, albeit generally at lower concentrations than monitored in adult serum. The unexpected observations were that cord serum contained several neurosteroid sulfates and bile acid sulfates that were not detectable in adult serum. Conclusion: Our data are the first to demonstrate that cord serum contains bile acid sulfates that are synthesized early in the hydroxylase, neutral and acidic pathways of primary bile acid biosynthesis and support previous publications of cord blood perfluoralkyl toxins in newborns. Lay abstract: Umbilical cord blood offers the potential to increase our understanding of fetal development during pregnancy and during development after delivery. Our studies of complex sterols in umbilical cord blood (bile acid sulfates) suggest that with further studies these may be useful biomarkers of abnormal fetal liver development.Peer reviewe

Hyvän tieteellisen ohjaustyön eväät

Peer reviewe

Microbiome and type 1 diabetes

The steep increase in the incidence of type 1 diabetes (T1D), in the Western world after World War II, cannot be explained solely by genetic factors but implies that this rise must be due to crucial interactions between predisposing genes and environmental changes. Three parallel phenomena in early childhood – the dynamic development of the immune system, maturation of the gut microbiome, and the appearance of the first T1D-associated autoantibodies – raise the question whether these phenomena might reflect causative relationships. Plenty of novel data on the role of the microbiome in the development of T1D has been published over recent years and this review summarizes recent findings regarding the associations between islet autoimmunity, T1D, and the intestinal microbiota.Peer reviewe

Development of atopic sensitization in Finnish and Estonian children : A latent class analysis in a multicenter cohort

Background: The prevalence of atopy is associated with a Western lifestyle, as shown by studies comparing neighboring regions with different socioeconomic backgrounds. Atopy might reflect various conditions differing in their susceptibility to environmental factors. Objective: We sought to define phenotypes of atopic sensitization in early childhood and examine their association with allergic diseases and hereditary background in Finland and Estonia. Methods: The analysis included 1603 Finnish and 1657 Estonian children from the DIABIMMUNE multicenter young children cohort. Specific IgE levels were measured at age 3, 4, and 5 years, respectively, and categorized into 3 CAP classes. Latent class analysis was performed with the statistical software package poLCA in R software. Results: Both populations differed in terms of socioeconomic status and environmental determinants, such as pet ownership, farm-related exposure, time spent playing outdoors, and prevalence of allergic diseases (all P Conclusion: Despite profound differences in environmental exposures, there might exist genuine patterns of atopic sensitization. The distribution of these patterns might determine the contribution of atopic sensitization to disease onset.Peer reviewe

Autoantibodies to N-terminally Truncated GAD(65)(96-585) : HLA Associations and Predictive Value for Type 1 Diabetes

Objective To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD(65)(96-585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential human leukocyte antigen (HLA) associations with such autoantibodies. Design In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention study, the DIABIMMUNE study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD(65) (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants. Results T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 (range 0.2-61.5) years. t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77% vs 53%; P < 0.001). Conclusions Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96-585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D.Peer reviewe

Coeliac disease and HLA-conferred susceptibility to autoimmunity are associated with IgE sensitization in young children.

Non peer reviewe

Characteristics of Slow Progression to Type 1 Diabetes in Children With Increased HLA-Conferred Disease Risk

Context: Characterization of slow progression to type 1 diabetes (T1D) may reveal novel means for prevention of T1D. Slow progressors might carry natural immunomodulators that delay beta-cell destruction and mediate preservation of beta-cell function. Objective: To identify demographic, genetic, and immunological characteristics of slow progression from seroconversion to clinical T1D. Design: H LA-susceptible children (n = 7410) were observed from birth for islet cell antibody (ICA), insulin autoantibody (IAA), glutamic acid decarboxylase (GADA), and islet antigen-2 autoantibodies (IA-2A), and for clinical T1D. Disease progression that lasted >= 7.26 years (slowest) quartile from initial seroconversion to diagnosis was considered slow. Autoantibody and genetic characteristics including 45 non-HLA single nucleotide polymorphisms (SNPs) predisposing to T1D were analyzed. Results: By the end of 2015, 1528 children (21 %) had tested autoantibody positive and 247 (16%) had progressed to T1D. The median delay from seroconversion to diagnosis was 8.7 years in slow (n = 62, 25%) and 3.0 years in other progressors. Compared with other progressors, slow progressors were less often multipositive, had lower ICA and IAA titers, and lower frequency of IA-2A at seroconversion. Slow progressors were born more frequently in the fall, whereas other progressors were born more often in the spring. Compared with multipositive nonprogressors, slow progressors were younger, had higher ICA titers, and higher frequency of IAA and multiple autoantibodies at seroconversion. We found no differences in the distributions of non-HLA SNPs between progressors. Conclusions: We observed differences in autoantibody characteristics and the season of birth among progressors, but no characteristics present at seroconversion that were specifically predictive for slow progression.Peer reviewe