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Background: Type 1 diabetes (T1D) is a chronic metabolic condition requiring intensive daily self-care to avoid both high and low blood glucose levels. Self-care and glycemic outcomes are particularly problematic in adolescence, a period known for its increased risk of emotional problems. However, the true scope of mood and anxiety disorders in adolescents with T1D is unknown. Earlier studies are limited by a small sample size, lack of diagnostic interview data, a focus on depression only, non-adolescent specific estimates, lack of information about parental emotional problems and/or a cross-sectional design. Diabetes LEAP is a two-year prospective observational cohort study examining (a) the prevalence and course of depression and anxiety in adolescents with T1D and their parents/caregivers, (b) the risk factors predicting the presence of

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Aims To identify the sociodemographic and clinical correlates of fear of hypoglycaemia among parents of children (aged 4–18 years) with Type 1 diabetes and to examine the relationships between parental fear of hypoglycaemia, mindfulness and mindful parenting. Methods Sociodemographic, self‐reported clinical and psychological data were extracted from the cross‐sectional Diabetes MILES Youth – The Netherlands dataset. Questionnaires included the Hypoglycaemia Fear Survey – Parent Worry (parental fear of hypoglycaemia), the Freiburg Mindfulness Inventory – Short version (mindfulness) and the Interpersonal Mindfulness in Parenting Scale (mindful parenting). Results A total of 421 parents (359 mothers) participated. Hierarchical linear regression analyses showed that greater parental fear of hypoglycaemia was related to younger parental age, low educational level, non‐Dutch nationality, more frequent blood glucose monitoring, and less general mindfulness. Adding mindful parenting to the model negated the previous contribution of general mindfulness. In this model, lower mindful parenting was related to greater parental fear of hypoglycaemia. In particular, parents with an increased ability to be less judgemental of themselves as parents and less reactive to emotions within parenting interactions reported less fear of hypoglycaemia. In total, 21% of the variance in parental fear of hypoglycaemia was explained. Conclusion Parental fear of hypoglycaemia was associated largely with parental characteristics, including non‐modifiable sociodemographics (i.e. age, education, nationality) and modifiable psychological factors (i.e. mindful parenting). These findings suggest that it is important to further explore mindfulness‐based interventions for parents to reduce fear of hypoglycaemia next to interventions to reduce hypoglycaemia.

OBJECTIVE: The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes. RESEARCH DESIGN AND METHODS: Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring. RESULTS: Totally 1113 (53% male) children (mean age 8.0 ± 2.1 years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3 ± 0.8% (53 mmol/mol ± 8.7) to 8.9 ± 1.1% (74 mmol/mol ± 12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac. CONCLUSIONS: The diabetes care teams' cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes.

AIMS: Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries.METHODS: Data were obtained for children and/or adults with Type 1 diabetes from the following countries (or regions): Western Australia, Austria, Denmark, England, Champagne-Ardenne (France), Germany, Epirus, Thessaly and Thessaloniki (Greece), Galway (Ireland), several Italian regions, Latvia, Rotterdam (The Netherlands), Otago (New Zealand), Norway, Northern Ireland, Scotland, Sweden, Volyn (Ukraine), USA and Wales) from population or clinic-based registries. The sample size with available data varied from 355 to 173 880. Proportions with HbA1c < 58 mmol/mol (< 7.5%) and ≥ 75 mmol/mol (≥ 9.0%) were compared by age and sex.RESULTS: Data were available for 324 501 people. The proportions with HbA1c 58 mmol/mol (< 7.5%) varied from 15.7% to 46.4% among 44 058 people aged < 15 years, from 8.9% to 49.5% among 50 766 people aged 15-24 years and from 20.5% to 53.6% among 229 677 people aged ≥ 25 years. Sex differences in glycaemic control were small. Proportions of people using insulin pumps varied between the 12 sources with data available.CONCLUSION: These results suggest that there are substantial variations in glycaemic control among people with Type 1 diabetes between the data sources and that there is room for improvement in all populations, especially in young adults.

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.

Aims: To assess the importance of family factors in determining metabolic outcomes in adolescents with type1 diabetes across varying international contexts. Methods: Adolescents with type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, across 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 (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. A capillary blood sample was drawn from each patient and analyzed centrally for HbA1c. Results: 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

OBJECTIVE-There is evidence that monocytes of patients with type 1 diabetes show proinflammatory activation and disturbed migration/adhesion, but the evidence is inconsistent. Our hypothesis is that monocytes are distinctly activated/disturbed in different subforms of autoimmune diabetes. RESEARCH DESIGN AND METHODS-We studied patterns of inflammatory gene expression in monocytes of patients with type 1 diabetes (juvenile onset, n = 30; adult onset, n = 30) and latent autoimmune diabetes of the adult (LADA) (n = 30) (controls subjects, n = 49; type 2 diabetic patients, n = 30) using quantitative PCR. We tested 25 selected genes: 12 genes detected in a prestudy via whole-genome analyses plus an additional 13 genes identified as part of a monocyte inflammatory signature previously reported. RESULTS-We identified two distinct monocyte gene expression clusters in autoimmune diabetes. One cluster (comprising 12 proinflammatory cytokine/compound genes with a putative key gene PDE4B) was detected in 60% of LADA and 28% of adult-onset type 1 diabetic patients but in only 10% of juvenile - onset type 1 diabetic patients. A second cluster (comprising 10 chemotaxis, adhesion, motility, and metabolism genes) was detected in 43% of juvenile-onset type 1 diabetic and 33% of LADA patients but in only 9% of adult-onset type 1 diabetic patients. CONCLUSIONS-Subgroups of type 1 diabetic patients show an abnormal monocyte gene expression with two profiles, supporting a concept of heterogeneity in the pathogenesis of autoimmune diabetes only partly overlapping with the presently known diagnostic categories.

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 Udgivelsesdato: 2008/4

To assess possible side-effects of GH treatment with supraphysiological doses on carbohydrate (CH) metabolism in girls with Turner syndrome (TS) during long term GH treatment and after discontinuation of GH treatment, the results of oral glucose tolerance tests and hemoglobin A1c measurements were analyzed in 68 girls with TS participating in a randomized dose-response trial. These previously untreated girls, aged 2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m2 x day (-0.045 mg/kg x day); group B, first year ,4 IU/m2 day; thereafter, 6 IU/m2 x day (approximately 0.0675 mg/kg x day); group C, first year, 4 IU/m2 x day; second year, 6 IU/m2 x day; thereafter, 8 IU/m2 x day (approximately 0.090 mg/kg x day). After the first 4 yr, girls 12 yr of age or older started with 5 microg/kg BW-day 17beta-estradiol for induction of puberty. To assess the effects of long term high dose GH treatment on CH metabolism, the 7-yr data from the oral glucose tolerance tests in 9 girls of group C were evaluated (group C1). To determine whether the changes in CH metabolism during GH treatment would persist after discontinuation of GH treatment, the data for 28 girls who had reached adult height (group A, n = 9; group B, n = 10; group C, n = 9) were evaluated at baseline, after 4 yr of GH treatment, and 6 months after discontinuation of GH. Seven-year data for group C1 showed that glucose levels did not significantly change during GH treatment, whereas fasting insulin levels as well as glucose-induced insulin levels increased significantly. The data for the 28 girls who were treated with GH for a mean (SD) period of 85.3 (13.3) months demonstrated that the GH-induced higher insulin levels decreased to values close to or equal to pretreatment values after discontinuation of GH treatment. Changes in CH variables were not significantly related to the GH dose. Hemoglobin A1c levels never showed an abnormal value. The prevalence of impaired glucose tolerance was low

The reactivity of islet cell cytoplasmic antibodies (ICA)-positive and ICA-negative sera of recent onset type 1 diabetic patients was studied in human fetal pancreata of 12-18 weeks' gestation and compared with the reactivity of these sera in adult human control pancreata. The aims of the study were: (1) to observe the presence of ICA staining in human fetal islet cells; (2) to compare endpoint titres (in Juvenile Diabetes Foundation units) of ICA-positive patient sera in fetal pancreata and adult human control pancreata. Ten ICA-positive sera and eight ICA-negative sera from newly diagnosed diabetic patients and four sera from healthy controls were tested on three human adult and eight human fetal pancreata. As in the adult control pancreata. ICA-positive sera reacted to insulin-, glucagon-, and somatostatin-positive cells of fetal pancreata of all gestational ages. This was observed both in single cells and in cells in islet-like cell clusters. Dilution of a reference serum gave similar results in both adult and fetal pancreata. In contrast, the ICA-positive patient sera yielded a striking heterogeneity in fetal as well as in adult pancreata. However, end-point titres between adult and fetal pancreata did not differ significantly (P>0.05). In conclusion, ICA-positive sera from recent onset diabetic patients show that the expression of molecules to which ICA react is present in all islet cells and starts before week 12 of gestation.

The value of a test for islet cell cytoplasmic antibodies together with a test for GAD65 antibodies to predict the subsequent development of diabetes over a period of 11.5 years was assessed in an open childhood population comprising 2,805 individuals. A single serum sample was obtained from each individual between 1975 and 1977 and screened for islet cell cytoplasmic antibodies for which eight individuals were positive (0.29%). During the average follow-up period of 11.5 years, four of eight islet cell antibody positive and three islet cell antibody negative individuals developed clinical diabetes. Sera from all individuals, who were islet cell antibody positive and/ or developed diabetes (total of 11) and from 100 randomly selected control subjects were analysed for GAD65 antibodies. Six of eight islet cell antibody positive individuals were GAD65 antibody positive including all four who subsequently developed IDDM. Furthermore, one of the three islet cell antibody negative individuals who developed IDDM was GAD65 antibody positive both in 1976 and in 1989. Thus, a positive test for GAD65 antibodies alone correctly predicted diabetes in five of seven children, who developed the disease. Only one of the children, who developed diabetes was positive for insulin autoantibodies and this individual was also positive for islet cell cytoplasmic antibodies and GAD65 antibodies. One of the 100 control subjects was positive for GAD65 antibodies (1%). The results suggest that a single GAD65 antibody test may have a higher sensitivity for predicting IDDM than a test for islet cell cytoplasmic antibodies, but that a combined positive test for both antibodies increases the specificity for predicting IDDM over a period of 11.5 years.

Type 1 diabetes mellitus or insulin dependent diabetes mellitus is a disease characterized by the selective destruction of insulin producing B-cells in the islets of Langerhans. The exact cause of this destruction is unknown, but is mediated by cells of the immune system. The immune system has a remarkable ability to recognize self from non-self, thereby providing a constant surveillance-mechanism that protects us for foreign invaders. This mechanism has failed in type 1 diabetes and attacks and destroys B-cells. The autoimmune basis of type 1 diabetes is described in chapter 1. The central problem in autoimmunity is why and how the immune system sometimes fails to distinguish between self and non-self. Re-instructing the immune system or blocking faulty immune reactions could result in primaryor secondary prevention of type 1 Diabetes Mellitus. This requires however, the molecular dissection of the process, including the identification of B-cell proteins involved in the autoimmune reactions. This thesis aims to contribute to this by the identification and characterization of two humoral autoantigens in type 1 Diabetes Mellitus, a 64kD and a 38kD protein. These aims are specified as follows: 1. Identification of the 64kD autoantigen in type 1 Diabetes Mellitus. 2. Biochemical and Cell biological characterization of the 64kD protein. 3. Identification of the 38kD autoantigen in type 1 Diabetes Mellitus. 4. Biochemical and Cell biological characterization of the 38kD protein. 5. Analysis of the frequencies of autoantibodies to the 64kD and the 38kD autoantigen at clinical diagnosis and in the prediabetic period. 6. Assessment of the predictive value of these autoantibodies, in particular in relation to other markers of autoimmune B-cell destruction.