Increasing plasma glucose before the development of type 1 diabetes-the TRIGR study.

OBJECTIVE: The ß-cell stress hypothesis suggests that increased insulin demand contributes to the development of type 1 diabetes. In the TRIGR trial we set out to assess the profile of plasma glucose and HbA1c before the diagnosis of clinical diabetes compared to nondiabetic children. RESEARCH DESIGN AND METHODS: A cohort of children (N = 2159) with an affected first-degree relative and increased HLA risk were recruited 2002-2007 and followed until 2017. To study the relationship between plasma glucose/HbA1c and the development of autoantibodies or clinical disease Kaplan-Meir curves were developed. Mixed models were constructed for plasma glucose and HbA1c separately. RESULTS: A family history of type 2 diabetes was related to an increase in plasma glucose (p < 0.001). An increase in glucose from the previous sample predicted clinical diabetes (p < 0.001) but not autoantibodies. An increase of HbA1c of 20% or 30% from the previous sample predicted the development of any autoantibody (p < 0.003 resp <0.001) and the development of diabetes (p < 0.002 resp <0.001. Participants without autoantibodies had lower HbA1c (mean 5.18%, STD 0.24; mean 33.08 mmol/mol, STD 2.85) than those who progressed to clinical disease (5.31%, 0.42; 34.46 mmol/mol, 4.68; p < 0.001) but higher than those who developed any autoantibody (5.10%, 0.30; 32.21 mmol/mol, 3.49; p < 0.001), or multiple autoantibodies (5.11%, 0.35; 32.26 mmol/mol, 3.92; p < 0.003). CONCLUSIONS: A pronounced increase in plasma glucose and HbA1c precedes development of clinical diabetes, while the association between plasma glucose or HbA1c and development of autoantibodies is complex. Increased insulin demand may contribute to development of type 1 diabetes.

Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk.

AIMS/HYPOTHESIS: We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes. METHODS: Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and length/height and followed for IA (at least one positive out of insulin autoantibodies, islet antigen-2 autoantibody, GAD autoantibody and zinc transporter 8 autoantibody) and development of type 1 diabetes from birth to 10-14 years. In this secondary analysis, Cox proportional hazard regression models were adjusted for birthweight and length z score, sex, HLA risk, maternal type 1 diabetes, mode of delivery and breastfeeding duration, and stratified by residence region (Australia, Canada, Northern Europe, Southern Europe, Central Europe and the USA). Longitudinal exposures were studied both by time-varying Cox proportional hazard regression and by joint modelling. Multiple testing was considered using family-wise error rate at 0.05. RESULTS: In the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, 305 (14.2%) developed IA and 172 (8%) developed type 1 diabetes. The proportions of children overweight (including obese) and obese only were 28% and 9% at 10 years, respectively. Annual growth measures were not associated with IA, but being overweight at 2-10 years of life was associated with a twofold increase in the development of type 1 diabetes (HR 2.39; 95% CI 1.46, 3.92; p < 0.001 in time-varying Cox regression), and similarly with joint modelling. CONCLUSIONS/INTERPRETATION: In children at genetic risk of type 1 diabetes, being overweight at 2-10 years of age is associated with increased risk of progression from multiple IA to type 1 diabetes and with development of type 1 diabetes, but not with development of IA. Future studies should assess the impact of weight management strategies on these outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00179777.

Pediatric diabetes training for healthcare professionals in Europe: Time for change.

BACKGROUND: Training for healthcare professionals (HCPs) in Europe who care for children and young people (CYP) with type 1 diabetes and their families is variable depending on the country. Building on the work of SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) and using the German Certified Diabetes Educators (CDEs) curriculum, a European collaboration of pediatric diabetes experts aimed to (1) establish current core elements that should be included in a pediatric diabetes education training course and (2) create a template for a European CDE's training curriculum. METHODS: A qualitative methodology incorporating a survey questionnaire, focus group discussions, individual semi-structured interviews and workshops was employed to explore participants' experiences and opinions. HCPs-pediatric consultants, diabetes nurses, dietitians and psychologists, national and local diabetes leads, academic and education leads and children, and young people with diabetes and families took part in the study. The total number of participants equaled 186. RESULTS: A template for a European Certified Diabetes Educator Curriculum (EU-CDEC) was developed based on the themes that emerged from the participants' expertise and experiences. This provides a model for HCPs' pediatric diabetes training provision. CONCLUSIONS: There is a severe shortage of high quality, standardized training for HCPs across the majority of European countries. Lack of trained HCPs for CYP with diabetes will result in the delivery of suboptimal care and impact on health, wellbeing and clinical and psychological outcomes. The EU-CDEC template can be used to increase access to high quality training provision for all HCPs across Europe and worldwide.

Pharmacokinetic and prandial pharmacodynamic properties of insulin degludec/insulin aspart in children, adolescents, and adults with type 1 diabetes.

Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of long-acting insulin degludec and short-acting insulin aspart. This open-label, Phase 1 study aimed to determine the pharmacodynamic and pharmacokinetic properties of IDegAsp in children (6-11 yr), adolescents (12-17 yr), and adults (18-65 yr) with type 1 diabetes mellitus (T1DM). Thirty-eight subjects received single subcutaneous IDegAsp dosing (0.5 U/kg) immediately before a standardized liquid meal (17.3 g carbohydrates/100 mL; adjusted for body weight) followed by plasma glucose (PG) and pharmacokinetic blood sampling for 36 and 57 h, respectively. There were no apparent differences between age groups in PG lowering effect (AUCPG baseline,0-6 h,meal,SD ), maximum PG excursion (ΔPGmax,meal,SD ), or maximum PG concentration (PGmax,meal,SD ) after the standardized meal. Estimated ratios (ERs) for total exposure (AUCIAsp,0-12 h,SD ) and maximum concentration (Cmax,IAsp,SD ) of IAsp in IDegAsp were children/adults, 1.69 (95% confidence interval, CI: 1.02; 2.80) and 1.66 (95% CI: 1.10; 2.51); adolescents/adults, 1.14 (95% CI: 0.76; 1.69) and 1.16 (95% CI: 0.84; 1.61). ERs for total exposure (AUCIDeg,0-∞,SD ) and maximum concentration (Cmax,IDeg,SD ) of IDeg in IDegAsp were children/adults, 1.42 (95% CI: 0.94; 2.16) and 1.38 (95% CI: 1.09; 1.76); adolescents/adults, 1.23 (95% CI: 0.96; 1.58) and 1.16 (95% CI: 0.95; 1.42). IDegAsp was well tolerated across age groups. The fast onset of prandial coverage of IAsp in IDegAsp and the ultra-long pharmacokinetic properties of IDeg in IDegAsp were preserved in children and adolescents. Exposure to IAsp and IDeg seemed to be higher in children vs. adults, but no differences were observed in PG lowering effect. IDegAsp could be an alternative treatment option in children and adolescents with T1DM.

Evaluating the diet of children at increased risk for type 1 diabetes: first results from the TEENDIAB study.

OBJECTIVE: The development of type 1 diabetes (T1D) is potentially influenced by nutrition. The aim of our study was to assess food and nutrient intakes of children at increased risk of T1D. DESIGN: Dietary intake of the last 4 weeks was assessed using a diet history interview. The daily nutrient and food intakes were compared with the German Dietary Reference Intakes, the Optimized Mixed Diet recommendations and those of a representative sample of children from the EsKiMo study. SETTING: Children included in the analysis participated in the prospective TEENDIAB study. SUBJECTS: First-degree relatives of people with T1D (n 268), aged 8-12 years. RESULTS: The TEENDIAB children consumed 52·0 % of their total energy from carbohydrates, 32·6 % from fat and 14·3 % from protein. Compared with the reference values, their intake was lowest for folate at 61·3 % of the reference, for iodine at 58·1 % and for vitamin D at 8·9 %, and exceeded the reference for vitamin K about 5-fold, for Na about 3·5-fold and for protein about 1·5-fold. Their nutrient intakes were similar to those of a control cohort without increased T1D risk. The consumption of non-desirable food groups (meat products, sweets/snacks) was above the recommendations and the consumption of desirable food groups (fruits, vegetables, carbohydrate-rich foods) was below the recommendations. CONCLUSIONS: The TEENDIAB children had intakes considerably below the recommendations for vitamin D, iodine, folate and plant-based foods, and intakes above for vitamin K, Na, protein, meat products and sweets/snacks. They showed similar dietary patterns to non-risk children.

Insulin degludec's ultra-long pharmacokinetic properties observed in adults are retained in children and adolescents with type 1 diabetes.

Insulin degludec (IDeg) is a basal insulin with an ultra-long pharmacokinetic profile in adults that at steady-state produces remarkably flat and stable insulin levels; however, no studies have yet reported on the pharmacokinetic properties of IDeg in subjects younger than 18 years of age. This was a single-centre, randomised, single-dose, double-blind, two-period crossover trial conducted in children (6-11 years), adolescents (12-17 years), and adults (18-65 years) with type 1 diabetes. Subjects received a single subcutaneous dose of 0.4 U/kg IDeg or insulin glargine (IGlar), respectively, on two separate dosing visits, with pharmacokinetic blood sampling up to 72-h postdose. A total of 37 subjects (12 children, 13 adolescents, and 12 adults) completed the trial. Total exposure of IDeg after a single dose (AUCIDeg ,0-∞, SD ) was higher in children compared to adults [estimated ratio children/adults 1.48 (95% confidence interval, CI: 0.98; 2.24)] and in adolescents compared to adults [estimated ratio adolescents/adults 1.33 (95% CI: 1.08; 1.64)]; however, the difference was only statistically significant for the latter comparison. No statistically significant difference in maximum concentration of IDeg (Cmax, IDeg , SD ) was observed. Estimated ratios for Cmax, IDeg , SD were (children/adults) 1.20 (95% CI: 0.90; 1.60) and (adolescents/adults) 1.23 (95% CI: 1.00; 1.51). Simulated mean steady state pharmacokinetic profiles supported a flat and stable IDeg exposure across a 24-h dosing interval. IDeg was detectable in serum for at least 72 h (end of blood sampling period) in all subjects following single dose. In conclusion, the ultra-long pharmacokinetic properties of IDeg observed in adults are preserved in children and adolescents with type 1 diabetes.

Continuous rise of insulin resistance before and after the onset of puberty in children at increased risk for type 1 diabetes - a cross-sectional analysis.

BACKGROUND: Insulin resistance has been postulated to be linked to the frequent onset of type 1 diabetes (T1D) during puberty. Very few studies have investigated the time course of insulin resistance in childhood. To address the question of how insulin resistance develops with age and how this is related to puberty onset, we examined insulin resistance and pubertal development over time in children at increased risk for T1D. METHODS: Homeostasis model assessment of insulin resistance (HOMA-IR) was measured in 1848 fasting samples of 1177 children (aged 5-15 years) in a cross-sectional analysis. All children had a first degree relative with T1D, 120 developed islet autoantibodies. Pubertal development was determined by Tanner staging. RESULTS: Insulin resistance rose continuously from age 5 to 13 years in girls and from age 5 to 14 years in boys with an average increase of 0.09 (95 % confidence interval [CI]: 0.08-0.10) per year for girls and 0.07 (95 % CI: 0.06-0.08) for boys. The rise preceded the onset of puberty (Tanner stage 2), which was reported between 10 and 12 years of age in 80.4 % of the children (mean age: 11.2 ± 0.06 years). No difference was seen between children with or without islet autoantibodies. CONCLUSIONS: There was a constant age-dependent rise of insulin resistance during childhood without observed associations to the onset of puberty or the presence of islet autoimmunity in children at increased risk for T1D. Our data show that insulin resistance emerges well before the initiation of physical changes of puberty.

Harmonize care to optimize outcome in children and adolescents with diabetes mellitus: treatment recommendations in Europe.

OBJECTIVE: Identify and evaluate current treatment recommendations in Europe for the care of children with diabetes in view of the European Union (EU) recommendations for Reference Centers. METHODS: A questionnaire was sent in 2008 to representatives of all EU countries and Norway, all known to be actively involved in pediatric diabetes care. Participants were asked whether specific guidelines were recommended and applied in their countries; when possible, they were invited to forward their national guidelines. As a second step, we evaluated the guideline mostly used in relationship to the recommendations of the EU. RESULTS: Information was obtained from all EU countries (including Scotland and Norway). National guidelines, as available, were forwarded for review. A 15/29 reported to use the International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines (CPCG), whereas 10 reported using national guidelines. These national guidelines were partly based on and/or compatible with ISPAD guidelines, but in most cases were far less detailed. The size and presentation differed (web based, booklet, page or chapter in adult guidelines). In four countries, no specific guidelines were used. As ISPAD CPCG were used most frequently, its content was evaluated within the EU Centres of Reference recommendations and minor changes were made in agreement with the ISPAD editor. DISCUSSION: Differences between guidelines may influence surveillance and quality of care in pediatric diabetes within Europe. Although a majority of countries is using or at least mentioning the ISPAD CPCG, their implementation as EU standard needs further endorsement. As language difficulties may hamper its implementation on a wider scale, further translation of the ISPAD guidelines should be endorsed to render it accessible to all healthcare professionals. With respect to the content, some changes were then made in agreement with the editors, adjusting them to the European context. For European Reference Centers, some further guidance on research may be included. Once implemented on an EU wide level, benchmarking of carefully defined robust quality of care and quality of life indicators will allow us to improve these guidelines on a regular basis ensuring an evidence-based care for all children with diabetes.

Technical solution for data collection, data safety and data privacy legislation: experiences from the SWEET study.

BACKGROUND: One of the most important tasks of the SWEET study is benchmarking the data collected. Information on the occurrence of the disease of diabetes, the treatment, and their outcomes in children from the different member states of European Union (EU) is crucial. How the collection of data is realized is essential, concerning both the technical issues and the results. The creation of SWEET Centers of Reference (CoR), all over Europe will be facilitated by the access to safe data collection, where legal aspects and privacy are ascertained. OBJECTIVE: To describe the rationale for- and the technical procedure in the data collection implementation, in the SWEET study. SUBJECTS: Selected data on all patients treated at SWEET CoR are collected. METHODS: The SWEET project data collection and management system, consists of modular components for data collection, online data interchange, and a database for statistical analysis. CONCLUSION: The SWEET study and the organization of CoR aims for the goal of offering an updated, secure, and continuous evaluation of diabetes treatment regimens for all children with diabetes in Europe. To support this goal, an appropriate and secure data management system as described in this paper has been created.

A pediatric diabetes toolbox for creating centres of reference.

INTRODUCTION: ISPAD guidelines recommend age appropriate diabetes education concepts for young patients and their families as well as tools for nutritional management, psychosocial assessment, and psychological advice but their implementation in Europe is presently unknown. METHODS: On the basis of a structured survey among the European SWEET members information on established tools and programs in national languages were analyzed using an extensive literature and desk search. These were differentiated according to five age-groups and five target groups (young people with diabetes, parents, and other close relations, carers in school and nursery, and healthcare professionals). RESULTS: Responses and original tools were received from 11 SWEET countries reflecting the European status in 2011. More or less structured information for parents, close relations, and carers in school or nursery are available in all 11 participating countries. However, only two countries followed the recommendations of having published a structured, curriculum lead, and evaluated program for different age-groups and carers. One of these was evaluated nationwide and funded by the respective National Health Care System after accreditation. In addition a huge variety of creative tools, e.g., booklets, leaflets, games, videos, and material for educating children of different age-groups and their parents are available - but most of them are not linked to a structured education program. CONCLUSIONS: Harmonizing and integrating these materials into quality assured structured holistic national education programs will be an important future task for the ongoing SWEET project. A comprehensive European diabetes educational toolbox is aimed to be published and continuously updated on the SWEET website.

Criteria for Centers of Reference for pediatric diabetes--a European perspective.

'SWEET' is an acronym standing for 'Better control in pediatric and adolescent diabeteS: Working to crEate CEnTers of Reference (CORs)' and is based on a partnership of established national and European diabetes organizations such as International Diabetes Federation, Federation of European Nurses in Diabetes, and Primary Care Diabetes Europe (PCDE, www.sweet-project.eu). A three-level classification of centers has been put forward. In addition to centers for local care, SWEET collaborating centers on their way to being a COR have been defined. Peer-audited CORs with a continuous electronic documentation of at least 150 pediatric patients with diabetes treated by a multidisciplinary team based on the International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice recommendations have been created in 12 European countries. In 2011, they cared for between 150 to more than 700 youth with diabetes with an average hemoglobin A1c between 7.6 and 9.2%. Although these clinics should not be regarded as representative for the whole country, the acknowledgment as COR includes a common objective of targets and guidelines as well as recognition of expertise in treatment and education at the center. In a first step, the SWEET Online platform allows 12 countries using 11 languages to connect to one unified diabetes database. Aggregate data are de-identified and exported for longitudinal health and economic data analysis. Through their network, the CORs wish to obtain political influence on a national and international level and to facilitate dissemination of new approaches and techniques. The SWEET project hopes to extend from the initial group of centers within countries, throughout Europe, and beyond with the help of the ISPAD network.

[Type 1 diabetes in children and adolescents--new strategies in management and treatment]. / Typ-1-Diabetes bei Kindern und Jugendlichen. Neue Strategien in Diagnostik und Therapie.

Type 1 diabetes (T1D) is the most common metabolic disease in childhood with an increasing incidence of about 3 to 5% per year, particularly in preschool children. Despite substantial progresses in diabetes research concerning its pathogenesis and etiology in the last decades, there is no strategy for primary prevention in subjects with subclinical signs of diabetes. Nowadays, it is well-known that T1D is caused by partial or total destruction of pancreatic islet cells, resulting in progressive incapacity to produce insulin. This inflammation is of an autoimmune nature, resulting both from environmental and genetic influences. Children with T1D usually have a several day history of typical symptoms such as frequent urination, excessive thirst and weight loss, which appear when about 80% of the pancreatic beta cells are already destroyed. If those symptoms are misinterpreted, the continuing hyperglycaemic metabolism leads to a potential life-threatening condition the diabetic ketoacidosis. Patients with T1D require daily subcutaneous injections of insulin, with the overall aim to mimic the physiological release of insulin during meal-associated and fasting periods (intensive insulin therapy). The most important parameters to evaluate the effectiveness of insulin treatment are blood glucose monitoring and HbA1c. The increased availability of systems for continuous glucose monitoring may help patients to have a better insight into their metabolic conditions. Sensor-based insulin treatment is likely to have a significant impact on paediatric diabetes therapy and education in the future.