Karin Lange

Effects of High-Dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes: The Pre-POINT Randomized Clinical Trial

IMPORTANCE Exposing the oral mucosa to antigen may stimulate immune tolerance. It is unknown whether treatment with oral insulin can induce a tolerogenic immune response in children genetically susceptible to type 1 diabetes. OBJECTIVE To assess the immune responses and adverse events associated with orally administered insulin in autoantibody-negative, genetically at-risk children. DESIGN, SETTING, AND PARTICIPANTS The Pre-POINT study, a double-blind, placebo-controlled, dose-escalation, phase 1/2 clinical pilot study performed between 2009 and 2013 in Germany, Austria, the United States, and the United Kingdom and enrolling 25 islet autoantibody-negative children aged 2 to 7 years with a family history of type 1 diabetes and susceptible human leukocyte antigen class II genotypes. Follow-up was completed in August 2013. INTERVENTIONS Children were randomized to receive oral insulin (n = 15) or placebo (n = 10) once daily for 3 to 18 months. Nine children received insulin with dose escalations from 2.5 to 7.5 mg (n = 3), 2.5 to 22.5 mg (n = 3), or 7.5 to 67.5 mg (n = 3) after 6 months; 6 children only received doses of 22.5 mg (n = 3) or 67.5 mg (n = 3). MAIN OUTCOMES AND MEASURES An immune response to insulin, measured as serum IgG and saliva IgA binding to insulin, and CD4+ T-cell proliferative responses to insulin. RESULTS Increases in IgG binding to insulin, saliva IgA binding to insulin, or CD4+ T-cell proliferative responses to insulin were observed in 2 of 10 (20% [95% CI, 0.1%-45%]) placebo-treated children and in 1 of 6 (16.7% [95% CI, 0.1%-46%]) children treated with 2.5 mg of insulin, 1 of 6 (16.7%[ 95% CI, 0.1%-46%]) treated with 7.5 mg, 2 of 6 (33.3% [95% CI, 0.1%-71%]) treated with 22.5 mg, and 5 of 6 (83.3% [ 95% CI, 53%-99.9%]) treated with 67.5 mg (P = .02). Insulin-responsive T cells displayed regulatory T-cell features after oral insulin treatment. No hypoglycemia, IgE responses to insulin, autoantibodies to glutamic acid decarboxylase or insulinoma-associated antigen 2, or diabetes were observed. Adverse events were reported in 12 insulin-treated children (67 events) and 10 placebo-treated children (35 events). CONCLUSIONS AND RELEVANCE In this pilot study of children at high risk for type 1 diabetes, daily oral administration of 67.5 mg of insulin, compared with placebo, resulted in an immune response without hypoglycemia. These findings support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in such children. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN76104595.

Prerequisites for age-appropriate education in type 1 diabetes: a model programme for paediatric diabetes education in Germany

Abstract:  Continuous diabetes education for children, adolescents and their parents are widely accepted as an integral part of every type 1 diabetes therapy. Especially in paediatric diabetes care age‐appropriate, demand‐oriented and individualized practical information and skills training are mandatory for achieving good metabolic control and psychosocial well‐being. A paediatric multidisciplinary diabetes team experienced in an intensified insulin therapy with a differential substitution of prandial and basal insulin needs (MDI or CSII) and in child psychology is required to initiate and maintain lifelong diabetes self‐management. In Germany an education programme for children aged 6–12 years and another programme for adolescents and young adults have previously been evaluated in multicenter studies. Programmes were considered with respect to applicability, acceptance by target groups and efficacy (knowledge, competence, quality of life and glycaemic control). Furthermore, a programme specifically designed for parents of children affected was evaluated. Contents, modular structures, developmental psychological background and didactic concepts of all above mentioned programmes are presented in detail. Apart from teaching insulin therapy according to current guidelines special emphasis is laid on translating this knowledge into everyday self‐management behaviour. In addition, emotional coping with the chronic disease and its psychosocial consequences is supported. In the context of the Disease‐Management–Program for Type 1 Diabetes in Germany these programmes for young people were certified and reimbursed nationwide by health insurances.

Current practice of insulin pump therapy in children and adolescents - the Hannover recipe.

Abstract:  Increasing evidence points to the importance of achieving low blood glucose variability and also a low hemoglobin A1c (HbA1c) to prevent diabetic late complications. Continuous subcutaneous insulin infusion (CSII) is associated with lower blood glucose variability in children. Frequent indications for starting CSII in youth are recurrent hypoglycemia, need for increased flexibility, poor glycemic control, dawn phenomenon, or needle phobia. At our center, about one‐third of all patients across all age groups are currently on CSII. Although the average glycemic control is not very different from those on multiple daily injections, fewer patients are seen in the segment of very high and very low HbA1c with CSII. Across centers, the ‘recipes’ tailoring CSII treatment to individual patients and cultures are based more on experience than on evidence. However, several typical pediatric features have been identified. Patterns of the hourly basal rate and prandial insulin requirements vary with age. While many adolescents have increased requirements at dawn and dusk, young children show increasing needs in the second half of the day. Low insulin requirements, particularly in neonates, may need insulin dilution. The selection of catheters and needles has to be appropriate for the age. The opportunity to have an electronic memory read‐out of all entries and alarms offers new possibilities of therapeutic monitoring, particularly in those youth not keeping good logbooks. This feature can be helpful, if a trustful relationship between the diabetes team and the family is established.

ISPAD Clinical Practice Consensus Guidelines 2014. Diabetes education in children and adolescents.

Karin Langea, Peter Swiftb, Ewa Pańkowskac and Thomas Danned aDepartment of Medical Psychology, Hannover Medical School, OE 5430, 30625, Hannover, Germany; bChildrens Hospital, Leicester Royal Infirmary, Leicester, LE1 5WW, UK; cThe Institute of Diabetology, ul. Żegańska 46a, 04-736, Warszawa, Poland; and dDiabetes Centre for Children and Adolescents at the Kinderund Jugendkrankenhaus, Auf der Bult, Janusz-Korczak-Allee 12, 30173, Hannover, Germany

Metabolic outcomes in young children with type 1 diabetes differ between treatment centers: the Hvidoere Study in Young Children 2009

To investigate whether center differences in glycemic control are present in prepubertal children <11 yr with type 1 diabetes mellitus.

Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study

Introduction Type 1 diabetes can be diagnosed at an early presymptomatic stage by the detection of islet autoantibodies. The Fr1da study aims to assess whether early staging of type 1 diabetes (1) is feasible at a population-based level, (2) prevents severe metabolic decompensation observed at the clinical manifestation of type 1 diabetes and (3) reduces psychological distress through preventive teaching and care. Methods and analysis Children aged 2–5 years in Bavaria, Germany, will be tested for the presence of multiple islet autoantibodies. Between February 2015 and December 2016, 100 000 children will be screened by primary care paediatricians. Islet autoantibodies are measured in capillary blood samples using a multiplex three-screen ELISA. Samples with ELISA results >97.5th centile are retested using reference radiobinding assays. A venous blood sample is also obtained to confirm the autoantibody status of children with at least two autoantibodies. Children with confirmed multiple islet autoantibodies are diagnosed with pre-type 1 diabetes. These children and their parents are invited to participate in an education and counselling programme at a local diabetes centre. Depression and anxiety, and burden of early diagnosis are also assessed. Results Of the 1027 Bavarian paediatricians, 39.3% are participating in the study. Overall, 26 760 children have been screened between February 2015 and November 2015. Capillary blood collection was sufficient in volume for islet autoantibody detection in 99.46% of the children. The remaining 0.54% had insufficient blood volume collected. Of the 26 760 capillary samples tested, 0.39% were positive for at least two islet autoantibodies. Discussion Staging for early type 1 diabetes within a public health setting appears to be feasible. The study may set new standards for the early diagnosis of type 1 diabetes and education. Ethics dissemination The study was approved by the ethics committee of Technische Universität München (Nr. 70/14).

Lessons from the Hvidoere International Study Group on childhood diabetes: be dogmatic about outcome and flexible in approach.

Type 1 diabetes is one of the most commonchronic diseases of childhood. Between 1989 and 2003, the incidence of type 1 diabetes in youth increased at approximately 3.9% per year with a projected doubling of cases in children aged <5 yr between 2005 and 2015 (1). This has substantial impact on those affected, their families, on pediatric diabetes care, and on national health care budgets. Much has changed over the last decade in terms of management strategies in type 1 diabetes, however, as Edwin Gale editorialized in 2005 that the challenges of diabetes remain much the same (2). In short, there are more cases resulting in increasing disease years characterized by greater medical and psychosocial complexity. The Hvidoere International Study Group on Childhood Diabetes evolved in 1994 during a meeting that was held in the immediate post Diabetes Control and Complication Trial (DCCT, 3) era to discuss strategies that could improve the quality of pediatric diabetes care and thereby improve subsequent adult outcomes. The objectives and mission statement of the Hvidoere group can be found on its website http://www.hvidoeregroup.org/. In short, this unique collaboration of 26 pediatric diabetes centers from 23 countries (Europe, North America, Japan, and Australia) has undertaken a series of research projects investigating critical determinants for long-term outcome of type 1 diabetes care discriminating in terms of outcomes and which aspects of care are universally effective. In all the Hvidoere studies, HbA1c was analyzed centrally at the Steno Diabetes Center, Denmark. In the period from 1997 to December 2002 HbA1c was analyzed using an automated high pressure liquid chromatographic method (Bio-Rad Variant, Bio-Rad Laboratories, Hercules, CA, USA) using the same calibrator lots as the DCCT laboratory. From 2003 till now, HbA1c was analyzed by the DCCT aligned TOSOH Automated Glycohemoglobin Analyzer HLC-723G7, Tosoh Corporation, Tokyo, Japan. Five major studies have been undertaken, both crosssectional and longitudinal, serving this goal. The findings detailed below show that these studies have led to an internationally recognized remission parameter (4) and have validated well-being and quality-of-life (QOL) questionnaires (with relevant translation, (5). The key thematic and practical findings of this body of work (published in 28 peer reviewed medical and scientific journals) are summarized in this review.

Health-Related Quality of Life Among German Youths With Early-Onset and Long-Duration Type 1 Diabetes

OBJECTIVE To evaluate self- and parent reports of general health status and health-related quality of life (QoL) in children and adolescents with early-onset and long-lasting type 1 diabetes compared with the general population in Germany. RESEARCH DESIGN AND METHODS A total of 629 subjects aged 11 to 17 years, with a type 1 diabetes onset occurring from age 0 to 4 years during the years 1993–1999, and their parents, completed questionnaires, including the generic KINDL-R Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents, revised version, to assess QoL. The comparison group (n = 6,813) was a representative sample from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study. Regression analyses were conducted using sociodemographic and health-related covariates. RESULTS Intensified insulin therapy was used to treat 93% of children and adolescents with type 1 diabetes. They reported “excellent” general health as often as peers (adjusted OR 0.83 [95% CI 0.66–1.04] for an “excellent” rating), but the parent-rated general health was worse than that in the general population (OR 0.60 [0.48–0.74]). The patients reported increased self-esteem (adjusted difference β = 4.39 [SE 0.82]; P < 0.001) and well-being at school (β = 3.41 [0.77]; P < 0.001) but lower well-being within their families (β = –2.42 [0.80]; P = 0.002). The self- and parent-reported total QoL did not differ between the patient group and the general population. The adjusted difference (SE) between the two samples in total QoL was β = 0.89 (0.52; P = 0.087) in the self-reports and β = –0.98 (0.53; P = 0.066) in the parent-reports. CONCLUSIONS Compared with the general population, the QoL and general health status were not impaired among those aged 11–17 years with early-onset type 1 diabetes, despite the challenges of modern therapy.

New developments in the treatment of type 1 diabetes in children

Both type 1 and type 2 diabetes can occur in children and adolescents. Of the 230 million people affected by diabetes worldwide, 4.9 million have type 1 diabetes. Type 1 diabetes is the most common chronic disease in children in the developed countries. Classification of childhood diabetes has become increasingly difficult as better measures of genetic testing have identified different forms of monogenetic diabetes masquerading as type 1 diabetes. Also the distinction between type 1 and 2 is not always clear-cut, particularly in overweight adolescents. Every year approximately 70 000 children under the age of 15 develop type 1 diabetes worldwide. The paediatric incidence of type 1 diabetes is growing by 3–5% each year. “Diabetes is different in children” is the motto of World Diabetes Day announced by the International Diabetes Federation following the United Nations resolution on diabetes in December 2006 and dedicating the next triennium to diabetes in children and adolescents. Recent developments indicate that the efforts of diabetes teams implementing the new approaches in paediatric diabetes care are successful. The Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study confirmed that an improvement in long-term glucose control, as obtained with intensified insulin therapy, can also reduce the incidence of complications and delay the progression of existing complications in type 1 diabetes in paediatric patients.1 2 Although only a subgroup of adolescents participated in the DCCT, longitudinal studies in the paediatric population such as the Berlin Retinopathy Study have revealed comparable results (fig 1).3 Reductions in HbA1c lead to the most dramatic fall in the rate of retinopathy when HbA1c is above 9%, a level which is deemed unacceptable in most guidelines. In addition, lower rates of retinopathy are achieved with every further drop in HbA1c. In particular, …

Real-time glucose sensors in children and adolescents with type-1 diabetes.

The increased availability of continuous glucose sensors is likely to have a significant impact on pediatric diabetes therapy and education in the future. While a recent meta-analysis of retrospective first-generation Holter-type sensors was not able to show advantages compared to self-monitoring of blood glucose levels, this review focuses on current real-time sensors. Our own experience with 23 children aged 10 (3–15) years with sensor-augmented pump therapy showed high ratings for overall satisfaction and ease of use of the system (5.8 on a 7 point Likert scale). The results of our ongoing international pediatric ONSET trial will show the impact of this technology on learning to live with diabetes by having the biofeedback of glucose excursions from the onset of diabetes. Families previously relying on self-monitoring of blood glucose need to understand the difference between estimating the absolute blood glucose value (point accuracy) and the change in blood glucose (rate accuracy), and how to take into consideration the inherent interstitial time lag. Selection of patients capable and motivated to use continuous sensors accompanied with proper age-appropriate education remain key factors for the long-term success of these new technological advances in diabetes therapy as long as closed loop systems are not available.