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Kharagjitsingh AV, de Ridder MAJ, Alizadeh BZ, Veeze HJ, Bruining GJ, Roep BO, Koeleman BPC. Genetic correlates of early accelerated infant growth associated with juvenile-onset type 1diabetes. Objective: We previously showed that accelerated growth predisposing to development of childhood-onset type 1 diabetes (T1D) is restricted to the first year after birth. We assessed whether this phenomenon of increased early growth is associated with variants of two genes, insulin-like growth factor-1 (IGF1) and insulin variable number of tandem repeats ( INS-VNTR), whose products are components of the growth axis. Patients and methods: Patients and their siblings were genotyped for the INS-VNTR and for an IGF1 microsatellite. We tested for difference in first year growth, i.e., increased weight standard deviation score (SDS), a reliable measure of especially first year growth, between carriers and non-carriers of these gene variants, using a repeated measurement and regression analysis. Results: In patients, growth did not differ between carriers and non-carriers of the INS-VNTR*III allele, while carriership of this allele in siblings was positively associated with increased first year growth. In both patients and siblings, non-carriership of the IGF1*194 allele was positively associated with growth. Birth size was not associated with either variant. Conclusions/discussion: Non-carriership of the IGF1*194 allele was positively associated with accelerated first year growth in both patients and siblings, independent of disease. This IGF1 variant may therefore contribute to increased first year growth, but cannot explain the association of first year growth with diabetes. An effect on growth of the INS-VNTR was detected in healthy siblings, but not in patients, suggesting that disease supersedes a growth effect of INS-VNTR. [ABSTRACT FROM AUTHOR]

Antipyrine salivary clearance and half-life and the rate of formation of three principal metabolites of antipyrine (4-hydroxyantipyrine, 3- hydroxymethylantipyrine and norantipyrine) were assessed in nine children with congenital adrenal hyperplasia, six of whom were salt- losers and three of whom were non-salt-losers. No differences were found in comparison with data obtained in normal children. [ABSTRACT FROM AUTHOR]

Secular growth changes have not been linked with type-1 diabetes. Longitudinal growth analysis in prediabetic type-1 children indicated increased body mass index (BMI) in the first year of life and an increased growth in length in the next 2 years. These heavier and taller children presented with autoantibodies against pancreatic islet tyrosine phosphatases at diagnosis many years later. It is possible that increased BMI during the first year of life and the development of such autoantibodies represents an additional risk marker towards earlier clinical onset of disease. [ABSTRACT FROM AUTHOR]

Background: Cortisol is produced in a circadian rhythm controlled by the hypothalamus-pituitary-adrenal axis, making it cumbersome to measure long-term cortisol exposure. Hair has proven to be a reliable matrix for long-term cortisol measurement in adults and can be used as diagnostic tool for (cyclic) Cushing's syndrome. The diagnostic applicability in children has not been studied, nor have the effects of development and hair care been evaluated in children. We aimed to establish reference ranges of hair cortisol concentrations (HCC) in healthy children and to evaluate the effects of age, gender, puberty and characteristics of hair care., Methods: In 128 healthy children aged 4-14 years, HCC were measured in a small 3-cm hair lock from the back of the head., Results: HCC increased with age (p = 0.04) up to age 10 years, with a mean of 5.0, 5.8, 6.8 and 8.5 pg/mg at age 4-5, 6-7, 8-9 and 10-14 years, respectively. Children aged 4-7 years had significantly lower HCC compared to healthy adults (p = 0.007). We did not find any influence of gender, puberty or hair care characteristics on hair cortisol., Conclusion: HCC can be reliably measured in childhood, and reference ranges increase with age. HCC in children are not dependent on hair care or hair characteristics., (© 2014 S. Karger AG, Basel.)

To date, seven studies have provided evidence for an association between the gene encoding for myosin IXB (MYO9B) and celiac disease (CD), and inflammatory bowel diseases, including single nucleotide polymorphisms (SNPs) rs2305767, rs1457092, and rs2305764. We investigated whether MYO9B is associated with T1D. The three SNPs were genotyped in Dutch samples from 288 T1D patients and 1615 controls. The A allele of SNP rs2305767A>G showed some evidence of association with T1D (nominal p for genotype = 0.06; OR carrier = 1.51, 95% CI = 1.04-2.19), but not in British samples from 4301 case patients and 4706 controls (p = 0.53), or when the Dutch and UK data were pooled (N patients = 4582, N controls= 6224; Mantel-Hansel p = 0.83). Furthermore, the nonsynonymous rs1545620 C>A SNP that has been associated with the inflammatory bowel disease, showed no association with T1D in British case-control set (p = 0.57). We conclude that MYO9B might not be a strong determinant of T1D, although there was some association in our initial Dutch study. Further studies are needed to evaluate the role of MYO9B in T1D., (Copyright 2010 American Society for Histocompatibility and Immunogenetics. All rights reserved.)

Objective: Accelerated early growth prior to childhood type 1 diabetes onset is associated with an increased risk for type 1 diabetes (T1D). We aimed to study early growth, correcting for the previously neglected confounder of familial effects., Design: Infant growth was studied in a retrospective family case-control study of diabetic children in which siblings acted as matched familial controls allowing correction for confounders related to family particulars., Patients: Weight and height data were collected from 213 juvenile onset type 1 diabetic children and their 255 healthy siblings. Growth in the first 4 years of life was studied using repeated measurement. The degree of early overgrowth was correlated with age of clinical onset., Results: Birth weight and length did not differ between later diabetic children and their siblings. In the first year of life, weight standard deviation score (SDS) differed between patients and sibs (P = 0.0001). After the first year, both diabetic children and sibs showed parallel enhanced weight and height gain SDS until age 4 years. Earlier onset diabetes was associated with a higher weight SDS at 6 months of age., Conclusion: In this family case-control study the association of increased growth with development of T1D is limited to the first year of life implying that increased growth beyond the first year can be attributed to familial growth patterns, rather than predisposition to T1D per se. Age at disease onset correlated with increased weight in the first 6 months of life, indicating importance of features very early in life on later development of T1D.

Previous studies have shown that enteroviral RNA can be detected in blood at the onset of type 1 diabetes (T1D). The infection may play a role in triggering T1D and genetic host factors may contribute to this process. We investigated (1) whether enterovirus is present at the onset of T1D in peripheral blood mononuclear cells (PBMC), plasma, throat, or stool, and (2) whether enteroviral presence is linked with HLA-DR type and/or polymorphisms in melanoma differentiation-associated gene 5 (MDA5) and 2'-5' oligoadenylate synthetase 1 (OAS1), factors of antiviral immunity. To this end, PBMC, plasma, throat, and stool samples from 10 T1D patients and 20 unrelated controls were tested for the presence of enteroviruses (RT-PCR), for HLA-DR type, and polymorphisms in MDA5 and OAS1. Enterovirus RNA was detected in PBMC of 4/10 T1D patients, but none of 20 controls. Plasma was positive in 2/10 T1D patients and none of 20 controls, suggesting that enteroviruses found at the onset of T1D are mainly present in PBMC. All throat samples from positive T1D patients were virus-negative and only 1 fecal sample was positive. The negative results for all throat and most stool samples argues against acute infection. Enterovirus presence was linked with HLA-DR4, but not with polymorphisms in MDA5 or OAS1.

Background: KCNJ11 mutations are a common cause of diabetes diagnosed in the first 6 months of life, and approximately 25% of patients have neurological features. Sulphonylureas have been shown to improve glycaemic control and also motor function, but the impact on cognitive function has not been extensively addressed previously., Methods: The patient had a low birth weight and was found to have diabetes at the age of 2 days. The patient was treated with insulin from diagnosis. The child also had marked developmental delay so that his average functional age was 2.5 years when he was 12 years old. A V59M mutation in KCNJ11 was found on sequencing, resulting in a diagnosis of intermediate developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. Identification of a Kir6.2 mutation allowed insulin injections to be replaced by glibenclamide tablets., Results: This resulted not only in improved glycaemic control (HbA(1c) fell from 8.1 to 6.5%), but also an impressive improvement in many aspects of cognitive function, with the functional age increasing to 4 years within 6 months of treatment change., Conclusions: This is the first clear report of cognitive function improving in a patient with the neurological features associated with a K(ATP) channel mutation following transfer to sulphonylureas. The finding of cognitive improvement suggests that glibenclamide is likely to be acting directly on the brain and not just on nerve and muscle, improving muscle strength.

Aims/hypothesis: Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the K(ATP) channels in pancreatic beta cells are a common cause of neonatal diabetes. One-third of patients also have developmental delay, which probably results from mutated K(ATP) channels in muscle, nerve and brain. Sulfonylureas, which bind to the sulfonylurea receptor 1 subunit of the K(ATP) channel, can replace insulin injections in patients with KCNJ11 mutations. The aim of this study was to investigate the long-term outcome and impact on neurological features of sulfonylurea treatment., Methods: We report the response to sulfonylurea treatment in a boy with neonatal diabetes and marked developmental delay resulting from the KCNJ11 mutation V59M., Results: Glibenclamide (glyburide) treatment was started at 23 months and resulted in insulin being discontinued, lower overall glycaemia, reduced glucose fluctuations and reduced hypoglycaemia. Good control (HbA(1c) 6.5%) was maintained 2 years after discontinuing insulin, despite a reduction in the glibenclamide dose (from 0.41 to 0.11 mg.kg(-1).day(-1)). Within 1 month of starting glibenclamide there was marked improvement in motor function, resulting in the patient progressing from being unable to stand unaided to walking independently, but there was no improvement in mental function., Conclusions/interpretation: This 2-year follow-up of a patient highlights that sulfonylurea treatment can result in prolonged, excellent glycaemic control and may improve motor features, but not mental features, associated with KCNJ11 mutations. This suggests that the neurological actions of sulfonylurea are initially principally on peripheral (nerve or muscle) rather than on central (brain) K(ATP) channels. Early molecular diagnosis is important in patients with neonatal diabetes and neurological features.

Two families are presented with a child suffering from microcephaly with a simplified gyral pattern of the brain (SGP) and early onset insulin dependent diabetes mellitus (IDDM). The first patient was diagnosed postmortally with Wolcott-Rallison syndrome, after her younger brother developed IDDM, and a homozygous mutation in the eukaryotic translation initiation factor 2-alpha kinase 3 was found. The younger brother did not undergo magnetic resonance imaging (MRI). The patient from the second family has no EIF2AK3 mutation. SGP is considered to arise from decreased neuronal proliferation or increased apoptosis at an early stage of embryonal development, but insight into the pathways involved is minimal. EIF2AK3 is involved in translation initiation. It has been proposed that loss of function mutations reduce the ability of the cell to respond to endoplasmic reticulum stress, resulting in apoptosis of pancreatic Langerhans cells. Our findings suggest that in some cases, early onset IDDM and SGP can arise from common mechanisms leading to increased apoptosis.

Neonatal diabetes mellitus (DM) is by definition diagnosed within the first 3 months of life and can be either transient (TNDM) or permanent (PNDM). Recently, activating mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the K(ATP) channel, have been identified as a cause of TNDM, the main cause of PNDM, and the cause of a new syndrome: developmental delay, epilepsy and neonatal diabetes. Patients with neonatal DM are normally dependent on life-long insulin injections, but patients with neonatal DM due to a KCNJ11 mutation are able to achieve control with sulphonylurea tablets. The mutations are predominantly spontaneous but have also been described as due to autosomal dominant inheritance and paternal mosaicism. Mutations at codon 201 and 59 are thus far the most prevalent. Because mutated K(ATP) channels do not close in response to ATP, the beta-cell membrane is hyperpolarised and insulin secretion does not occur. Mutated K(ATP) channels in muscle, nerve and brain are responsible for the neurological symptoms.

Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL polymorphisms have been described that are associated with MBL serum concentration, impaired function, and diabetic complications. We investigated 86 new-onset juvenile type 1 diabetic patients and compared these with their nondiabetic siblings and healthy unrelated control subjects. Polymorphisms of MBL exon 1 and promoter were determined, and serum concentration and MBL-complex activity were measured. Although the genetic polymorphisms of MBL were not different between patients and control subjects, MBL serum concentration as well as MBL complex activity was significantly higher in new-onset diabetic patients compared with their siblings matched for high-producing MBL genotypes (P = 0.0018 and P = 0.0005, respectively). The increase in MBL complex activity in high-MBL-producing patients could only partially be explained by high MBL production, as demonstrated by an increased MBL complex activity-to-MBL concentration ratio (P = 0.004). We conclude that MBL serum concentration and complex activity are increased in early-onset diabetic patients upon manifestation independently of genetic predisposition to high MBL production, indicating a possible role in the immunopathogenesis of type 1 diabetes, in addition to the adaptive islet autoimmunity.

Killer cell immunoglobulin-like receptors (KIRs) modulate natural killer cell and T-cell function by interacting with HLA class 1 ligands on target cells. Both KIR and HLA are highly polymorphic. We studied the influence of KIR and HLA class 1 genes on the susceptibility to develop type 1 diabetes. The results showed increased numbers of activating KIR genes in patients compared with control subjects (P = 0.049). The combination of the activating KIR2DS2 gene, together with its putative HLA ligand, was present more frequently in patients than in diabetes high-risk HLA-matched control subjects (P = 0.030). Moreover, our results imply that an increase in activating KIR2DS2-HLA ligand pairs combined with a lack of inhibitory KIR-HLA ligand pairs is associated with an additional risk to develop type 1 diabetes in individuals with diabetes high-risk HLA alleles (P = 0.035). We propose that the genetic imbalance between KIR and their HLA class 1 ligands may enhance the activation of T-cells with a low affinity for pancreatic self-antigens, thereby contributing to the pathogenesis of type 1 diabetes.

Glutamic acid decarboxylase (GAD) and insulinoma antigen 2 (IA2) antibodies are increasingly used as a tool to predict type I diabetes in children and as a differential diagnostic tool to distinguish type I and type II diabetes in adults. However, the background frequency of these antibodies in the general population has not been extensively studied and may differ between countries. The current study aims to establish the frequency of GAD and IA2 antibodies in an unselected population of schoolchildren and confirm the previously reported low prevalence of islet cell antibodies (ICA) in the general Dutch population. The study population consisted of 1403 unselected schoolchildren. All children were tested for GAD antibodies, and 1085 children were analyzed for IA2 antibodies by radiobinding assay. Development of diabetes was recorded during a 7-year follow-up. Five children (0.4%) were positive for GAD antibodies, one child (0.1%) was positive for IA2 antibodies. Two children developed diabetes during follow-up, one was positive for GAD antibodies only, the second was positive for both GAD and IA2 antibodies. The frequency of GAD and IA2 antibodies in the southwestern part of The Netherlands is low. This observation is in concordance with earlier studies on ICA in Dutch schoolchildren. For future diabetes prediction and intervention trials it is important to establish the background frequencies and predictive power of antibody screening in different populations.

The association of HLA class II phenotype with the development of insulin-dependent (Type 1) diabetes mellitus (IDDM) is well established but the contribution of the various HLA-DR and -DQ alleles and haplotypes to disease predisposition is not fully understood. We have determined haplotype and genotype odds ratios, and further employed multivariate tree analysis to explore the contribution of individual HLA-DRDQ haplotypes to the genetic risk for developing IDDM in the Dutch population. Next to haplotype and genotype odds ratios, multivariate tree analysis techniques provide overall risk calculations for each modeled parameter, and offer insight in the interaction of the model parameters via tree-shaped reports, in which subsequent stratifications on the data can easily be followed. We compared 206 Dutch IDDM patients with 840 serologically typed random healthy unrelated Dutch Caucasoid controls. The multivariate tree analysis showed that the HLA-DR7DQ9 and DR15DQ6 haplotype were strongly associated with disease protection (OR = 0.04, P = 0.0003, and OR = 0.07, P < or = 0.0001, respectively). The highest ORs were found for the DR4DQ8/DR8DQ4 genotype (OR = 21.04, P = 0.001), followed by DR4DQ8/DR17DQ2 (OR = 12.45, P < 0.0001) and DR9DQ9/DR17DQ2 (OR = 10.87, P = 0.02). DR4DQ8 homozygous and DR17DQ2 homozygous individuals have a disease OR of 9.0 and 3.0 (P = 0.01 and 0.03), respectively. In conclusion, the results from haplotype, genotype, and tree analyses provide insight into the disease associations for combinations of HLA-DRDQ haplotypes. We confirm that the DR9DQ9/DR17DQ2 genotype is associated with susceptibility in the Dutch population, which has previously been noticed as a HLA risk genotypes in Asian populations only.

Pancreatic agenesis is a rare condition, of which only a limited number of cases have been described. One recent paper reported a homozygous mutation in the pancreatic duodenal homeobox gene 1 (PDX-1) in a child with pancreatic agenesis. We report a 6-year-old boy with pancreatic agenesis, treated medically, without abnormalities in the PDX-1 gene coding sequence and with normal gastroduodenal endocrine cell distribution. Genes other than PDX-1 also appear to be involved in human pancreatic agenesis.

We have recently diagnosed a patient with anaemia, severe tubulopathy, and diabetes mellitus. As the clinical characteristics resembled Pearson marrow-pancreas syndrome, despite the absence of malfunctioning of the exocrine pancreas in this patient, we have performed DNA analysis to seek for deletions in mtDNA. DNA analysis showed a novel heteroplasmic deletion in mtDNA of 8034bp in length, with high proportions of deleted mtDNA in leukocytes, liver, kidney, and muscle. No deletion could be detected in mtDNA of leukocytes from her mother and young brother, indicating the sporadic occurrence of this deletion. During culture, skin fibroblasts exhibited a rapid decrease of heteroplasmy indicating a selection against the deletion in proliferating cells. We estimate that per cell division heteroplasmy levels decrease by 0.8%. By techniques of fluorescent in situ hybridisation (FISH) and mitochondria-mediated transformation of rho(o) cells we could show inter- as well as intracellular variation in the distribution of deleted mtDNA in a cell population of cultured skin fibroblasts. Furthermore, we studied the mitochondrial translation capacity in cybrid cells containing various proportions of deleted mtDNA. This result revealed a sharp threshold, around 80%, in the proportion of deleted mtDNA, above which there was strong depression of overall mitochondrial translation, and below which there was complementation of the deleted mtDNA by the wild-type DNA. Moreover, catastrophic loss of mtDNA occurred in cybrid cells containing 80% deleted mtDNA.

Insulin-dependent (Type 1) diabetes mellitus (IDDM) is a genetically controlled T-cell mediated autoimmune disease. Recently, subtyping of HLA-DRB1*04 identified the HLA-DRB1*0403 allele to be associated with protection in Caucasoids with the highest risk heterozygous genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201. Some studies confirmed this finding, but other reports were not consistent with a dominantly protective trait. We here report the frequency of HLA-DRB1*0403 in a large cohort (n=200) of Dutch patients with IDDM, their first-degree family members (n=370), and random controls (n=420) of the general population in The Netherlands. We found that HLA-DRB1*0403 is strongly associated with dominant protection against development of IDDM in unrelated subject, even in the context of the highest risk HLA-DQ phenotypes and HLA-DR4-DQB1*0302 (P < 0.0001).

Plasma semicarbazide-sensitive amine oxidase is raised in patients with Type I (insulin-dependent) diabetes mellitus. It has been suggested that this enzyme is involved in the development of microvascular damage through its ability to convert amines (e.g. methylamine and aminoacetone) into aldehydes, hydrogen peroxide and ammonia. Plasma semicarbazide-sensitive amine oxidase was found to be equally raised both in patients with Type I diabetes (n = 73) and Type II (non-insulin-dependent) diabetes mellitus (n = 88) compared with control subjects (621 +/- 209 and 619 +/- 202 vs 352 +/- 102 mU/l, p < 0.0001) and to correlate in multiple regression analysis with HbA1c. Since the enzyme could protect the islets from the inhibitory effects of methylamine on insulin secretion, we also tested sera of 100 children, collected consecutively at first diagnosis of Type I diabetes, for semicarbazide-sensitive amine oxidase. The activity was greatly increased compared with serum values of 76 control (siblings) children (757 +/- 300 vs 455 +/- 138 mU/l, p < 0.0001), but not associated with HbA1c. Our study confirms the increase of plasma semicarbazide-sensitive amine oxidase in Type I diabetes and extends this finding to Type II diabetes as well as to childhood Type I at first clinical diagnosis. In the last case increased enzyme activities could serve to protect the islets from inhibitory effects of methylamine but cause damage by generation of hydrogen peroxide, aldehydes and ammonia. In the long run the increased enzyme activities could also contribute to vascular damage by direct cytotoxic action on endothelial cells, including increased oxidative stress and glycosylation of proteins.