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Context Burosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents are lacking. Objective To assess the effects of 12 months of burosumab treatment on mineral metabolism in children (aged Design Prospective national registry. Setting Hospital clinics. Patients A total of 93 patients with XLH (65 children, 28 adolescents). Main Outcome Measures Z scores for serum phosphate, alkaline phosphatase (ALP), and renal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) at 12 months. Results At baseline, patients showed hypophosphatemia (−4.4 SD), reduced TmP/GFR (−6.5 SD), and elevated ALP (2.7 SD, each P < .001 vs healthy children) irrespective of age, suggesting active rickets despite prior therapy with oral phosphate and active vitamin D in 88% of patients. Burosumab treatment resulted in comparable increases in serum phosphate and TmP/GFR in children and adolescents with XLH and a steady decline in serum ALP (each P < .001 vs baseline). At 12 months, serum phosphate, TmP/GFR, and ALP levels were within the age-related normal range in approximately 42%, 27%, and 80% of patients in both groups, respectively, with a lower, weight-based final burosumab dose in adolescents compared with children (0.72 vs 1.06 mg/kg, P < .01). Conclusions In this real-world setting, 12 months of burosumab treatment was equally effective in normalizing serum ALP in adolescents and children, despite persistent mild hypophosphatemia in one-half of patients, suggesting that complete normalization of serum phosphate is not mandatory for substantial improvement of rickets in these patients. Adolescents appear to require lower weight-based burosumab dosage than children.

Aim Screening for coeliac disease in asymptomatic children with new-onset type 1 diabetes is controversial. The aim of this study was to analyse whether the confirmation of coeliac disease in children with new-onset type 1 diabetes and positive screening results can be postponed. Methods This was a multicentre population-based cohort study based on the German/Austrian/Swiss/Luxembourgian Prospective Diabetes Follow-up Registry (Diabetes Patienten Verlaufsdokumentation [DPV]). Participants aged ≤18 years diagnosed with type 1 diabetes between 1995 and June 2021 and with elevated IgA tissue transglutaminase antibodies (anti-tTGA) at diabetes onset on screening for coeliac disease were included. We compared outcomes of participants with a diabetes duration of more than 1 year between those in whom coeliac disease was confirmed histologically within the first 6 months and those in whom coeliac disease was confirmed between 6 and 36 months after diabetes diagnosis. Results Of 92,278 children and adolescents with a diagnosis of type 1 diabetes, 26,952 (29.2%) had documented anti-tTGA data at diabetes onset. Of these, 2340 (8.7%) had an elevated anti-tTGA level. Individuals who screened positive were younger (median age 9.0 vs 9.8 years, pp1c levels (62.8 mmol/mol vs 62.2 mmol/mol [7.9% vs 7.8%]), cardiovascular risk markers (lipids, rate of microalbuminuria, blood pressure), rates of acute diabetes complications (diabetic ketoacidosis, severe hypoglycaemia) and the proportions of participants reaching anti-tTGA levels within the normal range did not differ between groups. Participants with delayed histological confirmation of coeliac disease showed no negative effects on growth or weight gain during the observation period. Conclusions Our study suggests that the histological confirmation of coeliac disease in asymptomatic individuals with new-onset type 1 diabetes could be postponed. Graphical abstract

To study diabetic cataract in type 1 diabetes in a large pediatric cohort.The 92,633 patients aged 0.5-21 years from German/Austrian multicenter diabetes registry (DPV) were analyzed. The 235 patients (0.25%) with diabetic cataract were found, 200 could be categorized: 67 with early cataract (3 months before diabetes onset - 12 months afterwards), 133 with late cataract (12 months after diabetes onset). Regression models adjusted for age and gender were used to compare clinical parameters at diabetes onset. Regression models for patients with late cataract were implemented for the total documentation period and additionally adjusted for diabetes duration.Rate of cataract development shows a peak at diabetes onset and declines with longer diabetes duration. Patients with cataract showed strong female preponderance. Patients developing early cataract were older at diabetes onset (12.8 years [11.8/13.9] vs. 8.9 [8.9/9.0]; p 0.001) and showed higher HbA1c than patients without cataract (9.0% [8.55/9.38] vs. 7.6% [7.60/7.61]; p 0.001). They had lower height-SDS, (-0.22 [-0.48/0.04] vs. 0.25 [0.24/0.26]; p 0.001), lower weight-SDS (-0.31 [-0.55/-0.08] vs. 0.21 [0.20/0.21]; p 0.001) and lower BMI-SDS (-0.25 [-0.49/-0.02] vs. 0.12 [0.12/0.13); p = 0.002). Patients with late cataract showed higher HbA1c at diabetes onset (8.35% [8.08/8.62] vs. 8.04% [8.03/8.05]; p = 0.023) and higher mean HbA1c during total documentation period (8.00% [7.62/8.34] vs. 7.62% [7.61/7.63]; p = 0.048).Our data confirm known demographic and clinical characteristics of patients developing early cataract. Hyperglycemia-induced osmotic damage to lens fibers at diabetes onset might be the main pathomechanism. Long term glycemic control is associated with cataract development.

Context Autoimmune diseases affect ~8% of the population. Type 1 diabetes mellitus (T1DM) is linked to other autoimmune diseases (AIDs), such as autoimmune thyroid disease or Addison’s disease (AD), that may impact diabetes therapy and outcome. Objective To analyze demographic and clinical characteristics of other AIDs in T1DM from a large standardized registry, the Prospective Diabetes Follow-up Registry (DPV). Methods We searched the registry for T1DM with the additional diagnosis of Hashimoto’s thyroiditis (HT), Graves’ disease (GD), and/or AD. T1DM with other AIDs (n = 6166, 5.4%) were compared with isolated T1DM (n = 107 457). For group comparisons, we used multivariable regression models with age, sex, diabetes duration, migration background, and type of insulin regimen as basic adjustments (microvascular endpoints: additionally adjusted for glycated hemoglobin). Results Patients with additional AIDs were more often female (54.7 vs 32.0%, P Conclusion T1DM with additional AIDs show heterogeneous differences compared with isolated T1DM. T1DM plus AD or HT requires more insulin. Further, the rate of neuropathy is higher in HT or GD, whereas the rate of microalbuminuria is lower.

Objectives To describe clinical presentation and long-term outcomes in a large cohort of children diagnosed with thiamine-responsive megaloblastic anemia (TRMA)-related diabetes. Methods Data from the Diabetes Patienten Verlaufsdokumentation (DPV) and Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference (SWEET) registries were used to identify cases. Complementary information was collected through a chart review of each case. Descriptive analyses with medians and interquartile ranges and numbers (proportions) were tabulated. Results We identified 23 cases (52% male) in the 2 registries. Eighteen (78%) had genetic confirmation of TRMA. Median age at diabetes onset was 1.4 (quartiles 0.8 to 3.6) years and median age at initiation of thiamine treatment was 5.9 (2.4 to 12.4) years. At their most recent visit, patients’ median age was 14.3 (8.1 to 17.5) years, glycated hemoglobin level was 6.9% (6.1% to 7.9%), insulin dose was 0.9 (0.4 to 1.2) units/kg per day and thiamine dose was 200 (100 to 300) mg/day. Three patients were not treated with insulin or antidiabetic drugs. There was no difference in diabetes outcomes in patients with initiation of thiamine ≤1 year after diabetes onset compared to patients with initiation of thiamine >1 year after diabetes onset. Conclusions This is the longest case series of pediatric TRMA-related diabetes reported to date. Diabetes onset often occurs several years before initiation of thiamine supplementation. Early initiation of thiamine (within 1 year of diabetes onset) was not linked to improved diabetes outcome. However, the role of thiamine in pancreatic function needs further assessment. Patients with TRMA-related diabetes maintained good glycemic control even after 9 years (median) of follow up.

Objective In children with presymptomatic type 1 diabetes, intermittent hyperglycemia and rising hemoglobin A1c levels are a known signal of progression toward insulin-dependency. Episodes of hypoglycemia, however, have also been reported in one published case. We investigated the prevalence of hypoglycemia and its association with disease progression in children with presymptomatic type 1 diabetes.Methods We compared the frequency of hypoglycemic fasting blood glucose levels (

Background Increasing evidence link sleep curtailment and circadian misalignment with adverse metabolic outcome. Adolescents might be most affected, given their late sleep timing and early school and work start times. Objective Our aim was to examine the impact of poor sleeping habits on glycemic control in adolescents with type 1 diabetes. Subjects and Methods This was a non-interventional multicenter study across Germany recruiting pubertally mature adolescents with type 1 diabetes. Medical records were used to collect information on diabetes duration, treatment, and complications. Participants self-reported sleep quality, timing, chronotype, and social jetlag—a measure of circadian misalignment. Hemoglobin A1c (HbA1c) was determined at the time of questionnaire response. We used multivariable linear regression models to examine associations between sleep and glycemic control. Results A total of 191 patients aged 16.5 years (mean HbA1c 8.0% [64 mmol/mol]) were included in this study. In multivariable adjusted analyses, sleep quality was significantly associated with HbA1c (mean difference; β = −0.07, P = .05). Stratified analysis indicated that this association might be stronger in boys and also in children with migration background. In contrast, neither sleep duration, sleep debt, chronotype, nor social jetlag was associated with HbA1c . Secondary analyses showed that social jetlag was significantly associated with levels of insulin requirements (mean difference; β = 0.035, P = .03). Conclusions Our study suggests that poor sleep quality is associated with increased HbA1c in adolescents with type 1 diabetes and that higher levels of circadian misalignment are associated with increased insulin requirements. If replicated, our results indicate a clinical relevance of sleep habits in adolescents with type 1 diabetes.

Worsening metabolic control, weight changes and increasing insulin dose during puberty have emerged as a challenge in diabetes care. However, individual variation is large. Data from the German/Austrian/Luxembourgian diabetes registry DPV were used to identify distinct patterns of hemoglobin A1c (HbA1c), age/sex-standardized body mass index (BMI-SDS) and daily insulin dose from childhood to young adulthood. Longitudinal data from 9,239 participants with T1D aged 8 to 18 years with duration >=2 years and >=5 years of follow-up were analyzed. We applied group-based multitrajectory (GBMT) modeling, a generalization of the group-based trajectory approach, to identify latent groups of subjects following similar developmental curves over time across multiple variables (Nagin, 2018). The GBMT approach revealed five unique groups of heterogeneous HbA1c, BMI-SDS and insulin dose patterns over time (Fig1). Differences in age at onset, gender, migration background as well as height-SDS, insulin pump and CGM usage, frequency of SMBG and physical activity were found across all groups. The present study identified for the first time five distinct multitrajectories of HbA1c, BMI-SDS and insulin dose during puberty. This approach demonstrates that variability between individuals is obscured by statistics on central tendency. Disclosure A. Schwandt: None. O. Kuss: None. D.P. Dunstheimer: None. B. Karges: None. T.M. Kapellen: None. T. Meissner: None. M. Witsch: None. M. Flury: Other Relationship; Self; Pfizer Inc. S. Straubinger: None. R.W. Holl: None. Funding German Center for Diabetes Research; Robert Koch Institute; German Diabetes Association

OBJECTIVE Worsening of glycemic control in type 1 diabetes during puberty is a common observation. However, HbA1c remains stable or even improves for some youths. The aim is to identify distinct patterns of glycemic control in type 1 diabetes from childhood to young adulthood. RESEARCH DESIGN AND METHODS A total of 6,433 patients with type 1 diabetes were selected from the prospective, multicenter diabetes patient registry Diabetes-Patienten-Verlaufsdokumentation (DPV) (follow-up from age 8 to 19 years, baseline diabetes duration ≥2 years, HbA1c aggregated per year of life). We used latent class growth modeling as the trajectory approach to determine distinct subgroups following a similar trajectory for HbA1c over time. RESULTS Five distinct longitudinal trajectories of HbA1c were determined, comprising group 1 = 40%, group 2 = 27%, group 3 = 15%, group 4 = 13%, and group 5 = 5% of patients. Groups 1–3 indicated stable glycemic control at different HbA1c levels. At baseline, similar HbA1c was observed in group 1 and group 4, but HbA1c deteriorated in group 4 from age 8 to 19 years. Similar patterns were present in group 3 and group 5. We observed differences in self-monitoring of blood glucose, insulin therapy, daily insulin dose, physical activity, BMI SD score, body-height SD score, and migration background across all HbA1c trajectories (all P ≤ 0.001). No sex differences were present. Comparing groups with similar initial HbA1c but different patterns, groups with higher HbA1c increase were characterized by lower frequency of self-monitoring of blood glucose and physical activity and reduced height (all P < 0.01). CONCLUSIONS Using a trajectory approach, we determined five distinct longitudinal patterns of glycemic control from childhood to early adulthood. Diabetes self-care, treatment differences, and demographics were related to different HbA1c courses.

Background: The occurrence of antidrug antibodies is common in children treated with recombinant human growth hormone (rhGH). However, their clinical significance is unclear. Objective: This study aimed to examine the clinical significance of anti-GH antibodies by analyzing the phenotype of patients who tested positive in relation to the quantity of anti-GH antibodies. Method: In this laboratory-based retrospective study encompassing a time span of 6 years, all positive samples were identified, and senders were contacted. Anti-GH antibodies were measured using a radioprecipitation assay; positive samples underwent a confirmatory assay. Results: Out of a total of 104 samples from 66 patients, positive test results were found in 28 samples from 13 patients. Clinical data were available from all but one. The group with positive test results comprised 6 patients with a normal response to GH provocative tests (group A) and 6 with an insufficient response or with isolated GH deficiency (IGHD) type 1A (group B). Diagnoses in group A were neurosecretory dysfunction, bioinactive GH syndrome and constitutional delay of growth and puberty. Diagnoses in group B were IGHD type 1A, septo-optic dysplasia, and cerebral midline defect with multiple pituitary hormone deficiency. Insufficient growth response to rhGH was absent except in one sibling pair with IGHD type 1A and a patient with cerebral midline defect. These patients had the highest concentrations of anti-GH antibodies. Conclusions: The biological significance of anti-GH antibodies seems to be limited to patients with high concentrations of anti-GH antibodies. For all other patients, we recommend a careful “wait and see” strategy and monitoring antibody titers.

Background The long-acting insulin analogue degludec is a therapeutic option for patients with type 1 (T1D) or type 2 diabetes (T2D). Aim of this analysis was to investigate differences in clinical characteristics of patients before and after initiating degludec use in a cohort of German/Austrian patients. Methods 1064 subjects with T1D/T2D and documented degludec use from the Diabetes-Patient-Follow-Up (DPV) registry were included. The follow-up cohort (n = 421) comprised patients with available data before and 3–15 months after switching to degludec. A t-test for paired values was implemented to compare rates of severe hypoglycaemia, and mean values for HbA1C, BMI, basal insulin dose/kg bodyweight/day, and the number of basal insulin injections/day before and after switching to degludec Results were stratified by type of diabetes. In T1D, subgroup analyses were conducted (age, sex, basal insulin used before switching). P Findings In T1D (n = 360), basal insulin dose (0.43 ± 0.17 to 0.38 ± 0.13 IU) and the number of basal injections/day (1.7 ± 0.6 to 1.1 ± 0.3) decreased whereas BMI increased from 23.2 ± 4.8 to 24.0 ± 5.0 kg/m2 (all p Conclusions The DPV registry provides data from real-life diabetes care. Our analysis predominantly confirmed results from clinical trials and provides additional information complementing the clinical study program of degludec.

OBJECTIVE—To give an up-to-date profile of nephropathy and the involvement of risk factors in a large, prospective cohort of patients with type 1 diabetes and largely pediatric and adolescent onset of disease. RESEARCH DESIGN AND METHODS—A total of 27,805 patients from the nationwide, prospective German Diabetes Documentation System survey were included in the present analysis. Inclusion criteria were at least two documented urine analyses with identical classification. Urine analyses, treatment regimens, diabetes complications, and risk factors were recorded prospectively. Baseline characteristics were age at diagnosis 9.94 years (median [interquartile range 5.8–14.3]), age at last visit 16.34 years (12.5–22.2), and follow-up time 2.5 years (0.43–5.3). Cumulative incidence of nephropathy was tested by Kaplan-Meier analysis and association with risk factors by logistic regression. RESULTS—Nephropathy was classified as normal in 26,605, microalbuminuric in 919, macroalbuminuric in 78, and end-stage renal disease (ESRD) in 203 patients. After calculated diabetes duration of 40 years, 25.4% (95% CI 22.3–28.3) had microalbuminuria and 9.4% (8.3–11.4) had macroalbuminuria or ESRD. Risk factors for microalbuminuria were diabetes duration (odds ratio 1.033, P < 0.0001), A1C (1.13, P < 0.0001), LDL cholesterol (1.003, P < 0.0074), and blood pressure (1.008, P < 0.0074), while childhood diabetes onset (1.011, P < 0.0001) was protective. Male sex was associated with the development of macroalbuminuria. CONCLUSIONS—Diabetes duration, A1C, dyslipidemia, blood pressure, and male sex were identified as risk factors for nephropathy. Therefore, besides the best possible metabolic control, early diagnosis and prompt treatment of dyslipidemia and hypertension is mandatory in patients with type 1 diabetes.