Comparing family-based treatment with inpatient treatment in youth with anorexia nervosa eligible for hospitalization: A 12-month feasibility study.

OBJECTIVE: Family-based treatment (FBT) for youth with anorexia nervosa (AN), has not been compared to inpatient, multimodal treatment (IMT). METHOD: Prospective, non-randomized pilot feasibility study of adolescents with AN receiving FBT (n = 31), and as a reference point for exploratory outcome comparisons IMT (n = 31), matched for baseline age and percent median BMI (%mBMI). Feasibility of FBT in youth fulfilling criteria for IMT was assessed via study recruitment and retention rates; acceptability via drop-out and caregiver strain; safety via adverse events; preliminary treatment effectiveness between groups was assessed via a change in %mBMI, AN psychopathology (Eating Disorder Examination-Questionnaire, EDE-Q), and hospital days, over 12 months with intent-to-treat, mixed models repeated measures analyses covering post-intervention usual care until 12 months. RESULTS: Taking into account that 8 FBT patients (25.8%) crossed over to IMT due to lack of weight gain or psychiatric concerns, FBT and IMT were similarly feasible, acceptable, and safe, apart from more physical antagonism toward others in FBT (p = .010). FBT lasted longer (median [interquartile range, IQR]; 33.6 [17.4, 49.9] vs. 17.3 [14.4, 24] weeks, p < .001), but required fewer hospital days than IMT (median, [IQR], FBT = 1 [0, 16] vs. IMT = 123 [101, 180], p < .001). Baseline comorbidity-adjusted changes over 12 months did not differ between groups in %mBMI (FBT = 12.6 ± 11.9 vs. IMT = 13.7 ± 9.1; p = .702) and EDE-Q global score (median, [IQR]; FBT = -1.2 [-2.3, 0.2] vs. IMT = -1.3 [-2.8, -0.4]; p = .733). DISCUSSION: Implementing FBT in this pilot study was feasible, acceptable, and safe for youth eligible for IMT according to German S3 guidelines. Non-inferiority of FBT versus IMT requires confirmation in a sufficiently large multicenter RCT. PUBLIC SIGNIFICANCE: This pilot study with 62 adolescent patients with anorexia nervosa demonstrated that for 2/3rd of patients eligible for a long hospitalization in the German health care system, outpatient, Family-based treatment (FBT) was a safe and feasible treatment alternative. Over 12 months, FBT lead to similar weight gain and reduction in eating disorder cognitions as inpatient treatment with fewer hospital days. This pilot study needs to be followed up by a larger, multicenter trial.

Real-world evidence on clinical outcomes of people with type 1 diabetes using open-source and commercial automated insulin dosing systems: A systematic review.

AIMS: Several commercial and open-source automated insulin dosing (AID) systems have recently been developed and are now used by an increasing number of people with diabetes (PwD). This systematic review explored the current status of real-world evidence on the latest available AID systems in helping to understand their safety and effectiveness. METHODS: A systematic review of real-world studies on the effect of commercial and open-source AID system use on clinical outcomes was conducted employing a devised protocol (PROSPERO ID 257354). RESULTS: Of 441 initially identified studies, 21 published 2018-2021 were included: 12 for Medtronic 670G; one for Tandem Control-IQ; one for Diabeloop DBLG1; two for AndroidAPS; one for OpenAPS; one for Loop; three comparing various types of AID systems. These studies found that several types of AID systems improve Time-in-Range and haemoglobin A1c (HbA1c ) with minimal concerns around severe hypoglycaemia. These improvements were observed in open-source and commercially developed AID systems alike. CONCLUSIONS: Commercially developed and open-source AID systems represent effective and safe treatment options for PwD of several age groups and genders. Alongside evidence from randomized clinical trials, real-world studies on AID systems and their effects on glycaemic outcomes are a helpful method for evaluating their safety and effectiveness.

International comparison of glycaemic control in people with type 1 diabetes: an update and extension.

AIMS: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. METHODS: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c (IQR) and proportions of individuals with HbA1c < 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. RESULTS: Median HbA1c varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c < 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c  < 58 mmol/l (<7.5%) increased and proportions of people with HbA1c ≥ 75 mmol/mol (≥9.0%) decreased. CONCLUSIONS: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.

Size matters: Influence of center size on quality of diabetes control in children and adolescents with type 1 diabetes-A longitudinal analysis of the DPV cohort.

BACKGROUND: Treatment of patients with type 1 diabetes requires experience and a specific infrastructure. Therefore, center size might influence outcome in diabetes treatment. OBJECTIVE: To analyze the influence of center size on the quality of diabetes treatment in children and adolescents in Germany and Austria. PATIENTS AND METHODS: In 2009 and 2018, we analyzed metabolic control, acute complications, and rates of recommended screening tests in the DPV cohort. Diabetes centers were classified according to the number of patients from "XS" to "XL" (<20 [XS], ≥20 to <50 [S], ≥50 to <100 [M], ≥100 to <200 [L], ≥200 [XL]). RESULTS: Over the 10-year period, metabolic control improved significantly in "M", "L" and "XL" diabetes centers. Treatment targets are best achieved in "M" centers, while "XS" centers have the highest mean hemoglobin A1c. The relation between hemoglobin A1c and center size follows a "v-shaped" curve. In 2009, conventional insulin therapy was most frequently used in "XS" centers, but in 2018, there was no difference in mode of insulin therapy according to center size. Use of CSII and sensor augmented CSII/hybrid closed loop increased with center size. Patients cared for in "XS" diabetes centers had the fewest follow-up visits per year. The rates of severe hypoglycemia and DKA were lowest in "XL" diabetes centers, and the rate of DKA was highest in "XS" centers. CONCLUSION: Center size influences quality of care in pediatric patients with type 1 diabetes. Further investigations regarding contributing factors such as staffing and financial resources are required.

Clinical presentation and long-term outcome of patients with KCNJ11/ABCC8 variants: Neonatal diabetes or MODY in the DPV registry from Germany and Austria.

OBJECTIVE: To describe clinical presentation/longterm outcomes of patients with ABCC8/KCNJ11 variants in a large cohort of patients with diabetes. RESEARCH DESIGN AND METHODS: We analyzed patients in the Diabetes Prospective Follow-up (DPV) registry with diabetes and pathogenic variants in the ABCC8/KCNJ11 genes. For patients with available data at three specific time-points-classification as K+ -channel variant, 2-year follow-up and most recent visit-the longitudinal course was evaluated in addition to the cross-sectional examination. RESULTS: We identified 93 cases with ABCC8 (n = 54)/KCNJ11 (n = 39) variants, 63 of them with neonatal diabetes. For 22 patients, follow-up data were available. Of these, 19 were treated with insulin at diagnosis, and the majority of patients was switched to sulfonylurea thereafter. However, insulin was still administered in six patients at the most recent visit. Patients were in good metabolic control with a median (IQR) A1c level of 6.0% (5.5-6.7), that is, 42.1 (36.6-49.7) mmol/mol after 2 years and 6.7% (6.0-8.0), that is, 49.7 (42.1-63.9) mmol/mol at the most recent visit. Five patients were temporarily without medication for a median (IQR) time of 4.0 (3.5-4.4) years, while two other patients continue to be off medication at the last follow-up. CONCLUSIONS: ABCC8/KCNJ11 variants should be suspected in children diagnosed with diabetes below the age of 6 months, as a high percentage can be switched from insulin to oral antidiabetic drugs. Thirty patients with diabetes due to pathogenic variants of ABCC8 or KCNJ11 were diagnosed beyond the neonatal period. Patients maintain good metabolic control even after a diabetes duration of up to 11 years.

Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic ß cells.

Pancreatic ß cells store insulin within secretory granules which undergo exocytosis upon elevation of blood glucose levels. Crinophagy and autophagy are instead responsible to deliver damaged or old granules to acidic lysosomes for intracellular degradation. However, excessive consumption of insulin granules can impair ß cell function and cause diabetes. Atp6ap2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy. Here, we show that Cre recombinase-mediated conditional deletion of Atp6ap2 in mouse ß cells causes a dramatic accumulation of large, multigranular vacuoles in the cytoplasm, with reduction of insulin content and compromised glucose homeostasis. Loss of insulin stores and gigantic vacuoles were also observed in cultured insulinoma INS-1 cells upon CRISPR/Cas9-mediated removal of Atp6ap2. Remarkably, these phenotypic alterations could not be attributed to a deficiency in autophagy or acidification of lysosomes. Together, these data indicate that Atp6ap2 is critical for regulating the stored insulin pool and that a balanced regulation of granule turnover is key to maintaining ß cell function and diabetes prevention.

Emotional and Physical Health Impact in Children and Adolescents and Their Caregivers Using Open-source Automated Insulin Delivery: Qualitative Analysis of Lived Experiences.

BACKGROUND: Given the limitations in the access and license status of commercially developed automated insulin delivery (AID) systems, open-source AID systems are becoming increasingly popular among people with diabetes, including children and adolescents. OBJECTIVE: This study aimed to investigate the lived experiences and physical and emotional health implications of children and their caregivers following the initiation of open-source AID, their perceived challenges, and sources of support, which have not been explored in the existing literature. METHODS: Data were collected through 2 sets of open-ended questions from a web-based multinational survey of 60 families from 16 countries. The narratives were thematically analyzed, and a coding framework was identified through iterative alignment. RESULTS: A range of emotions and improvements in quality of life and physical health were reported, as open-source AID enabled families to shift their focus away from diabetes therapy. Caregivers were less worried about hypoglycemia at night and outside their family homes, leading to increased autonomy for the child. Simultaneously, the glycemic outcomes and sleep quality of both the children and caregivers improved. Nonetheless, the acquisition of suitable hardware and technical setup could be challenging. The #WeAreNotWaiting community was the primary source of practical and emotional support. CONCLUSIONS: Our findings show the benefits and transformative impact of open-source AID and peer support on children with diabetes and their caregivers and families, where commercial AID systems are not available or suitable. Further efforts are required to improve the effectiveness and usability and facilitate access for children with diabetes, worldwide, to benefit from this innovative treatment. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/15368.

Comorbidity of inflammatory bowel disease in children and adolescents with type 1 diabetes.

AIM: To determine the prevalence of inflammatory bowel disease (IBD) in patients with type 1 diabetes (T1D) and to characterise patients with both diseases. METHODS: Data of 65.147 patients with T1D ≤18 years of 379 centres in Germany and Austria participating in the DPV initiative were analysed. A total of 63 children had comorbid IBD; IBD prevalence was 0.1%. Regression models were used to analyse differences in metabolic control, acute complications and steroid intake. RESULTS: Mean BMI-SDS in patients with T1D and IBD was lower (-0.15 ± 0.11) compared to patients with T1D only (0.27 ± 0.00, p < .001). Patients with T1D and IBD had a significantly higher use of steroids (22% ± 0.05% vs. 1% ± 0.00, p < .001) and a significantly higher rate of severe hypoglycaemic events per patient year (0.33 ± 0.07 vs. 0.16 ± 0.00, p = .001). No differences were found in HbA1c levels, insulin dose and occurrence of DKA. CONCLUSION: Although children and adolescents with T1D and IBD take steroids more often, they suffer from severe hypoglycaemia more frequently and have a lower BMI-SDS. These findings might be explained by chronic intestinal inflammation leading to malabsorption, malnutrition and increased severe hypoglycaemia.

Why #WeAreNotWaiting-Motivations and Self-Reported Outcomes Among Users of Open-source Automated Insulin Delivery Systems: Multinational Survey.

BACKGROUND: Automated insulin delivery (AID) systems have been shown to be safe and effective in reducing hyperglycemia and hypoglycemia but are not universally available, accessible, or affordable. Therefore, user-driven open-source AID systems are becoming increasingly popular. OBJECTIVE: This study aims to investigate the motivations for which people with diabetes (types 1, 2, and other) or their caregivers decide to build and use a personalized open-source AID. METHODS: A cross-sectional web-based survey was conducted to assess personal motivations and associated self-reported clinical outcomes. RESULTS: Of 897 participants from 35 countries, 80.5% (722) were adults with diabetes and 19.5% (175) were caregivers of children with diabetes. Primary motivations to commence open-source AID included improving glycemic outcomes (476/509 adults, 93.5%, and 95/100 caregivers, 95%), reducing acute (443/508 adults, 87.2%, and 96/100 caregivers, 96%) and long-term (421/505 adults, 83.3%, and 91/100 caregivers, 91%) complication risk, interacting less frequently with diabetes technology (413/509 adults, 81.1%; 86/100 caregivers, 86%), improving their or child's sleep quality (364/508 adults, 71.6%, and 80/100 caregivers, 80%), increasing their or child's life expectancy (381/507 adults, 75.1%, and 84/100 caregivers, 84%), lack of commercially available AID systems (359/507 adults, 70.8%, and 79/99 caregivers, 80%), and unachieved therapy goals with available therapy options (348/509 adults, 68.4%, and 69/100 caregivers, 69%). Improving their own sleep quality was an almost universal motivator for caregivers (94/100, 94%). Significant improvements, independent of age and gender, were observed in self-reported glycated hemoglobin (HbA1c), 7.14% (SD 1.13%; 54.5 mmol/mol, SD 12.4) to 6.24% (SD 0.64%; 44.7 mmol/mol, SD 7.0; P<.001), and time in range (62.96%, SD 16.18%, to 80.34%, SD 9.41%; P<.001). CONCLUSIONS: These results highlight the unmet needs of people with diabetes, provide new insights into the evolving phenomenon of open-source AID technology, and indicate improved clinical outcomes. This study may inform health care professionals and policy makers about the opportunities provided by open-source AID systems. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/15368.

Open-Source Technology for Real-Time Continuous Glucose Monitoring in the Neonatal Intensive Care Unit: Case Study in a Neonate With Transient Congenital Hyperinsulinism.

BACKGROUND: Use of real-time continuous glucose monitoring (rtCGM) systems has been shown to be a low-pain, safe, and effective method of preventing hypoglycemia and hyperglycemia in people with diabetes of various age groups. Evidence on rtCGM use in infants and in patients with conditions other than diabetes remains limited. OBJECTIVE: This case study describes the off-label use of rtCGM and the use of an open-source app for glucose monitoring in a newborn with prolonged hypoglycemia secondary to transient congenital hyperinsulinism during the perinatal period. METHODS: The Dexcom G6 rtCGM system (Dexcom, Inc) was introduced at 39 hours of age. Capillary blood glucose checks were performed regularly. In order to benefit from customizable alert settings and detect hypoglycemic episodes, the open-source rtCGM app xDrip+ was introduced at 9 days of age. RESULTS: Time in range (45-180 mg/dL) for interstitial glucose remained consistently above 90%, whereas time in hypoglycemia (<45 mg/dL) decreased. Mean glucose was maintained above 70 mg/dL at 72 hours of life and thereafter. Daily sensor glucose profiles showed cyclic fluctuations that were less pronounced over time. CONCLUSIONS: While off-label use of medication is both common practice and a necessity in newborn infants, there are few examples of off-label uses of medical devices, rtCGM being a notable exception. Real-time information allowed us to better understand glycemic patterns and to improve the quality of glycemic control accordingly. Severe hypoglycemia was prevented, and measurement of serum levels of insulin and further lab diagnostics were performed much faster, while the patient's individual burden caused by invasive procedures was reduced. Greater customizability of threshold and alert settings would be beneficial for user groups with glycemic instability other than people with diabetes, and for hospitalized newborn infants in particular. Further research in the field of personal and off-label rtCGM use, efficacy studies evaluating the accuracy of low glucose readings, and studies on the differences between algorithms in translating raw sensor data, as well as customization of commercially available rtCGM systems, is needed.

[Care of children and adolescents with type 1 diabetes: solutions for technical and psychosocial challenges]. / Versorgung von Kindern und Jugendlichen mit Typ-1-Diabetes: Lösungen für technische und psychosoziale Herausforderungen.

Type 1 diabetes mellitus is the most common endocrine disease in children and adolescents below age 15 years. A cure for the autoimmune disease against the insulin-secreting beta cells is still not in sight. Nevertheless, in recent years technical advances in innovation concerning glucose sensor technology, insulin pumps, and new algorithms that regulate insulin delivery have led to a constant improvement of metabolic control achieved in children and adolescents with type 1 diabetes.This review article shows the current care situation of children and adolescents with type 1 diabetes and their parents. The multidisciplinary care in specialized pediatric diabetes teams of pediatric diabetologists, diabetes educators, social workers, and psychotherapists has been established for many years and has set grounds for a very good quality of care for children and adolescents with type 1 diabetes in Germany. The focus is on diabetes education, in particular self-management, psychosocial support and intervention, and the inclusion of children and adolescents with diabetes in school, kindergarten, and daycare centers. We also address new, social developments in the online diabetes community. A current example is the patient-operated ecosystem of the Do-It-Yourself Artificial Pancreas System (DIY APS) movement, which, as a patient-operated, open-source project, has meanwhile also become an innovator for industry. Finally, we highlight related opportunities and shifts in classical doctor-patient roles.

Evaluation of a rare glucose-dependent insulinotropic polypeptide receptor variant in a patient with diabetes.

AIMS: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that augments insulin secretion in pancreatic ß-cells via its glucose-dependent insulinotropic polypeptide receptor (GIPR). Recent genome-wide association studies identified a single nucleotide variant (SNV) in the GIPR encoding gene (GIPR), rs1800437, that is associated with obesity and insulin resistance. In the present study, we tested whether GIPR variants contribute to obesity and disturb glucose homeostasis or diabetes in specific patient populations. MATERIALS AND METHODS: Exon sequencing of GIPR was performed in 164 children with obesity and insulin resistance and in 80 children with paediatric-onset diabetes of unknown origin. The Study of Health in Pomerania (SHIP) cohort, comprising 8320 adults, was screened for the GIPR variant Arg217Leu. GIPR variants were expressed in COS-7 cells and cAMP production was measured upon stimulation with GIP. Cell surface expression was determined by ELISA. Protein homology modelling of the GIPR variants was performed to extract three-dimensional information of the receptor. RESULTS: A heterozygous missense GIPR variant Arg217Leu (rs200485112) was identified in a patient of Asian ancestry. Functional characterization of Arg217Leu revealed reduced surface expression and signalling after GIP challenge. The homology model of the GIPR structure supports the observed functional relevance of Arg217Leu. CONCLUSION: In vitro functional studies and protein homology modelling indicate a potential relevance of the GIPR variant Arg217Leu in receptor function. The heterozygous variant displayed partial co-segregation with diabetes. Based on these findings, we suggest that GIPR variants may play a role in disturbed glucose homeostasis and may be of clinical relevance in homozygous patients.

Asthma in children and adolescents with type 1 diabetes in Germany and Austria: Frequency and metabolic control.

OBJECTIVE: To investigate the prevalence of asthma in young patients with type 1 diabetes mellitus (T1D) from Austria and Germany and its influence on their metabolic control. METHODS: This prospective, multicenter observational cohort study was based on the DPV-registry (German/Austrian DPV initiative) including 51 926 patients with T1D (<20 years). All clinical data were documented prospectively. To identify patients with additional asthma, the entry of the diagnosis asthma as well as asthma medication was used for classification. RESULTS: 1755 patients (3.4%) of the cohort had the diagnosis asthma or received asthma-specific drugs. Patients with asthma needed higher insulin doses (0.88 ± 0.3 vs 0.84 ± 0.3 U/kg, P < .01) and had decreased height-standard deviation score (SDS) (-0.002 ± 1.04 vs 0.085 ± 1.02, P < .01); they were more often males (61% vs 52%, P < .01), had an increased body mass index (BMI)-SDS (0.31 ± 0.89 vs 0.28 ± 0.89, P = .04) and experienced more severe hypoglycemia (4.5 [4.2; 4.8] vs 3.2 [3.2; 3.3] events/100 pts. years, P < .01). Glycated hemoglobin A1c (HbA1c) did not differ between patients with and without asthma overall, only sub groups (corticosteroids vs leukotriene antagonist and corticosteroids vs sympatomimetics) revealed differences. No influence of asthma medication on metabolic control or BMI-SDS could be found. CONCLUSION: In our DPV-database, frequency of asthma and T1D seems similar to the prevalence of asthma in the healthy German background population. The concomitant diagnosis of asthma and T1D had minor influence on metabolic control and diabetes complication rate, although there was no difference in HbA1c overall. Patients with both diseases seem to be slightly growth restricted and require slightly higher insulin doses.

Diabetes mellitus in pediatric solid organ recipients without and with cystic fibrosis: An analysis from the German-Austrian diabetes database (Diabetes Patienten Verlaufsdokumentation).

INTRODUCTION: Posttransplantation diabetes mellitus (PTDM) increases the risk of cardiovascular disease, graft loss, and decreased survival. Follow-up treatment after solid organ transplantation (SOT) needs to focus on, inter alia, maintaining balanced glucose metabolism. This study aimed to ascertain the prevalence of PTDM and describe patient characteristics in the large DPV (Diabetes Patienten Verlaufsdokumentation) pediatric diabetes database. METHODS: DPV data of 71 902 patients from the January 01, 1995 to January 04, 2015 period were analyzed for patients with and without cystic fibrosis (CF) after SOT (kidney, liver, heart, and lung). Multivariable analysis served to assess differences between SOT patient groups at risk for developing diabetes. RESULTS: Out of 109 SOT patients, 51 had CF; 72.5% received steroids and 62% were additionally given tacrolimus. PTDM developed in 45% of CF patients and 12% of non-CF patients. SOT patients were older at diabetes onset (mean age, 12.50 ± 3.98 years), shorter (height z-score, -1.67 ± 1.25), and lighter (weight z-score, -1.59 ± 1.57) than non-SOT diabetes patients (P < 0.01). With transplantation, glycated hemoglobin (HbA1c) was significantly lower and treatment for hypertension and dyslipidemia was increased. Among SOT patients, weight and body mass index (BMI) z-scores were significantly lower in patients with CF-related diabetes (P < 0.05). CONCLUSIONS: SOT was present in 6.6% of children with diabetes, and this might aggravate the risk of cardiovascular disease in populations with already increased rates of hypertension and dyslipidemia. Dystrophy and short stature were also present, particularly in transplant recipients with CF and diabetes. Comorbidities and long-term consequences call for multidisciplinary collaboration.

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

Tracking of metabolic control from childhood to young adulthood in type 1 diabetes.

OBJECTIVE: This prospective longitudinal survey was designed to follow patients with diabetes from disease onset in childhood over an extended period of time including puberty until young adulthood with respect to metabolic control. STUDY DESIGN: An electronic diabetes patient documentation system used in diabetes centers in Austria and Germany was utilized for standardized data collection. Complete documentation of metabolic control for prepuberty (≤ 13 years), puberty (14-19 years), and adulthood (≥ 20 years) was available in 1146 patients. RESULTS: Median age at diabetes manifestation was 7.2 (IQR 4.7-9.4) years; 49% were male. In the prepubertal stage, median glycated hemoglobin A1c (HbA1c) was 7.5 (IQR 6.8-8.3), during puberty 8.0 (IQR 7.3-8.9), and after puberty 7.8 (IQR 7.1-9.0). A significant intra-individual correlation was found for prepuberty to puberty HbA1c levels (R = 0.55, P < .001), puberty to adulthood (R = 0.59, P < .001), as well as prepuberty to adulthood (R = 0.30, P < .001). When patients were divided into tertiles of prepubertal HbA1c, HbA1c increased in all 3 groups over time, however, significant group differences tracked into adulthood (P < .001 at all stages). A regression model identified pre-pubertal HbA1c as a significant and relevant predictor of metabolic control in young adulthood adjusted for confounders (P < .001). CONCLUSIONS: This survey provides evidence for long-term tracking of metabolic control from childhood until adulthood, suggesting an early focus on metabolic control.

Occurrence of giant focal forms of congenital hyperinsulinism with incorrect visualization by (18) F DOPA-PET/CT scanning.

CONTEXT: Congenital hyperinsulinism (CHI) is a rare disease characterized by severe hypoglycaemic episodes due to pathologically increased insulin secretion from the pancreatic beta cells. When untreated, CHI might result in irreversible brain damage and death. Currently, two major subtypes of CHI are known: a focal form, associated with local distribution of affected beta cells and a nonfocal form, affecting every single beta cell. The identification of focal forms is important, as the patients can be cured by limited surgery. (18) F DOPA-PET/CT is an established non-invasive approach to differentiate focal from nonfocal CHI. OBJECTIVE: The purpose of this study was to identify possible limitations of (18) F DOPA-PET/CT scan in patients with focal forms nonfocal CHI. DESIGN: A retrospective chart review of 32 patients (from 2008 through 2013) who underwent (18) F DOPA-PET/CT and partial pancreatectomy for focal CHI at the reference centres in Berlin, Germany and London, UK. RESULTS: In most cases (n = 29, 90·7%), (18) F DOPA-PET/CT was sufficient to localize the complete focal lesion. However, in some patients (n = 3, 9·3%), (18) F DOPA-PET/CT wrongly visualized only a small portion of the focal lesion. In this group of patients, a so-called 'giant focus' was detected in histopathological analysis during the surgery. CONCLUSIONS: Our data show that in most patients with focal CHI (18) F DOPA-PET/CT correctly predicts the size and anatomical localisation of the lesion. However, in those patients with a 'giant focal' lesion (18) F DOPA-PET/CT is unreliable for correct identification of 'giant focus' cases.

Pulse pressure in children and adolescents with type 1 diabetes mellitus in Germany and Austria.

BACKGROUND: Impaired blood pressure regulation contributes to the development of diabetic complications. The influence of systolic (SBP) vs.diastolic blood pressure (DBP) is still controversial. Peripheral pulse pressure(PP), the difference between SBP and DBP, is an indicator for arterial stiffness. Only little data are available for PP in children. Therefore, we studied PP regulation in type 1 diabetic children and adolescents.Methods: Blood pressure values of 46 737 patients with T1DM younger than 20 years are documented in the DPV database and were compared with the control populations of the '4th report on high blood pressure (4th report)' and the German KIGGS study. RESULTS: PP is increased in 63% (4th report) or 67% (KIGGS) of the patients,respectively. The rate of increased PP remains stable between 59 and 68%,irrespective of sex, age, and the control population. Absolute PP is elevated independently of the control population (PP T1DM 49.13±11.1 vs. 4th report 45.38 ± 3 vs. KIGGS 44.58 ± 4.6 mmHg; all p<0.0001, Wilcoxon test)and increases with age in both sexes. Age, male sex, diabetes duration, insulin dose, and body mass index (BMI) are independent factors contributing to elevated absolute PP levels and to the prevalence of wide PP. HbA1c is negligible negatively related to increased PP levels (multiple linear regression). CONCLUSIONS: In T1DM increased PP is a marker for accelerated arterial stiffness and aging and should be considered as an additional risk factor in the treatment of diabetic children. Elevated PP in children with T1DM may contribute to the high risk for early development of atherosclerosis.

Insulin Secretion Defect in Children and Adolescents with Obesity: Clinical and Molecular Genetic Characterization.

Introduction: Childhood obesity is increasing worldwide and presents as a global health issue due to multiple metabolic comorbidities. About 1% of adolescents with obesity develop type 2 diabetes (T2D); however, little is known about the genetic and pathophysiological background at young age. The objective of this study was to assess the prevalence of impaired glucose regulation (IGR) in a large cohort of children and adolescents with obesity and to characterize insulin sensitivity and insulin secretion. We also wanted to investigate adolescents with insulin secretion disorder more closely and analyze possible candidate genes of diabetes in a subcohort. Methods: We included children and adolescents with obesity who completed an oral glucose tolerance test (OGTT, glucose + insulin) in the outpatient clinic. We calculated Matsuda index, the area under the curve (AUC (Ins/Glu)), and an oral disposition index (ISSI-2) to estimate insulin resistance and beta-cell function. We identified patients with IGR and low insulin secretion (maximum insulin during OGTT < 200 mU/l) and tested a subgroup using next generation sequencing to identify possible mutations in 103 candidate genes. Results: The total group consisted of 903 children and adolescents with obesity. 4.5% showed impaired fasting glucose, 9.4% impaired glucose tolerance, and 1.2% T2D. Matsuda index and Total AUC (Ins/Glu) showed a hyperbolic relationship. Out of 39 patients with low insulin secretion, we performed genetic testing on 12 patients. We found five monogenetic defects (ABCC8 (n = 3), GCK (n = 1), and GLI2/PTF1A (n = 1)). Conclusion: Using surrogate parameters of beta-cell function and insulin resistance can help identify patients with insulin secretion disorder. A prevalence of 40% mutations of known diabetes genes in the subgroup with low insulin secretion suggests that at least 1.7% of patients with adolescent obesity have monogenic diabetes. A successful molecular genetic diagnosis can help to improve individual therapy.