Ketoacidosis at diagnosis of type 1 diabetes: Effect of prospective studies with newborn genetic screening and follow up of risk children

We studied the frequency of diabetic ketoacidosis (DKA) in children at diagnosis of type 1 diabetes (T1D) in a region where newborn infants have since 1995 been recruited for genetic screening for human leukocyte antigen (HLA)-conferred disease susceptibility and prospective follow up. The aim was to study whether participation in newborn screening and follow up affected the frequency of DKA, and to follow the time trends in DKA frequency. We first included children born in Oulu University Hospital since 1995 when the prospective studies have been ongoing and diagnosed with T1DPeer reviewe

Ketoacidosis at diagnosis of type 1 diabetes: Effect of prospective studies with newborn genetic screening and follow up of risk children

We studied the frequency of diabetic ketoacidosis (DKA) in children at diagnosis of type 1 diabetes (T1D) in a region where newborn infants have since 1995 been recruited for genetic screening for human leukocyte antigen (HLA)-conferred disease susceptibility and prospective follow up. The aim was to study whether participation in newborn screening and follow up affected the frequency of DKA, and to follow the time trends in DKA frequency. We first included children born in Oulu University Hospital since 1995 when the prospective studies have been ongoing and diagnosed with T1DPeer 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

Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes : Phase and Endotype Specific Effects

The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic beta-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls. Survival analysis using Cox regression was applied for time periods from birth to seroconversion and from seroconversion to type 1 diabetes. The appearance of autoantibodies was also analyzed in endotypes, which are defined by the first appearing autoantibody, either IAA or GADA. Analyzing the time period from birth to seroconversion, we were able to replicate our previous association findings at PTPN22, INS, and NRP1. Novel findings included associations with ERBB3, UBASH3A, PTPN2, and FUT2. In the time period from seroconversion to clinical type 1 diabetes, prior associations with PTPN2, CD226, and PTPN22 were replicated, and a novel association with STAT4 was observed. Analyzing the appearance of autoantibodies in endotypes, the PTPN22 association was specific for IAA-first. In the progression phase, STAT4 was specific for IAA-first and ERBB3 to GADA-first. In conclusion, our results further the knowledge of the function of non-HLA risk polymorphisms in detailing endotype specificity and timing of disease development.Peer reviewe

John William Halderman—In Memoriam

INTRODUCTION: The balance between T(H)1, T(H)2, T(H)17, and regulatory T cells has been suggested to be disturbed in type 1 diabetes (T1D). We investigated this balance in peripheral blood mononuclear cells (PBMC) from children at risk of developing T1D and children with T1D. METHODS: We studied PBMC expression levels of markers related to T(H)1 (T-bet, IL-12Rβ(1), IL-12Rβ(2)), T(H)2 (GATA-3, IL-4Rα), T(H)17 (IL-17A), and regulatory T cells (Foxp3, ICOS, and CTLA-4) with real-time polymerase chain reaction from 17 children with T1D, 13 children with β-cell autoimmunity, 15 children with T1D risk-associated human leukocyte antigen (HLA) haplotypes, and 24 healthy, control children. RESULTS: We observed decreased expression levels of GATA-3 by PBMC of healthy children with autoantibodies compared to healthy, control children (p = 0.014) or children with HLA risk alleles (p = 0.032). Children with T1D demonstrated lower expression levels of T-bet, IL-12Rβ(1), and IL-4Rα both at diagnosis and 12 months later. CONCLUSION: We found no indication of aberrant activation of T(H)1, T(H)17, or Treg in peripheral blood from children with or without risk of T1D. The observed immunological differences between children at risk of and with T1D should be considered when immunopathogenesis of β-cell destruction is studied

Torque Teno Virus Primary Infection Kinetics in Early Childhood

Human torque teno viruses (TTVs) are a diverse group of small nonenveloped viruses with circular, single-stranded DNA genomes. These elusive anelloviruses are harbored in the blood stream of most humans and have thus been considered part of the normal flora. Whether the primary infection as a rule take(s) place before or after birth has been debated. The aim of our study was to determine the time of TTV primary infection and the viral load and strain variations during infancy and follow-up for up to 7 years. TTV DNAs were quantified in serial serum samples from 102 children by a pan-TTV quantitative PCR, and the amplicons from representative time points were cloned and sequenced to disclose the TTV strain diversity. We detected an unequivocal rise in TTV-DNA prevalence, from 39% at 4 months of age to 93% at 2 years; all children but one, 99%, became TTV-DNA positive before age 4 years. The TTV-DNA quantities ranged from 5 x 10(1) to 4 x 10(7) copies/mL, both within and between the children. In conclusion, TTV primary infections occur mainly after birth, and increase during the first two years with high intra- and interindividual variation in both DNA quantities and virus strains.Peer reviewe

Torque Teno Virus Primary Infection Kinetics in Early Childhood

Human torque teno viruses (TTVs) are a diverse group of small nonenveloped viruses with circular, single-stranded DNA genomes. These elusive anelloviruses are harbored in the blood stream of most humans and have thus been considered part of the normal flora. Whether the primary infection as a rule take(s) place before or after birth has been debated. The aim of our study was to determine the time of TTV primary infection and the viral load and strain variations during infancy and follow-up for up to 7 years. TTV DNAs were quantified in serial serum samples from 102 children by a pan-TTV quantitative PCR, and the amplicons from representative time points were cloned and sequenced to disclose the TTV strain diversity. We detected an unequivocal rise in TTV-DNA prevalence, from 39% at 4 months of age to 93% at 2 years; all children but one, 99%, became TTV-DNA positive before age 4 years. The TTV-DNA quantities ranged from 5 × 101 to 4 × 107 copies/mL, both within and between the children. In conclusion, TTV primary infections occur mainly after birth, and increase during the first two years with high intra- and interindividual variation in both DNA quantities and virus strains

Exocrine pancreas function decreases during the progression of the beta-cell damaging process in young prediabetic children

Objective: The function of the exocrine pancreas is decreased in patients with type 1 diabetes but it is not known when this defect develops. The current study set out to determine whether the reduced exocrine function becomes manifest after the initiation of islet autoimmunity. Methods: The study was nested in the prospective Type 1 Diabetes Prediction and Prevention study where children with human leukocyte antigen (HLA)-conferred susceptibility are observed from birth. Elastase-1 levels were analyzed from stool samples collected at the time of seroconversion to islet autoantibody positivity and at diagnosis of type 1 diabetes, as well as from samples taken from matched control children of similar age. Results: Elastase levels were lower in case children at the time of the diagnosis of diabetes when compared to the control children. However, elastase concentrations did not differ between cases and controls at the time when autoantibodies appeared. Conclusion: The results suggest that the defect in the exocrine function develops after the appearance of islet autoantibodies. Further studies are needed to assess whether reduced elastase levels predict rapid progression of islet autoimmunity to clinical disease.Peer reviewe