Seasonal variation in month of diagnosis in children with type 1 diabetes registered in 23 European centers during 1989-2008: little short-term influence of sunshine hours or average temperature.

BACKGROUND: The month of diagnosis in childhood type 1 diabetes shows seasonal variation. OBJECTIVE: We describe the pattern and investigate if year-to-year irregularities are associated with meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population-based European registries during 1989-2008. METHODS: Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends. RESULTS: Significant sinusoidal pattern was evident in all but two small centers with peaks in November to February and relative amplitudes ranging from ± 11 to ± 38% (median ± 17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10-14 yr. There were no differences in seasonal pattern between four 5-yr sub-periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 °C excess) but not with sunshine hours. CONCLUSIONS: Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.

Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase.

AIMS/HYPOTHESIS: The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989-1998) and second (1999-2008) halves of the period. METHODS: All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied. RESULTS: Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half. CONCLUSIONS/INTERPRETATION: The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data.

AIMS/HYPOTHESIS: We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes. METHODS: Relevant studies published before February 2009 were identified from literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders.Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies. RESULTS: Data were available for 29 predominantly European studies (five cohort, 24 case-control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 [95% CI 1.01-1.11]; p=0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 [95% CI 1.04-1.19]; p=0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 [95% CI 1.00-1.06]; p=0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings. CONCLUSIONS/INTERPRETATION: Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes.

Target setting in intensive insulin management is associated with metabolic control: the Hvidoere childhood diabetes study group centre differences study 2005.

OBJECTIVE: To evaluate glycaemic targets set by diabetes teams, their perception by adolescents and parents, and their influence on metabolic control. METHODS: Clinical data and questionnaires were completed by adolescents, parents/carers and diabetes teams in 21 international centres. HbA1c was measured centrally. RESULTS: A total of 2062 adolescents completed questionnaires (age 14.4 +/- 2.3 yr; diabetes duration 6.1 +/- 3.5 yr). Mean HbA 1c = 8.2 +/- 1.4% with significant differences between centres (F = 12.3; p < 0.001) range from 7.4 to 9.1%. There was a significant correlation between parent (r = 0.20) and adolescent (r = 0.21) reports of their perceived ideal HbA1c and their actual HbA1c result (p < 0.001), and a stronger association between parents' (r = 0.39) and adolescents' (r = 0.4) reports of the HbA1c they would be happy with and their actual HbA1c result. There were significant differences between centres on parent and adolescent reports of ideal and happy with HbA1c (8.1 < F > 17.4;p < 0.001). A lower target HbA1c and greater consistency between members of teams within centres were associated with lower centre HbA1c (F = 16.0; df = 15; p < 0.001). CONCLUSIONS: Clear and consistent setting of glycaemic targets by diabetes teams is strongly associated with HbA1c outcome in adolescents. Target setting appears to play a significant role in explaining the differences in metabolic outcomes between centres.

Associations between physical activity, sedentary behavior, and glycemic control in a large cohort of adolescents with type 1 diabetes: the Hvidoere Study Group on Childhood Diabetes.

BACKGROUND: The Hvidoere Study Group on Childhood Diabetes has demonstrated persistent differences in metabolic outcomes between pediatric diabetes centers. These differences cannot be accounted for by differences in demographic, medical, or treatment variables. Therefore, we sought to explore whether differences in physical activity or sedentary behavior could explain the variation in metabolic outcomes between centers. METHODS: An observational cross-sectional international study in 21 centers, with demographic and clinical data obtained by questionnaire from participants. Hemoglobin A1c (HbA1c) levels were assayed in one central laboratory. All individuals with diabetes aged 11-18 yr (49.4% female), with duration of diabetes of at least 1 yr, were invited to participate. Individuals completed a self-reported measure of quality of life (Diabetes Quality of Life - Short Form [DQOL-SF]), with well-being and leisure time activity assessed using measures developed by Health Behaviour in School Children WHO Project. RESULTS: Older participants (p < 0.001) and females (p < 0.001) reported less physical activity. Physical activity was associated with positive health perception (p < 0.001) but not with glycemic control, body mass index, frequency of hypoglycemia, or diabetic ketoacidosis. The more time spent on the computer (r = 0.06; p < 0.05) and less time spent doing school homework (r = -0.09; p < 0.001) were associated with higher HbA1c. Between centers, there were significant differences in reported physical activity (p < 0.001) and sedentary behavior (p < 0.001), but these differences did not account for center differences in metabolic control. CONCLUSIONS: Physical activity is strongly associated with psychological well-being but has weak associations with metabolic control. Leisure time activity is associated with individual differences in HbA1c but not with intercenter differences.

Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes?

AIMS: To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries. METHODS: Adolescents with Type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, in 19 countries, and their parents were invited to participate. Questionnaires were administered recording demographic data, details of insulin regimens, severe hypoglycaemic events and number of episodes of diabetic ketoacidosis. Adolescents completed the parental involvement scale from the Diabetes Quality of Life for Youth--Short Form (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. Glycated haemoglobin (HbA(1c)) was analysed centrally on capillary blood. RESULTS: A total of 2062 adolescents completed a questionnaire, with 2036 providing a blood sample; 1994 parents also completed a questionnaire. Family demographic factors that were associated with metabolic outcomes included: parents living together (t = 4.1; P < 0.001), paternal employment status (F = 7.2; d.f. = 3; P < 0.001), parents perceived to be over-involved in diabetes care (r = 0.11; P < 0.001) and adolescent-parent disagreement on responsibility for diabetes care practices (F = 8.46; d.f. = 2; P < 0.001). Although these factors differed between centres, they did not account for centre differences in metabolic outcomes, but were stronger predictors of metabolic control than age, gender or insulin treatment regimen. CONCLUSIONS: Family factors, particularly dynamic and communication factors such as parental over-involvement and adolescent-parent concordance on responsibility for diabetes care appear be important determinants of metabolic outcomes in adolescents with diabetes. However, family dynamic factors do not account for the substantial differences in metabolic outcomes between centres.

Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies.

AIMS/HYPOTHESIS: The aim of this study was to investigate the evidence of an increased risk of childhood-onset type 1 diabetes in children born by Caesarean section by systematically reviewing the published literature and performing a meta-analysis with adjustment for recognised confounders. METHODS: After MEDLINE, Web of Science and EMBASE searches, crude ORs and 95% CIs for type 1 diabetes in children born by Caesarean section were calculated from the data reported in each study. Authors were contacted to facilitate adjustments for potential confounders, either by supplying raw data or calculating adjusted estimates. Meta-analysis techniques were then used to derive combined ORs and to investigate heterogeneity between studies. RESULTS: Twenty studies were identified. Overall, there was a significant increase in the risk of type 1 diabetes in children born by Caesarean section (OR 1.23, 95% CI 1.15-1.32, p < 0.001). There was little evidence of heterogeneity between studies (p = 0.54). Seventeen authors provided raw data or adjusted estimates to facilitate adjustments for potential confounders. In these studies, there was evidence of an increase in diabetes risk with greater birthweight, shorter gestation and greater maternal age. The increased risk of type 1 diabetes after Caesarean section was little altered after adjustment for gestational age, birth weight, maternal age, birth order, breast-feeding and maternal diabetes (adjusted OR 1.19, 95% CI 1.04-1.36, p = 0.01). CONCLUSIONS/INTERPRETATION: This analysis demonstrates a 20% increase in the risk of childhood-onset type 1 diabetes after Caesarean section delivery that cannot be explained by known confounders.

[Development of the medical treatment of diabetes in Luxembourg]. / Evolution du traitement médicamenteux du diabète au Luxembourg.

OBJECTIVES: The aims of the study were to estimate the prevalence of diabetes in Luxembourg in 2002, to compare it to the prevalence reported in 1991 and to evaluate if prescription attitudes have changed since 1991. METHODS: The prevalence of diabetes was estimated using the drug sales data. The key parameters, total amount of antidiabetic drugs sold in one year and the average daily dose or Prescribed Daily Dose (PDD), have been obtained from the National Social Security Organization and by a standardized questionnaire sent to all general practitioners and all internists and endocrinologists of the country. RESULTS: The PDD was calculated on 2,402 questionnaires on individual diabetic patients. By this mean, the proportion of patients only treated with appropriate diet could also be obtained. Compared to 1991, the total amount of antidiabetic drugs showed a four-fold increase in biguanides tablet prescriptions. A high percentage of combined treatments was found. The prevalence of diabetes in Luxembourg was found to be 3.05% of the total population. CONCLUSIONS: Compared to the status in 1991, prevalence of diabetes increased by 63%, which seems mainly due to type 2 diabetic patients as orally-treated diabetic patients almost doubled (2.11% vs 1.16%). A substantial change in prescriptions for diabetes has occurred, suggesting a positive influence of studies like the United Kingdom Prospective Diabetes Study (UKPDS).

European Union diabetes indicators: fact or fiction?

Diabetes mellitus is one of the major causes of morbidity and mortality in EU/EFTA countries. Monitoring risk factors for diabetes and its complications will offer the possibility to evaluate the development in time as well as the influence of possible interventions. In this investigation a list with core and secondary indicators is proposed. Availability of these indicators and their data sources is discussed. An important variability of data sources is used in EU/EFTA countries, interfering with the comparability of the outcome. Further harmonisation as well as continuous evaluation of data sources will be necessary to provide reliable tools to monitor diabetes mellitus and its outcome on a routine basis.

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.

Insulin autoantibodies and immune response to human insulin therapy in 24 type 1 (insulin-dependent) diabetic children: superiority of radio binding assay over solid phase assay.

To evaluate the immunization pattern against human insulin, 24 newly diagnosed diabetic children (12 females, 12 males; mean age: 7 +/- 4 years) were treated from diagnosis onwards with semisynthetic human insulin (NOVO). Informed consent was obtained from all parents. Blood samples were taken before, 1, 2, 3, 4, 6 and 8 weeks after the start of therapy and, thereafter, at monthly intervals for 2 years. Insulin (auto) antibodies (I(A)A) were measured by radio binding assay (RBA) and by enzyme-linked immunosorbent assay (ELISA). IAA, determined by RBA, were detected in eight children. Using ELISA, IgM IA were not detected after onset of therapy. By contrast, IgG IA were found in 8 children after 2 weeks of treatment and in 12 after 1 month. Using RBA, all children had IA after 2 months of therapy, whereas with ELISA, IA remained undetectable during the study period in 8 out of 24 patients. These results confirm previous observations suggesting that the 2 methods are not interchangeable and yield different estimations of the insulin immune reaction, not only before but also after the start of insulin therapy. In addition, the detection of IA by RBA in all treated patients unambiguously demonstrates that human insulin is immunogenic in man.

Psychological impact of continuous subcutaneous insulin infusion pump therapy in non-selected newly diagnosed insulin dependent (type 1) diabetic children: evaluation after two years of therapy.

Thirty type 1 (insulin dependent) diabetic children were treated from diagnosis onwards in a random order (using a table of random permutations) with either continuous subcutaneous insulin infusion pump therapy (CSII), or with conventional injection therapy (CT). After two years of therapy psychosocial measurements were obtained of fifteen CSII children (8 boys, 7 girls; mean age: 12+/-4 years) and thirteen CT children (6 boys, 7 girls; mean age: 10+/-4 years) and their parents. Two families of the CT group refused to participate. The examination consisted of six tests (for the children: junior dutch personality test, WISC-R intelligence test, family relation test, diabetes questionnaire; for the parents: family interaction scale and assessment of acceptance scale). Parents (and pediatricians) rated CSII children higher on compliance and better on metabolic control. Acceptance of diabetes, physical and psychological condition was rated equally by parents and doctors. Except for the diabetes questionnaire, the children of the two groups scored not significantly different. The CSII group expressed significantly less physical complaints and physical restrictions. CSII children showed a tendency to score higher on recalcitrance compared with CT children. How adequate this coping of CSII children may be, is discussed.

Continuous subcutaneous insulin infusion (CSII) versus conventional injection therapy in newly diagnosed diabetic children: two-year follow-up of a randomized, prospective trial.

The effect of continuous subcutaneous insulin infusion (CSII), begun at diagnosis, on blood glucose control and endogenous insulin production was studied in a group of consecutively referred newly diagnosed diabetic children. In a random order, 15 children started CSII (age 9.5 +/- 4.2 (+/- SD) years) and 15 conventional injection therapy (age 7.0 +/- 3.6 years). For 2 years HbA1 and urinary C-peptide were measured monthly, C-peptide responses to glucagon 6-monthly, and insulin antibodies every 3 months. None of the patients requested change of therapy during the study period, but at 28 months 1 adolescent girl changed to injection therapy from CSII. Severe hypoglycaemia was observed once in each group, but ketoacidosis only once, in the injection therapy group. From 2 months after diagnosis onwards the CSII group had significantly lower HbA1 levels. Urinary and plasma C-peptide levels did not differ between the two groups and similar insulin doses were used throughout the study. At the end of the 2 years of therapy, the CSII group had significantly lower insulin antibody levels. The observations suggest that CSII is well accepted in newly diagnosed children and improves metabolic control, but does not prolong endogenous insulin production.

Peripheral nerve function in children with end-stage renal failure.

Information on clinical and subclinical peripheral neuropathy in children with end-stage renal failure (ESRF) is scarce. We have studied the presence of clinical and subclinical peripheral neuropathy in children with ESRF comparing recently developed non-invasive methods with the measurement of nerve conduction velocities. Twelve children (7 boys, 5 girls; age range: 5-17 years; duration of haemodialysis: 0.5-60 months) participated. Thermal discrimination threshold (TDT) and vibration perception threshold (VPT) were determined twice before and after haemodialysis in each patient. Peroneal nerve conduction velocity was determined once before haemodialysis. No clinical or subclinical peripheral neuropathy was observed in any of the children. Except for two slightly increased TDT values after haemodialysis all results were within the normal range. No correlation was found with age or duration of haemodialysis and no association was found between the three methods. VPT values showed a significant improvement after haemodialysis treatment, although all VPT values were in the normal range. This suggests that haemodialysis has an influence on cutaneous sensation, but further study is needed to confirm this observation. Longitudinal investigations will be necessary to evaluate whether TDT and VPT determinations can be used for early screening of clinical and subclinical neuropathy in children with ESRF.

The incidence of type 1 (insulin-dependent) diabetes mellitus in subjects aged 0-19 years in Luxembourg: a retrospective study from 1977 to 1986.

A decrease in the incidence of Type 1 (insulin-dependent) diabetes mellitus in the age group 0-14 years has been observed from north to south over north-western Europe. To evaluate whether this trend could be found in Luxembourg (a small country between the Netherlands and France) we performed a retrospective study over a period of 10 years. Information concerning all Type 1 diabetic patients (aged 0-19 years at diagnosis), diagnosed between January 1, 1977 and December 31, 1986 was obtained through paediatricians, internists, general practitioners and the Luxembourg Diabetes Association (LDA). The LDA was used as the ascertainment group (to estimate the real number and incidence of Type 1 diabetes mellitus). During the study period 91 Type 1 diabetic patients aged between 0-19 years were diagnosed. An incidence of 11.2 was found in boys (0-19 years). Girls in the same age group showed a considerably lower incidence of 8.8. Standardised incidence (using as standard the world population) revealed an almost similar incidence in the Netherlands and Luxembourg (respectively 10.3 and 10.2) for the age group aged 0-14 years. In France a considerably lower incidence is found (3.6). To what extent different methodology contributes to the differences remains to be clarified. Further prospective studies are necessary to investigate the role of environmental and genetic factors.

Urinary C-peptide: a useful tool for evaluating the endogenous insulin reserve in cohort and longitudinal studies of diabetes in childhood.

Increasing research into the remission phase of type I diabetes mellitus stresses the importance of a non-traumatic and reliable method for the evaluation of endogenous insulin production. We compared 24-h urinary C-peptide excretion (UCE) with plasma C-peptide values before and after stimulation with 1 mg glucagon in 24 type I diabetic children. Fasting plasma C-peptide values and stimulated plasma C-peptide values showed a linear correlation with 24 h UCE. Mean plasma C-peptide levels correlated inversely with the exogenous insulin dose. A slightly better correlation was found between the exogenous insulin dose and 24 h UCE. Control data of 24 h UCE were obtained from healthy siblings. A linear correlation with age was found up to 10 years of age above which UCE values seem to reach a plateau. This effect of age, as well as the frequency of sampling was taken into account in the derivation of 95% reference intervals for UCE. The measurement of 24 h UCE appears to be a useful parameter to assess endogenous insulin production in diabetic children, provided that age is taken into account.

Insulin antibodies in diabetic children before treatment: a marker for islet B-cell destruction?

Insulin antibodies were measured in the sera of 28 newly diagnosed diabetic children (age 8.0 +/- 4.0 (+/- SD) years) prior to insulin therapy and after 3, 6, 9, and 12 months. The levels at diagnosis and after 12 months were compared to endogenous insulin production at onset and after 12 to 14 months. Endogenous insulin production was evaluated through the measurement of 24-h urinary C-peptide excretion, fasting plasma C-peptide levels and plasma C-peptide levels after glucagon stimulation. Insulin antibodies were detected in 29% of the patients (8 out of 28). In all but one patient antibodies binding porcine and human insulin were detected. No relationship was found between the presence of antibodies binding human or porcine insulin at diagnosis and age. After 1 year 27 out of 28 patients presented insulin antibodies. No relationship was found between the presence of insulin antibodies before therapy and 1 year after therapy. Insulin antibodies prior to diagnosis showed no relationship with the urinary C-peptide excretion at diagnosis (with antibodies 67 +/- 27%, without antibodies 76 +/- 11%). However, after 1 year significantly lower urinary C-peptide excretions were found in patients with insulin antibodies prior to therapy (with antibodies, 17 +/- 7%, without antibodies, 31 +/- 5%, p less than 0.02). Peak plasma C-peptide levels after 1 year were possibly lower in patients with insulin antibodies before treatment (with antibodies 0.17 +/- 0.06 nmol/l, without antibodies 0.26 +/- 0.04 nmol/l, p less than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)