[Individualization of diabetes treatment by automated insulin delivery]. / Individualisierung der Diabetestherapie durch Automatisierung der Insulingabe.

Insulin pumps and glucose sensors have been shown to be effective in improving diabetes treatment and reducing acute complications according to data from registries. Therefore, in pediatric diabetology the use of at least one technical device is standard. Both devices can also be combined to form automated insulin delivery (AID) systems.Many AID systems have been tested in clinical trials and have proven to be safe and effective. The supply situation in Germany currently only allows one system to be prescribed for people insured by the statutory health insurances. Currently, children younger than 7 years of age cannot be treated with this system. The reasons for this are legal hurdles and lack of certification by the manufacturers. The CE certification can also lead to problems with insulin prescriptions. Open-source systems are non-regulated variants to circumvent existing regulatory conditions. There are risks here for both users and prescribers.For permanent use a thorough knowledge of the features of each AID system is necessary for both the user and the practitioner. Complete automation does not yet work. For the evaluation of the AID treatment, the metric data of the glucose sensors, the time in range and the glucose management index are the recognized and suitable parameters, because they allow a consultation based on real data from the daily life of people with diabetes.As all glucose sensors are read out via cloud-based software or the data are obtained directly and automatically from a telephone-linked receiver device, this provides the ideal technical basis for telemedical care, which still needs to be configured.

Transition to adult diabetes care in Germany-High risk for acute complications and declining metabolic control during the transition phase.

OBJECTIVE: There is evidence that transition from pediatric to adult health care is frequently associated with deterioration of health in youths with type 1 diabetes (T1D). The aim of this study was to compare metabolic control, acute complications and microvascular complications in adolescents and young adults before and after transfer to an adult treatment center with respect to the time between first visit in the adult center and last visit in pediatric treatment. METHODS: All data were collected during routine care and retrieved from the German/Austrian DPV database. We analyzed data as of March 2017. RESULTS: We found 1283 young adults with available data of the last pediatric treatment year and the first year after transition to adult care. HbA1c increased significantly from 8.95% (74 mmol/mol) before to 9.20% (77 mmol/mol) in the first year after transition. Frequency of DKA with hospitalization (0.10-0.191 per annum, P < .0001) and severe hypoglycemia (0.23-0.46 per annum, P = .013) doubled during transition. Microvascular complications increased dramatically depending on the time between first visit in adult treatment and last visit in pediatric care. We could not find a significant correlation of this rise of microvascular complications to the duration of transition (short or long). CONCLUSION: This phase of life bears a high risk for detrimental outcome in young adults with T1D. Structured transition programs with case management are therefore needed to improve the transition process and outcomes.

[Evaluation and Utilization - Quality Management in a Paediatric University Outpatient Department]. / Evaluation und Inanspruchnahme - Qualitätssicherung in der pädiatrischen Ambulanz einer Universitätsklinik.

BACKGROUND: Based on an increasing number of outpatient treatments, an extensive demand planning is necessary to ensure the quality of medical care. University outpatient clinics are special parts of this sector and therefore it is necessary that a research demonstrates the nearly uninvestigated position of a paediatric outpatient clinic. PATIENTS: The research at the university hospital for children and adolescents in Leipzig started in 2009 to survey 2283 of in total 9391 patients and the physicians. METHODS: Sociodemographic data as well as economic and medical facts were determined by using questionnaires. In each case a questionnaire was answered by the children or their accompanying persons and a separate one was completed by the respective doctor. RESULTS: The results created a foundation, on the basis of patient volume per day and per daytime. Less than 20% of the children admitted to consult the clinic for their first time. The majority of patients visit them because of a letter of referral. Most of the patients (58%) were younger than 6 years old. Approximately 35% of patients did not come from the city region of Leipzig. CONCLUSION: The investigation evidenced the necessity of a day and night operating institution for children in the region of Leipzig as well as the high specialisation of the outpatient clinic. In need of further investigation is the cooperation between several physicians to find out if this lots of medical examination are necessary or if there took place overlapping.

Overweight and Obesity Based on Four Reference Systems in 18,382 Paediatric Patients with Type 1 Diabetes from Germany and Austria.

AIM: To evaluate the prevalence of overweight and obesity in paediatric type 1 diabetes (T1D) subjects, based on four commonly used reference populations. METHODS: Using WHO, IOTF, AGA (German pediatric obesity), and KiGGS (German Health Interview and Examination Survey for Children and Adolescents) reference populations, prevalence of overweight (≥90th percentile) and obesity (≥97th percentile) and time trend between 2000 (n = 9,461) and 2013 (n = 18,382) were determined in 2-18-year-old T1D patients documented in the German/Austrian DPV database. RESULTS: In 2000, the overweight prevalence was the highest according to IOTF (22.3%), followed by WHO (20.8%), AGA (15.5%), and KiGGS (9.4%). The respective rates in 2013 were IOTF (24.8%), WHO (22.9%), AGA (18.2%), and KiGGS (11.7%). Obesity prevalence in 2000 was the highest according to WHO (7.9%), followed by AGA (4.5%), IOTF (3.1%), and KiGGS (1.8%). In 2013, the respective rates were WHO (9.6%), AGA (6.2%), IOTF (4.5%), and KiGGS (2.6%). Overall, the prevalence of overweight and obesity increased from 2000 to 2006 (p < 0.001) but showed stabilization thereafter in girls and overweight in boys. CONCLUSION: Overweight and obesity prevalence in T1D subjects differs significantly if it is assessed by four separate reference populations. More detailed assessment of each child is required to determine obesity-related risks.

Impact of regular physical activity on blood glucose control and cardiovascular risk factors in adolescents with type 2 diabetes mellitus--a multicenter study of 578 patients from 225 centres.

INTRODUCTION: Regular physical activity (RPA) is a major therapeutic recommendation in children and adolescents with type 2 diabetes mellitus (T2DM). We evaluated the association between frequency of RPA and metabolic control, cardiovascular risk factors, and treatment regimes. METHODS: The Pediatric Quality Initiative (DPV), including data from 225 centers in Germany and Austria, provided anonymous data of 578 patients (10-20 yr; mean 15.7 ± 2.1 yr; 61.9% girls) with T2DM. Patients were grouped by the frequency of their self-reported RPA per week: RPA 0, none; RPA 1, 1-2×/wk; RPA 2, >2×/wk. RESULTS: The frequency of RPA ranged from 0 to 9×/wk (mean 1.1×/wk ±1.5). 55.7% of the patients reported no RPA (58.1% of the girls). Hemoglobin A1c (HbA1c) differed significantly among RPA groups (p < 0.002), being approximately 0.8 percentage points lower in RPA 2 compared to RPA 0. Body mass index (BMI-SDS) was higher in the groups with less frequent RPA (p < 0.00001). Multiple regression analysis revealed a negative association between RPA and HbA1c (p < 0.0001) and between RPA and BMI-SDS (p < 0.01). The association between RPA and high density lipoprotein (HDL)-cholesterol was positive (p < 0.05), while there was no association to total cholesterol, low density lipoprotein (LDL)-cholesterol or triglycerides. Approximately 80% of the patients received pharmacological treatment (oral antidiabetic drugs and/or insulin) without differences between RPA groups. CONCLUSION: More than half of the adolescents with T2DM did not perform RPA. Increasing physical activity was associated with a lower HbA1c, a lower BMI-SDS, a higher HDL-cholesterol, but not with a difference in treatment regime. These results suggest that regular exercise is a justified therapeutic recommendation for children and adolescents with T2DM.

[Off-label drug prescriptions among outpatient children and adolescents in Germany--a database analysis]. / Verwendung von Off-Label-Medikamenten bei ambulant betreuten Kindern und Jugendlichen in Deutschland.

BACKGROUND: Due to lack of respective studies children often receive medication that is applied beyond the approved indication. The consequence of this off-label use is often an increased risk of unexpected and undesirable side effects. This study deals with the amount of off-label drug prescriptions among children and adolescents receiving outpatient treatment in Germany. The aim is to outline age-, gender-, region-, and insurance specific differences and to determine risk factors for an off-label prescription. METHODS: This is a retrospective study that has been conducted by means of the IMS Patient Database Disease Analyzer for the year 2010 considering three therapy classes (analgesics, antibiotics and antidepressants). The evaluation of the risk factors for an off-label prescription resulted from a multivariate logistic regression. Age- and dose-specific prescriptions were analyzed but not indication-specific prescriptions. RESULTS: In total 189,285 children and adolescents with analgesics-, 147,089 with antibiotics-, and 15,405 with antidepressants prescriptions were identified. The percentage of patients with off-label prescriptions amounted to 0.9 % for analgesics, 2.5 % for antibiotics and 8.5 % for antidepressants. The off-label prescriptions made by general practitioners were significantly higher than those made by pediatricians and child psychiatrists. The number of off-label prescriptions in country sides was higher than in cities. In eastern states more off-label prescriptions were made than in western states of Germany. CONCLUSION: The study shows that outpatient treatment of children and adolescents occurs widely with drugs corresponding to age and dosage. Off-label prescriptions not conform to indication were not determined. However, off-label drug use should be reduced further for outpatient treatment to ensure a safe and low-risk medical treatment for children and adolescents.

[Morning hyperglycemia in children and adolescents with type 1 diabetes and different modes of therapy: an evaluation of the DPV data pool]. / Morgenhyperglykämie bei Kindern und Jugendlichen mit Typ-1-Diabetes bei unterschiedlichen Therapieformen: Eine Auswertung des DPV-Datenpools.

Early morning hyperglycemia is frequent among children and adolescents with type 1 diabetes. Reasons are a dawn phenomenon, a Somogyi phenomenon or a lack of insulin in the morning hours. Only few studies are published regarding incidence and relation to different modes of basal insulin treatment in this population.We analyzed all cases recorded in the DPV register from 1995 to 2010. 5 839 patients from 128 centers with at least 3 blood glucose measurements during the last night of a hospital stay were included.24.2% of patients showed a morning hyperglycemia above 200 mg/dl. 8.6% showed a dawn phenomenon, 7.0 % a lack of insulin and 2.0% a Somogyi phenomenon. A dawn phenomenon was significantly less frequent in patients treated with an insulin pump (1.1%) compared to long acting insulin analogs Glargin and Levemir (5.4%) or NPH insulin (8.2%). Lack of insulin was again less frequent during insulin pump treatment compared to other treatments (1.9% vs. 4.9% vs. 5.3%). Median rise of blood glucose levels was 33.4 mg/dl between midnight and 6 a.m. Mode of basal insulin treatment is an important factor: while treatment with an insulin pump led to a blood glucose fall of 28.5 mg/dl between 3 and 6 a.m., treatment with insulin analog or NPH insulin resulted in a rise of 28.5 or 35.9 mg/dl, respectively.This study shows that insulin pump treatment reduces the frequency of morning hyperglycemia caused by the dawn phenomenon or a lack of insulin.

Diabetes mellitus in children and adolescents with genetic syndromes.

BACKGROUND: Several genetic syndromes are associated with diabetes mellitus (DM). This study aimed to analyse data from the DPV database with regard to frequency, treatment strategies and long-term complications in paediatric DM patients with genetic syndromes, including Turner syndrome (TS), Prader-Willi syndrome (PWS), Friedreich ataxia (FA), Alström syndrome (AS), Klinefelter syndrome (KS), Bardet-Biedl syndrome (BBS), Berardinelli-Seip syndrome (BSS) and Down syndrome (DS). METHODS: Longitudinal data for 43 521 patients with DM onset at age < 20 years were collected from 309 treatment centres in Germany and Austria using the DPV software. Data included anthropometric parameters, type of diabetes, mean age, age at diabetes onset, daily insulin dose, HbA 1c , micro- and macroalbuminuria, retinopathy and dyslipidaemia. Descriptive statistics and standard statistical tests were used for data analysis. RESULTS: In total, 205 DM patients had one of the following syndromes: DS (141 patients), TS (24), PWS (23), FA (5), AS (5), KS (4), BBS (2) and BSS (1). Diabetes-specific antibodies were positive in the majority of patients with DS, TS and FA. CONCLUSION: Despite the well-known association between DM and certain syndromic disorders, the number of affected patients in the German and Austrian paediatric diabetic population is very low. Nevertheless, physicians should be aware of syndromic forms of diabetes. Joint multicentre analyses are needed to draw relevant conclusions.

Treatment of diabetic ketoacidosis (DKA) with 2 different regimens regarding fluid substitution and insulin dosage (0.025 vs. 0.1 units/kg/h).

Diabetic ketoacidosis (DKA) is still the most dangerous acute complication in type 1 diabetes. The aim of this study was to compare treatment of DKA with a regimen of a low insulin dose (0.025 units/kg/h) vs. a standard insulin dose (0.1 units/kg/h).We retrospectively analysed all cases of children and adolescents (age 0-18 years) with type 1 diabetes and DKA who needed treatment in the ICU in the time period of 1998-2005 in 2 pediatric diabetes centers. In a chart review of the first 48 h after onset of DKA the following parameters where evaluated: pH, blood glucose, sodium, potassium, and ketones in urine. Consciousness, neurological status and complications such as cerebral edema, hypoglycaemia or hypokalemia were also recorded.23 children were treated in center A (low insulin dose) whereas 41 where treated in center B (standard insulin dose). Mean age of the patients was 8.9 (range 1.58-17.7) and 13.5 years (1.25-17.7) respectively (p=0.134). Mean pH was 7.1 and HCO3 was 9.05 and 7.79 respectively (p=0.122). Initial blood glucose was 26 mmol/l (no difference between the 2 centres). Treatment with the standard insulin dose resulted in a slightly shorter duration of acidosis (8 h in center A, 6.5 h in center B) and a significantly faster normalization of blood glucose (18 h in A, vs. 10.5 h in B) (p<0.005). During the first day we found similar and very low rates of hypoglycaemia. In center B one case of suspected cerebral edema and cerebral infarction occurred.Low dose insulin substitution is as safe as the recommended standard dose in respect to the occurrence of acute complications. Acidosis is broken slightly earlier with the standard dose. Implications of this earlier normalisation of pH remain unclear.

Vaspin is related to gender, puberty and deteriorating insulin sensitivity in children.

BACKGROUND: Visceral adipose tissue-derived serine protease inhibitor (vaspin) has been suggested as a novel adipocytokine related to obesity and insulin sensitivity in adults. DESIGN: We quantified vaspin serum concentrations in 65 lean and 67 obese children and aimed to evaluate the relationship of vaspin with physical development, obesity, and metabolic and cardiovascular phenotypes in children. We further assessed the acute vaspin response to glucose provocation in 20 obese adolescents and evaluated tissue expression patterns of vaspin in humans. RESULTS: Vaspin levels were significantly higher in girls than in boys. In girls, vaspin increased with age and pubertal stage, whereas there was no change with development in boys. Obese girls had lower vaspin serum levels than those of lean controls, but there was no significant correlation with body mass index (BMI). Independent of sex, age and BMI, lower vaspin was associated with better insulin sensitivity, with higher systolic blood pressure and impaired endothelial function. In response to glucose provocation during an oral glucose tolerance test, vaspin serum levels declined by approximately 25% in adolescents with hyperinsulinemia, whereas there was no significant decline in normoinsulinemic patients. In support of our clinical data, we not only confirmed vaspin mRNA expression in adipose tissue but also found consistent expression of vaspin in the liver and indications for expression in the pancreas and the skin. CONCLUSION: We showed that gender differences in circulating vaspin levels develop during pubertal progression in girls. Although vaspin's association with obesity remains controversial, vaspin was increased with worsening insulin resistance already in children and was acutely down-regulated following glucose provocation in insulin-resistant adolescents independent of obesity. Besides adipose tissue, vaspin expression in the liver and the pancreas may potentially contribute to circulating vaspin levels and their regulation.

Sensor-augmented pump therapy from the diagnosis of childhood type 1 diabetes: results of the Paediatric Onset Study (ONSET) after 12 months of treatment.

AIMS/HYPOTHESIS: The value of managing children with type 1 diabetes using a combination of insulin pump and continuous glucose monitoring starting from diagnosis for improving subsequent glycaemic control and preserving residual beta cell function was determined. METHODS: A total of 160 children (aged 1-16 years, mean ± SD: 8.7 ± 4.4 years; 47.5% girls) were randomised to receive insulin pump treatment with continuous glucose monitoring or conventional self-monitoring blood glucose measurements. The primary outcome was the level of HbA(1c) after 12 months. Other analyses included fasting C-peptide, glycaemic variability, sensor usage, adverse events, children's health-related quality of life and parent's wellbeing. RESULTS: HbA(1c) was not significantly different between the two groups, but patients with regular sensor use had lower values (mean 7.1%, 95% CI 6.8-7.4%) compared with the combined group with no or low sensor usage (mean 7.6%, 95% CI 7.3-7.9%; p=0.032). At 12 months, glycaemic variability was lower in the sensor group (mean amplitude of glycaemic excursions 80.2 ± 26.2 vs 92.0 ± 33.7; p=0.037). Higher C-peptide concentrations were seen in sensor-treated 12- to 16-year-old patients (0.25 ± 0.12 nmol/l) compared with those treated with insulin pump alone (0.19 ± 0.07 nmol/l; p=0.033). Severe hypoglycaemia was reported only in the group without sensors (four episodes). CONCLUSION/INTERPRETATION: Sensor-augmented pump therapy starting from the diagnosis of type 1 diabetes can be associated with less decline in fasting C-peptide particularly in older children, although regular sensor use is a prerequisite for improved glycaemic control. TRIAL REGISTRATION: ISRCTN.org ISRCTN05450731 FUNDING: Medtronic International Trading Sàrl, Tolochenaz, Switzerland.

Entities and frequency of neonatal diabetes: data from the diabetes documentation and quality management system (DPV).

AIMS: The aim of this study was to elucidate the entities and the frequency of neonatal diabetes mellitus (NDM) in a large representative database for paediatric diabetes patients in Germany and Austria. METHODS: Based on the continuous diabetes data acquisition system for prospective surveillance (DPV), which includes 51,587 patients with onset of diabetes before the age of 18 years from 299 centres in Germany and Austria, we searched for patients with onset of diabetes mellitus in the first 6 months of life. RESULTS: Ninety patients were identified, comprising 0.17% of all paediatric cases in the DPV registry. This represented an incidence of approximately one case in 89,000 live births in Germany. A monogenic basis for NDM was established in 30 subjects (seven UPD6, 10 KCNJ11, seven ABCC8, two FOXP3, two PDX1, one INS, one EIF2AK3). Pancreatic hypoplasia or agenesis was reported in 10 patients and seven subjects were classified as having Type 1 diabetes by their centres. Transient neonatal diabetes (TNDM) accounted for approximately 10% of all cases with NDM. No aetiology was defined in 41 subjects, which may reflect incomplete genetic testing or novel genetic aetiologies. CONCLUSION: Based on a large database, we identified a higher rate of NDM in Germany than has been reported previously. Full molecular genetic testing should be performed in all patients diagnosed before 6 months of age.

[Use of herbal medicine in German children - prevalence, indications and motivation]. / Phytotherapie in der Kinderheilkunde - Prävalenz, Indikationen und Motivation.

BACKGROUND AND OBJECTIVES: Herbal medicine (phytotherapy) is increasingly used by the German population. But its use for children has been rarely analysed. This study determined prevalence, motivations and indications for the use of herbal medicine use. It also investigated parent-related variables associated with its use. METHODS: An anonymized questionnaire was filled in by parents of children and adolescents who attended the general pediatric out-patient department of two German university children's hospitals and the practice of two general pediatricians. RESULTS: 413 of 600 parents (68.8%) completed the questionnaire. Mean age of the children was 6.7 +/- 4.7 years. 353 (85.5%) were given one or more herbal products, chamomile (85.5%), fennel (81.3%), eucalyptus (43.9%). Bronchipret 43.1%) (thyme and primrose [tablets] or thyme with ivy [syrup] and Prospan (43.1%) (a syrup of ivy leaf extract) were the most commonly used, in the treatment of cough. Parents who give phytotherapeuticals to their children were significantly more often women, living in a large city, of good education and financially better off (p< 0.05). CONCLUSION: Herbal medicine is widely used in Germany during childhood and adolescence. To achieve high therapeutic safety it is important to ask parents explicitly about such use.

HLA-DR genotypes influence age at disease onset in children and juveniles with type 1 diabetes mellitus.

OBJECTIVE: To investigate HLA-DR genotype in association with chronological age or calendar year of disease onset and the time trend of genotype frequencies from 1969 to 2009. Additionally, to examine genotype frequency in relation to B-cell-, islet cell antibodies (ICA)-, autoantibodies to insulin-, insulinoma antigen 2 (IA2)-, glutamic acid decarboxylase-antibody positivity, thyroid antibody positivity, thyroid diseases or coeliac antibody positivity. Genotype associations with gender and ethnicity are also analyzed. SUBJECTS AND METHODS: HLA-typed children and juveniles (n=1445) aged 12 years the most prevalent HLA-DR genotype was X/X (18.1%). IA2 positivity was associated with HLA-DR4/X and HLA-DR3/4 positivity (P=0.011), and hypothyroidism was linked to HLA-DR4/4 (P=0.0103). More females carried the HLA-DR4/4 genotype (18.2 vs 12.7% P=0.0048) or were thyroid antibody positive (24.5 vs 14.7% P=0.0001). Larger numbers of <6 year olds were coeliac antibody positive than >12 year olds (14.8 vs 9.1% P=0.0037). No associations between migration background and B-cell-, thyroid- or coeliac-antibody positivity, and no time trend were found. CONCLUSION: HLA-DR genotype associated with age at disease onset, ICA positivity and hypothyroidism; female gender with thyroid antibody positivity and low age of diabetes onset with coeliac antibody positivity.

[Building bridges during transition of patients with type 1 diabetes. Adult medical and pediatric point of views]. / Brücken bauen bei der Transition von Patienten mit Typ-1-Diabetes. Internistische und pädiatrische Perspektiven.

The transition of patients with type 1 diabetes from pediatric to adult care services is challenging not only for patients but also for pediatricians and the further care providing physician. Around the time of transition, metabolic control is often unstable. Furthermore, psychiatric comorbidities or social background should be considered. Follow-up by a specialist, i.e. adults' endocrinologist/diabetologist, should be guaranteed. Typical differences between pediatric and adult health care services may hamper a successful transition. The handing-over of health care should be planned early and the timing should be adapted to the medical and psychosocial condition of the patient. An interdisciplinary transfer clinic seems the optimal setting for a successful transition. Close cooperation between pediatricians and adults' diabetologists is a prerequisite.

Changes in the use of analogue insulins in 37 206 children and adolescents with type 1 diabetes in 275 German and Austrian centers during the last twelve years.

AIMS: To describe changes in insulin treatment in children and adolescents in Germany/Austria regarding short acting (SA)- and long acting (LA) insulin analogues in different age groups over the last twelve years. METHODS: Use of different insulins and treatment regimens were analysed in 37 206 children and adolescents with the age of 0-20 years from 276 German and Austrian centers that were registered in the DPV-database (Dec. 2007). The group was subdivided into 4 age groups (A: 0-4 years; B:5-9 years;C:10-14 years,D:15-19 years). We further analysed the use of analogues from onset of diabetes. RESULTS: A significantly increasing percentage of pediatric patients in all age groups with Type 1 Diabetes use analogue insulins. In 2007, 48.5% used SA, 45.8% LA. 87.2% of pumps were running with short acting analogue. Age specific analysis: A: 2000: 9.1%SA, 0.7%LA vs. 2007: 50.0%SA, 10.0%LA; B: 2000:5.6%SA, 1.4%LA vs. 2007: 36.8%SA, 27.5%LA C: 2000:14.3%SA, 3.4%LA vs. 2007: 45.3%SA, 49.1%LA D: 2000:26.3%SA, 3.2%LA vs. 2007: 59.1%SA, 61.9%LA. This increase in usage of analogues was also found at onset of diabetes. Corrected for age, center and diabetes duration HbA1c was significantly lower in the group with regular insulin (8.18+/-0.047%) than with SA (8.32+/-0.048%) (p<0.0001) and BMI-SDS was only marginal lower in the group with regular insulin (0.45+/-0.01 kg/m (2)) than with SA (0.47+/-0.15) (p>0.007). Similar differences in HbA1c (8.09+/-0.05% vs. 8.40+/-0.05%) and BMI-SDS where seen when NPH was compared with LA respectively. After change to SA the reduction of severe hypoglycemia with (6.1/100 pat.years) and without coma (6.2/100 pat.years) was significant and after change to LA for severe hypoglycemia without coma respectively. CONCLUSIONS: Long-term data for the use of new drugs are sparse. In our analysis patients are followed not under study conditions. Still the higher BMI and HbA1c with either SA or LA usage have to be discussed carefully in the context of increasing use of both, long acting and short acting analogues and possible problems with reimbursement.