Revisiting infant growth prior to childhood onset type 1 diabetes.

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.

Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation.

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.

Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene.

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.

Microcephaly and simplified gyral pattern of the brain associated with early onset insulin-dependent diabetes mellitus.

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.

[From gene to disease; neonatal diabetes mellitus and the KCNJ11 gene]. / Van gen naar ziekte; neonatale diabetes mellitus en het KCNJ11-gen.

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.

Low prevalence of GAD and IA2 antibodies in schoolchildren from a village in the southwestern section of the Netherlands.

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.

HLA class II associations with Type 1 diabetes mellitus: a multivariate approach.

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.

Association between infant growth before onset of juvenile type-1 diabetes and autoantibodies to IA-2. Netherlands Kolibrie study group of childhood diabetes.

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.

Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrow-pancreas syndrome.

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.

Absence of a PDX-1 mutation and normal gastroduodenal immunohistology in a child with pancreatic agenesis.

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.

HLA-DRB1*0403 is associated with dominant protection against IDDM in the general Dutch population and subjects with high-risk DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype.

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).

Circulating semicarbazide-sensitive amine oxidase is raised both in type I (insulin-dependent), in type II (non-insulin-dependent) diabetes mellitus and even in childhood type I diabetes at first clinical diagnosis.

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.

Increase in IDDM incidence in Bulgarian children (1974-1995).

The incidence of insulin-dependent diabetes mellitus (IDDM) in children on the Balkan peninsula varies between 2.45 and 10.00/100,000. The present study aimed to assess the trends in the IDDM incidence in children 0-14 years for a 22-year period in Eastern Bulgaria. The data were collected on the basis of the Varna Paediatric Diabetes Registry, both retrospectively and prospectively, with ascertainment of the primary source up to 98.8%. The mean annual IDDM incidence was 6.32/100,000 (95% CI 5.91-6.78), with the incidence in towns significantly higher than in villages: 7.24 vs 4.58/100,000, p < 0.0001. A linear trend of increase in the incidence with time was found, applying Poisson regression analysis. According to the model the age-adjusted incidence rose by 1.9% annually. The analysis revealed a significant linear trend of increase for children living in towns and for those aged 10-14 years.

Low prevalence of antibodies to GAD65 in a 50- to 74-year-old general Dutch population. The Hoorn Study.

OBJECTIVE: To assess the prevalence of antibodies to GAD65 (GAD65-A) in relation to glucose tolerance disturbances and to blood glucose-lowering therapy in a general Dutch population. RESEARCH DESIGN AND METHODS: A population sample of 2,350 Dutch subjects, age 50-74 years, agreed to undergo an oral glucose tolerance test (OGTT). They were classified as having normal glucose tolerance, impaired glucose tolerance, newly detected diabetes, or known diabetes. GAD65-A levels were measured in serum by means of a standardized radioligand assay and subsequently were expressed as indexes. The prevalence rates were defined as the proportions of individuals of each category of glucose tolerance exceeding the value of the index at the 99th percentile of the entire study population. RESULTS: The prevalence rates and the 95% CIs of GAD65-A were 0.7% (0.4-1.2%) in cases of normal glucose tolerance, 2.4% (0.9-5.3%) in impaired glucose tolerance, 0% (0-3.3%) in newly detected diabetes, according to the World Health Organization (WHO) criteria, and 3.5% (0.7-10.0%) in known diabetes. A total of 2 out of 3 subjects with GAD65-A indexes above the 99th percentile and 10 out of 18 subjects with GAD65-A indexes above the 85th percentile received insulin therapy for their diabetes, which showed an association between GAD65-A and insulin therapy CONCLUSIONS: Low prevalence rates of latent autoimmunity to GAD were found in 50- to 74-year-old Dutch subjects with normal and abnormal glucose tolerance, and GAD65-A was associated with insulin use in known diabetic subjects.

Confirmation of high incidence of type 1 (insulin-dependent) diabetes mellitus in Moroccan children in The Netherlands.

The incidence of Type 1 (insulin-dependent) diabetes mellitus among Moroccan children aged (0-19 years) in The Netherlands was determined. Point of reference was the data derived from the second nationwide incidence study on Type 1 diabetes among children under 20 years of age. In that study the incidence among Dutch children was 13.2 100000(-1) year(-1). To scrutinize the data and to obtain more information a questionnaire was sent in 1993 to all specialists who had reported that they had diagnosed a patient with Type 1 diabetes during the years 1988-1990 whose parents originated from Morocco, Turkey or other foreign countries. The questionnaire requested information on origin and migration of child and parents. The response to the questionnaire was 86% for the Moroccan children, 75% for the Turkish children and 100% for the children from other countries. In only one case a wrong country had been recorded. None of the patients had been in The Netherlands for less than 6 months before the diagnosis. The incidence for Moroccan children was 20.0 (95% CI 14.6-26.9) and for Turkish children 4.5 (95% CI 2.2-8.0) 100,000(-1) year(-1). It is concluded that the incidence of Type 1 diabetes in Moroccan children (0-19 years) is 1.5 times higher than in Dutch children and 4.5 times higher than in Turkish children.

Fluctuations in GAD65 antibodies after clinical diagnosis of IDDM in young children.

OBJECTIVE: To investigate whether the presence of GAD antibodies at onset of IDDM correlates to a more aggressive rate of beta-cell destruction after clinical onset. RESEARCH DESIGN AND METHODS: We studied GAD antibodies at onset of disease, after 1 year, and after 6 years in 33 consecutively referred children (mean age 8.08, range 1.7-16.3). In a subset of 11 patients, GAD antibodies were studied very frequently. The correlation between GAD antibodies and clinical parameters, including glycosylated hemoglobin, residual insulin secretion, and insulin dosage, was evaluated. RESULTS: GAD antibody titers were highly variable. Four patients became GAD antibody positive weeks to years after clinical onset. Other patients switched between testing positive and negative for GAD antibodies shortly after clinical onset. No correlation was found between the presence of GAD antibodies and the rate of beta-cell destruction, but patients with high GAD antibody indexes at onset had significantly higher glycosylated hemoglobin levels. CONCLUSIONS: GAD antibodies at clinical onset do not predict the rate of beta-cell destruction in young children with newly diagnosed IDDM. The highly variable GAD antibody levels suggest variation of the autoimmune process.