Thomas Danne

TRANSCRIPTIONAL REGULATION OF THE HUMAN KiSS1 GENE

Kisspeptin, the product of the KiSS1 gene, has emerged as a key component of the mechanism by which the hypothalamus controls puberty and reproductive development. It does so by stimulating the secretion of gonadotropin releasing hormone (GnRH). Little is known about the transcriptional control of the KiSS1 gene. Here we show that a set of proteins postulated to be upstream components of a hypothalamic network involved in controlling female puberty regulates KiSS1 transcriptional activity. Using RACE-PCR we determined that transcription of KiSS1 mRNA is initiated at a single transcription start site (TSS) located 153-156bp upstream of the ATG translation initiation codon. Promoter assays performed using 293 MSR cells showed that the KiSS1 promoter is activated by TTF1 and CUX1-p200, and repressed by EAP1, YY1, and CUX1-p110. EAP1 and CUX-110 were also repressive in GT1-7 cells. All four TFs are recruited in vivo to the KiSS1 promoter and are expressed in kisspeptin neurons. These results suggest that expression of the KiSS1 gene is regulated by trans-activators and repressors involved in the system-wide control of mammalian puberty.

Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes

Insulin degludec (IDeg) once‐daily was compared with insulin detemir (IDet) once‐ or twice‐daily, with prandial insulin aspart in a treat‐to‐target, randomized controlled trial in children 1–17 yr with type 1 diabetes, for 26 wk (n = 350), followed by a 26‐wk extension (n = 280). Participants were randomized to receive either IDeg once daily at the same time each day or IDet given once or twice daily according to local labeling. Aspart was titrated according to a sliding scale or in accordance with an insulin:carbohydrate ratio and a plasma glucose correction factor. Randomization was age‐stratified: 85 subjects 1–5 yr. (IDeg: 43), 138 6–11 yr (IDeg: 70) and 127 12–17 yr (IDeg: 61) were included. Baseline characteristics were generally similar between groups overall and within each stratification. Non‐inferiority of IDeg vs. IDet was confirmed for HbA1c at 26 wk; estimated treatment difference (ETD) 0.15% [−0.03; 0.32]95%CI. At 52 wk, HbA1c was 7.9% (IDeg) vs. 7.8% (IDet), NS; change in mean FPG was −1.29 mmol/L (IDeg) vs. +1.10 mmol/L (IDet) (ETD −1.62 mmol/L [−2.84; −0.41]95%CI, p = 0.0090) and mean basal insulin dose was 0.38 U/kg (IDeg) vs. 0.55 U/kg (IDet). The majority of IDet treated patients (64%) required twice‐daily administration to achieve glycemic targets. Hypoglycemia rates did not differ significantly between IDeg and IDet, but confirmed and severe hypoglycemia rates were numerically higher with IDeg (57.7 vs. 54.1 patient‐years of exposure (PYE) [NS] and 0.51 vs. 0.33, PYE [NS], respectively) although nocturnal hypoglycemia rates were numerically lower (6.0 vs. 7.6 PYE, NS). Rates of hyperglycemia with ketosis were significantly lower for IDeg vs. IDet [0.7 vs. 1.1 PYE, treatment ratio 0.41 (0.22; 0.78)95%CI, p = 0.0066]. Both treatments were well tolerated with comparable rates of adverse events. IDeg achieved equivalent long‐term glycemic control, as measured by HbA1c with a significant FPG reduction at a 30% lower basal insulin dose when compared with IDet. Rates of hypoglycemia did not differ significantly between the two treatment groups; however, hyperglycemia with ketosis was significantly reduced in those treated with IDeg.

Treatment with insulin glargine reduces asymptomatic hypoglycemia detected by continuous subcutaneous glucose monitoring in children and adolescents with type 1 diabetes

Objective:  Unsatisfactory basal insulin substitution may lead to asymptomatic hypoglycemia in children and adolescents with type 1 diabetes (T1D). To investigate the effects of multiple daily injections before and after changing to insulin glargine (IG), continuous glucose monitoring system (CGMS) data were used to analyze glycemic control and hypoglycemic episodes during the two different therapy regimens.

SWEET – where are we heading with international type 1 diabetes registries?

In light of the technological advances in diabetes therapy becoming more widely available and with healthcare costs rising generally, economic data regarding health care are desperately needed to allocate resources appropriately. ‘SWEET’ is an acronym derived from ‘Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference’ and is based on a partnership of established national and European diabetes organizations (www.sweet-project.eu) led by the International Society for Pediatric and Adolescent Diabetes (ISPAD), with the initial participating pediatric centres being from the Czech Republic, France, Germany, Greece, Hungary, Italy, Luxembourg, the Netherlands, Poland, Portugal, Romania, Sweden, and the UK. In addition, the valuable contributions of the International Diabetes Federation (IDF) Europe, the Federation of European Nurses in Diabetes (FEND), and Primary Care Diabetes Europe (PCDE) need to be acknowledged. Co-funding for the initial project was granted by the European Public Health Executive Agency with additional funds from corporate partners and foundations (see acknowledgements for the complete list). The present Special Issue of Pediatric Diabetes summarizes the major findings of the project. Before SWEET, 17 out of 26 EU countries had officially recognized centers for pediatric diabetes, but only eight of them had defined criteria for becoming such a center. A system of quality control of pediatric diabetes at the national level was reported from 7/26 countries. Only 13/26 EU countries had a pediatric diabetes register. These SWEET results were based on 108 datasets from healthcare professionals caring for >29 000 children and adolescents with diabetes in Europe. Recommendations for diabetes care and treatment, as well as age-appropriate education for children and adolescents with diabetes and pediatric training programs for healthcare professionals have been developed by SWEET. The proposed Criteria for an European Pediatric Diabetes Reference Centre include a multidisciplinary approach, an ongoing electronic documentation of at least 150 pediatric diabetes patients ≤18 years (i.e., at least age, diabetes duration, gender, HbA1c, type of diabetes), and the readiness to participate in external peer-reviewed auditing process and quality control circles. An initial 12 centres were approved jointly by the ISPAD Executive Committee and IDF Europe. It has been our experience that this approval has helped to raise awareness for the efforts to achieve optimal diabetes care within the different local circumstances. There is reason to believe that the international comparison within the SWEET project will help to secure funding from payers to ensure quality delivery of care and to harmonize pediatric diabetes healthcare delivery on the highest achievable standard within the ramifications of the differing national health systems. Optimal functioning of a team requires clear identification of all team players, with the child and the family at the centre of care. So far, huge differences have been identified between the different multidisciplinary teams, not only in numbers of healthcare professionals, but as well their training and the services provided. Therefore, a Toolbox supporting the creation of Centres of Reference for pediatric and adolescent diabetes has been developed. For benchmarking and quality control, a platform was put in place that allows any participating centre to import and input data online using a standard diabetes data set for pediatric diabetes patients to monitor the long-term outcome after the conclusion of the initial SWEET project. This will allow adapting the current recommendations on the basis of the ongoing evaluations. Adolescents with type 1 and type 2 diabetes are particularly prone to poor metabolic and psychosocial outcomes due to the potentially long diabetes duration. At the same time, the study of the effect of diabetes in this age group provides an opportunity to study early vascular ageing without other concomitant diseases. Normal ageing with diabetes starts in childhood as many processes leading to debilitating complications later in life have their onset then. This offers a unique opportunity to identify potential factors that are important to delay accelerated biological ageing

Liraglutide in an Adolescent Population with Obesity: A Randomized, Double-Blind, Placebo-Controlled 5-Week Trial to Assess Safety, Tolerability, and Pharmacokinetics of Liraglutide in Adolescents Aged 12-17 Years

Objectives To investigate the safety, tolerability, and pharmacokinetics of liraglutide in adolescents with obesity. Study design This was a randomized, double‐blind, placebo‐controlled trial. Twenty‐one subjects, aged 12‐17 years and Tanner stage 2‐5, with obesity (body mass index [BMI] corresponding to both a BMI ≥95th percentile for age and sex and to a BMI of ≥30 kg/m2 for adults; additionally, BMI was ≤45 kg/m2) were randomized (2:1) to receive 5 weeks of treatment with liraglutide (0.6 mg with weekly dose increase to a maximum of 3.0 mg for the last week) (n = 14) or placebo (n = 7). The primary endpoint was number of treatment‐emergent adverse events (TEAEs). Secondary endpoints included safety measures, and pharmacokinetic and pharmacodynamic endpoints. Results All participants receiving liraglutide, and 4 receiving placebo (57.1%), had at least 1 TEAE. The most common TEAEs were gastrointestinal disorders. No severe TEAEs, TEAE‐related withdrawals, or deaths occurred. Twelve hypoglycemic episodes occurred in 8 participants receiving liraglutide and 2 in 1 participant receiving placebo. No severe hypoglycemic episodes were reported. Liraglutide exposure in terms of trough concentration increased with dose, although dose proportionality was confounded by unexpectedly low trough concentration values at the 2.4 mg dose. Exposure in terms of model‐derived area under the plasma concentration time curve from 0 to 24 hours after dose in steady state was similar to that in adults with obesity. Conclusions Liraglutide had a similar safety and tolerability profile compared with adults when administered to adolescents with obesity, with no unexpected safety/tolerability issues. Results suggest that the dosing regimen approved for weight management in adults may be appropriate for use in adolescents. Trial registration ClinicalTrials.gov: NCT01789086.

Lipoatrophy in Children With Type 1 Diabetes An Increasing Incidence

Objectives: The objectives were to evaluate the current prevalence of lipoatrophy at insulin injection sites in young patients with type 1 diabetes. Methods: Standardized examination of insulin injection sites in all 678 patients with type 1 diabetes treated in 2013 in our outpatient clinic were conducted. In case of lipoatrophy photo documentation and standardized interview with parents and patients were performed. Methods: We identified a total of 16 patients (43.8% male) with lipoatrophy (overall prevalence 2.4%). The current mean age (±SD) of the affected patients was 14.4 ± 3.9 years, age and diabetes duration at onset of lipoatrophy were 11.5 ± 3.8 years and 5.4 ± 3.6 years, respectively. All patients were using analogs at the onset of lipoatrophy. In all, 14 of 16 patients (87.5%) were on insulin pump compared with 52% without lipoatrophy (P = .0018). The use of steel needle and Teflon catheter was equal between the pump patients. Concomitant autoimmune diseases were present in 37.5% of the patients (thyroiditis: n = 3, thyroiditis and celiac disease: n = 2, celiac disease: n = 1) compared with 15.0% in those without lipoatrophy (P = .0128). Conclusions: Lipoatrophy was present in young patients treated with modern insulins and pumps; however, the prevalence was relatively low as expected with the use of modern insulins. Our data may support the hypothesis that a constant mechanical element such as a subcutaneous catheter may trigger the development of lipoatrophy, particularly in those patients with more than 1 autoimmune disease.

Effects of dapagliflozin on insulin-requirement, glucose excretion and ß-hydroxybutyrate levels are not related to baseline HbA1c in youth with type 1 diabetes

Youth with type 1 diabetes (T1D) infrequently achieve HbA1c targets. Therefore, this placebo‐controlled, randomized, crossover study was set up to assess the safety, effect and pharmacokinetics of a single dose of 10 mg dapagliflozin (DAPA) as add‐on to insulin in relationship to HbA1c in youth. A total of 33 youths (14 males, median age 16 years, diabetes duration 8 years) were included and stratified into 3 baseline HbA1c categories (<7.5%, 7.5%‐9.0% or >9.0; n = 11 each). During the study period of 24 hours, intravenous insulin administration and glucose‐infusion kept blood glucose levels at 160 to 220 mg/dL. DAPA reduced mean insulin dose by 13.6% ( P  < .0001 by ANOVA) and increased urinary glucose excretion by 610% (143.4 vs 22.4 g/24 h; P  < .0001), both irrespective of baseline HbA1c. Six independent episodes in 6 patients with plasma ß‐hydroxybutyrate levels between ≥0.6 and <1.0 mmol/L were observed after liquid meal challenges, 5 episodes in the DAPA group and 1 in the placebo group. This study provides a proof‐of‐concept, irrespective of preexisting HbA1c levels, for adjunct SGLT2‐inhibitor therapy in the paediatric age group by lowering insulin dose and increasing glucose excretion.

Improvement of BMI after Lifestyle Intervention Is Associated with Normalisation of Elevated ELF Score and Liver Stiffness in Obese Children

Background. Noninvasive tools to diagnose nonalcoholic fatty liver disease (NAFLD), including transient elastography (TE) and enhanced liver fibrosis panel (ELF), have only been evaluated in children with biopsy-proven NAFLD. We evaluated the prevalence of ELF and TE abnormalities in obese children without clinical liver disease and examined the effects of BMI stabilization on ELF and TE in a longitudinal approach. Methods. 39 obese children (17 m, age 12.3 (7.6–17.4) years) who participated in a 12-month lifestyle-intervention program underwent TE and ELF testing at baseline and at completion of the program. Results were compared with data from a nonobese paediatric cohort. Results. TE and ELF at baseline were significantly elevated compared to controls (TE: 5.9 (3.4–8.3) kPa versus 4.45 (2.45–8.85) kPa, P < 0.01; ELF: 9.0 (7.87–9.60) versus 8.6 (7.33–11.52), P = 0.033). All children with elevated TE and ELF results had normal transaminases. After the program, ELF and TE normalized. Reduction of ELF and TE was associated with a decrease in BMI centile. Conclusion. Abnormal TE and ELF results in obese children suggest presence of NAFLD even when transaminases are normal. TE and ELF might be used as monitoring tools for NAFLD. BMI stabilisation normalizes TE and ELF, underlining the impact of lifestyle intervention.

Adipositas, Diabetes und Fettstoffwechselstörungen im Kindesalter

Gegenwartig sind 6% der deutschen Kinder adipos und 13% ubergewichtig, mehr als doppelt so viele wie noch vor 10 Jahren. Aber auch die Zahlen des padiatrischen Typ-1-Diabetes verdoppelten sich innerhalb der letzten 12 Jahre. Heute geht

Folgeerkrankungen und Prognose des Typ-1-Diabetes

Vaskulare Folgeerkrankungen der kleinen Gefase (Mikroangiopathie), die sich am Auge (Retinopathie) und an der Niere (Nephropathie) manifestieren, aber auch andere Organsysteme (Neuropathie) betreffen konnen, sowie eine beschleunigte Arteriosklerosee (Makroangiopathie) sind heute bestimmend fur das Lebensschicksal von Kindern und Jugendlichen mit Typ-1-Diabetes. Da die diabetische Mikroangiopathie sich sehr langsam entwickelt, treten organische Dysfunktionen als Ausdruck diabetischer Folgeschaden meist erst nach 10- bis 15-jahriger Diabetesdauer in Erscheinung. Ein regelmasiges Screening zur Fruherkennung von subklinischen Organveranderungen ist daher von besonderer Bedeutung, da sich eine Verbesserung der glykamischen Stoffwechsellage sehr positiv auf die weitere Entwicklung der Folgeerkrankung auswirken kann. Bei Kindern und Jugendlichen werden bei Diabetesmanifestation Ausgangsuntersuchungen zum Ausschluss ophthalmologischer und nephrologischer Grundkrankheiten und im Verlauf jahrliche Untersuchungen ab 5 Jahre Diabetesdauer bzw. spatestens vom 11. Lebensjahr an empfohlen.