Lipid levels in a cohort of healthy Danish schoolchildren ages 5 to 17 years.

It is internationally recognized to use clinical decision limits (CDL) when interpreting the lipid levels in both adults and children, even though the evidence for children is scarce. The purpose of this study is to describe how lipid levels progress in healthy Danish children ages 5 to 17 years. This study is based on the Childhood Health, Activity, and Motor Performance School Study Denmark (CHAMPS-study DK) consisting of 1456 observations of schoolchildren aged 5 to 17 years. Participants have been tested for blood levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and remnant cholesterol levels are calculated. Finally, sex-specific percentile reference curves are presented. Percentile reference curves stratified by sex were generated for all cholesterols and showed that the total cholesterol level peaks at 4.32 mmol/l in 10-year-old boys and 4.46 mmol/l in nine-year-old girls. HDL levels in boys peak at 1.72 mmol/l in nine-year-old boys. HDL levels in girls and LDL levels in both sexes are nearly constant. Triglycerides kept rising to the age of 17 years in both sexes and remnant cholesterol decreased from age 5 to 17 years in both sexes. BMI z-score adjustment revealed no significant association with total cholesterol in both sexes but a significant association between HDL, LDL, triglycerides, and remnant cholesterol. This study is the first to generate percentile reference curves for blood levels of total cholesterol, LDL, HDL, triglycerides, and remnant cholesterol in a cohort of healthy Danish children aged 5 to 17 years.

Detection of capillary abnormalities in early diabetic retinopathy using scanning laser ophthalmoscopy and optical coherence tomography combined with adaptive optics.

This study tested if a high-resolution, multi-modal, multi-scale retinal imaging instrument can provide novel information about structural abnormalities in vivo. The study examined 11 patients with very mild to moderate non-proliferative diabetic retinopathy (NPDR) and 10 healthy subjects using fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), adaptive optics scanning laser ophthalmoscopy (AO-SLO), adaptive optics OCT and OCTA (AO-OCT(A)). Of 21 eyes of 11 patients, 11 had very mild NPDR, 8 had mild NPDR, 2 had moderate NPDR, and 1 had no retinopathy. Using AO-SLO, capillary looping, inflections and dilations were detected in 8 patients with very mild or mild NPDR, and microaneurysms containing hyperreflective granular elements were visible in 9 patients with mild or moderate NPDR. Most of the abnormalities were seen to be perfused in the corresponding OCTA scans while a few capillary loops appeared to be occluded or perfused at a non-detectable flow rate, possibly because of hypoperfusion. In one patient with moderate NPDR, non-perfused capillaries, also called ghost vessels, were identified by alignment of corresponding en face AO-OCT and AO-OCTA images. The combination of multiple non-invasive imaging methods could identify prominent microscopic abnormalities in diabetic retinopathy earlier and more detailed than conventional fundus imaging devices.

The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults.

AIMS/HYPOTHESIS: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual's clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. METHODS: Data were collected from the large INNODIA cohort of individuals (aged 1.0-45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10-17 years; and ≥18 years. RESULTS: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0-382.0) pmol/l (AUC 749.3 [466.2-1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). CONCLUSIONS/INTERPRETATION: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline.

Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial.

Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6-15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving ß cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004-0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41 .

Risk of New-onset Type 1 Diabetes in Danish Children and Adolescents After SARS-CoV-2 Infection: A Nationwide, Matched Cohort Study.

We investigated the association between SARS-CoV-2 infection and new-onset type 1 diabetes (T1D) in children and adolescents in a nationwide, matched cohort study. The hazard ratio of new-onset T1D within 6 months after SARS-CoV-2 infection was 1.22 (0.58-2.58). The risk of new-onset T1D in children and adolescents was not significantly increased after SARS-CoV-2 infection.

Validation of a novel automated system, Fluispotter®, for serial sampling of dried blood spots.

Repeated blood sampling is required in certain clinical and research settings, which is currently performed by drawing blood from venous catheters requiring manual handling of each sample at the time of collection. A novel body-worn device for repeated serial samples, Fluispotter®, with automated extraction, collection, and storage of up to 20 venous dried blood spot samples over the course of 20 h may overcome problems with current methods for serial sampling. The purpose of this study was to assess the performance and safety of Fluispotter for the first time in healthy subjects. Fluispotter consists of a cartridge with tubing, a reservoir for flushing solution, pumps and filterpaper, and a multi-lumen catheter placed in the brachial vein. We recruited healthy subjects for testing in an in-hospital setting. Fluispotter was attached by an anesthesiologist to 22 healthy subjects of which 9/22 (40.9%) participants had all 20 samples taken, which was lower than the goal of complete sampling in 80% of the subjects (P = 0.02). The main reason for sample failure was clogging of blood flow which was observed in 11/22 (50%) of the participants. No serious adverse events occurred, and the participants rated the pain from the insertion and the removal of catheter as very low. A cortisol profile showed nadir values at midnight and highest values at 05:00 h. Although full sampling was not successful in all participants, the Fluispotter technology proved safe and highly acceptable to the participants producing the expected cortisol profile without the requirement of staff during sample collection.

Pro-Inflammatory Cytokines Promote the Transcription of Circular RNAs in Human Pancreatic ß Cells.

Circular RNAs (circRNAs) have recently been implicated in impaired ß-cell function in diabetes. Using microarray-based profiling of circRNAs in human EndoC-ßH1 cells treated with pro-inflammatory cytokines, this study aimed to investigate the expression and possible regulatory roles of circRNAs in human ß cells. We identified ~5000 ß-cell-expressed circRNAs, of which 84 were differentially expressed (DE) after cytokine exposure. Pathway analysis of the host genes of the DE circRNAs revealed the enrichment of cytokine signaling pathways, indicative of circRNA transcription from inflammatory genes in response to cytokines. Multiple binding sites for ß-cell-enriched microRNAs and RNA-binding proteins were observed for the highly upregulated circRNAs, supporting their function as 'sponges' or 'decoys'. We also present evidence for circRNA sequence conservation in multiple species, the presence of cytokine-induced regulatory elements, and putative protein-coding potential for the DE circRNAs. This study highlights the complex regulatory potential of circRNAs, which may play a crucial role during immune-mediated ß-cell destruction in type 1 diabetes.

The metabolic syndrome is frequent in children and adolescents with type 1 diabetes compared to healthy controls.

OBJECTIVE: There is a rise in overweight and obesity among children and adolescents with type 1 diabetes (T1D) in parallel with the rise in the metabolic syndrome (MetS) among children and adolescents. The aim of the study was to describe the prevalence and characteristics of MetS in children and adolescents with T1D compared to their healthy counterparts. RESEARCH DESIGN AND METHODS: The study includes two Danish cohorts; (i) the Copenhagen cross sectional cohort 2016 of 277 children and adolescents with T1D that attend the pediatric outpatient clinic at a large hospital in greater Copenhagen and (ii) the CHAMPS-study DK which is a population-based cohort study of Danish children and adolescents (control cohort). Participants were categorized to have MetS if at least two of the following criteria were met: (i) systolic and/or diastolic blood pressure ≥ 90th percentile, (ii) waist circumference ≥90th percentile, and (iii) triglyceride ≥90th percentile and/or HDL ≤10th percentile. RESULTS: The prevalence of children with Mets in the T1D cohort was higher than in the control cohort (p = 0.002). Moreover, participants with T1D had MetS at a lower level of BMI (p < 0.001) and waist circumference (p < 0.001) than participants with MetS from the control cohort (z-scores = 0.90 and 1.51). Participants with MetS were younger than the other T1D participants (median 12.8 [9.9,14.8] vs. median 14.6 [11.2,16.9] years, p = 0.006). CONCLUSIONS: Children and adolescents with T1D have an increased risk of MetS compared to healthy controls and clinicians and caretakers should consider early prevention and health promotion strategies.

Reference serum percentile values of adiponectin, leptin, and adiponectin/leptin ratio in healthy Danish children and adolescents.

The adipokines adiponectin and leptin play key roles in human metabolic regulation and have gained great attention as biomarkers for various metabolic pathologies. Though, pediatric reference values are few and needed. This study aims to establish age- and sex-specific adipokine reference percentiles based on healthy Danish school children. Further, it elucidates sex-specific differences in associations between z-scores of examined adipokines and metabolic variables. Serum adiponectin and serum leptin from 853 observations of healthy Danish schoolchildren aged 8-17 years (median 10.0) were quantified by immunoassays. Age- and sex-specific adipokine reference percentiles were calculated cross-sectionally using the LMS method, and adipokine z-scores were calculated from the fitted model. Multiple linear regression models were used to examine sex-specific differences in associations between adipokine z-scores and various metabolic variables. Girls had a higher median value of adiponectin (11.31 vs. 10.65 µg/mL, p < .001) and leptin (2.30 vs. 1.00 ng/mL, p < .001) and a lower median value of adiponectin/leptin ratio (4.64 vs. 10.76, p < .001) compared to boys. Sex-specific differences were found in associations between adiponectin z-score and HDL (p = .010), between leptin z-score and waist circumference z-score (p = .027) and LDL (p = .048), and between adiponectin/leptin ratio z-scores and waist circumference z-score (p = .044) and LDL (p = .040). Reference percentiles of adiponectin, leptin, and adiponectin/leptin ratio are presented in this paper. To our knowledge, this study is the first to demonstrate sex-specific differences in associations between adipokine z-scores and waist circumference z-score and lipids, respectively in healthy children and adolescents.

Genetic Variants Associated with Neuropeptide Y Autoantibody Levels in Newly Diagnosed Individuals with Type 1 Diabetes.

(1) Autoantibodies to the leucine variant of neuropeptide Y (NPY-LA) have been found in individuals with type 1 diabetes (T1D). We investigated the association between the levels of NPY-LA and single nucleotide polymorphisms (SNP) to better understand the genetic regulatory mechanisms of autoimmunity in T1D and the functional impacts of increased NPY-LA levels. (2) NPY-LA measurements from serum and SNP genotyping were done on 560 newly diagnosed individuals with T1D. SNP imputation with the 1000 Genomes reference panel was followed by an association analysis between the SNPs and measured NPY-LA levels. Additionally, functional enrichment and pathway analyses were done. (3) Three loci (DGKH, DCAF5, and LINC02261) were associated with NPY-LA levels (p-value < 1.5 × 10−6), which indicates an association with neurologic and vascular disorders. SNPs associated with variations in expression levels were found in six genes (including DCAF5). The pathway analysis showed that NPY-LA was associated with changes in gene transcription, protein modification, immunological functions, and the MAPK pathway. (4) Conclusively, we found NPY-LA to be significantly associated with three loci (DGKH, DCAF5, and LINC02261), and based on our findings we hypothesize that the presence of NPY-LA is associated with the regulation of the immune system and possibly neurologic and vascular disorders.

Differences in insulin sensitivity in the partial remission phase of childhood type 1 diabetes; a longitudinal cohort study.

AIMS: Studies suggest that type 1 diabetes (T1D) contributes to impaired insulin sensitivity (IS). Most children with T1D experience partial remission but the knowledge regarding the magnitude and implications of impaired IS in this phase is limited. Therefore, we investigate the impact of IS on the partial remission phase. METHODS: In a longitudinal study of children and adolescents, participants were seen at three clinical visits during the first 14.5 months after diagnosis of T1D. Partial remission was defined as IDAA1c (HbA1c (%) + 4*daily insulin dose) ≤ 9. Beta-cell function was considered significant by a stimulated c-peptide > 300 pmol/L. Participants were characterized by (i) remission or non-remission and (ii) stimulated c-peptide levels above or below 300 pmol/L. IS, body mass index (BMI), total body fat, sex, age, pubertal status and ketoacidosis at onset were compared. RESULTS: Seventy-eight children and adolescents aged 3.3-17.7 years were included. At 14.5 months post-diagnosis, 54.5% of the participants with stimulated c-peptide > 300 pmol/L were not in partial remission. Participants not in remission had significant lower IS 2.5 (p = 0.032), and 14.5 (p = 0.022) months after diagnosis compared to participants in partial remission with similar c-peptide levels. IS did not fluctuate during the remission phase. CONCLUSIONS: A number of children and adolescents have impaired IS in the remission phase of paediatric T1D and are not in remission 14.5 months after diagnosis despite stimulated c-peptide > 300 pmol/L.

Plasma Exosome-Enriched Extracellular Vesicles From Lactating Mothers With Type 1 Diabetes Contain Aberrant Levels of miRNAs During the Postpartum Period.

Type 1 diabetes is an immune-driven disease, where the insulin-producing beta cells from the pancreatic islets of Langerhans becomes target of immune-mediated destruction. Several studies have highlighted the implication of circulating and exosomal microRNAs (miRNAs) in type 1 diabetes, underlining its biomarker value and novel therapeutic potential. Recently, we discovered that exosome-enriched extracellular vesicles carry altered levels of both known and novel miRNAs in breast milk from lactating mothers with type 1 diabetes. In this study, we aimed to characterize exosomal miRNAs in the circulation of lactating mothers with and without type 1 diabetes, hypothesizing that differences in type 1 diabetes risk in offspring from these groups are reflected in the circulating miRNA profile. We performed small RNA sequencing on exosome-enriched extracellular vesicles extracted from plasma of 52 lactating mothers around 5 weeks postpartum (26 with type 1 diabetes and 26 age-matched controls), and found a total of 2,289 miRNAs in vesicles from type 1 diabetes and control libraries. Of these, 176 were differentially expressed in plasma from mothers with type 1 diabetes (167 upregulated; 9 downregulated, using a cut-off of abs(log2FC) >1 and FDR adjusted p-value <0.05). Extracellular vesicles were verified by nanoparticle tracking analysis, transmission electron microscopy and immunoblotting. Five candidate miRNAs were selected based on their involvement in diabetes and immune modulation/beta-cell functions: hsa-miR-127-3p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-24-3p and hsa-miR-30d-5p. Real-time qPCR validation confirmed that hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-24-3p, and hsa-miR-30d-5p were significantly upregulated in lactating mothers with type 1 diabetes as compared to lactating healthy mothers. To determine possible target genes and affected pathways of the 5 miRNA candidates, computational network-based analyses were carried out with TargetScan, mirTarBase, QIAGEN Ingenuity Pathway Analysis and PantherDB database. The candidates showed significant association with inflammatory response and cytokine and chemokine mediated signaling pathways. With this study, we detect aberrant levels of miRNAs within plasma extracellular vesicles from lactating mothers with type 1 diabetes during the postpartum period, including miRNAs with associations to disease pathogenesis and inflammatory responses.

Treatment of type 2 diabetes in children: what are the specific considerations?

Introduction: The number of individuals under 18 years of age with type 2 diabetes is increasing at an alarming rate worldwide. These patients are often characterized by obesity and they often experience a more rapid disease progression than adults with type 2 diabetes. Thus, focus on prevention and management of complications and comorbidities is imperative. With emphasis on weight loss and optimal glycemic control, treatment includes lifestyle changes and pharmacotherapy, which in this patient group is limited to metformin, liraglutide and insulin. In selected cases, bariatric surgery is indicated.Areas covered: This perspective article provides an overview of the literature covering pathophysiology, diagnosis, characteristics and treatment of pediatric type 2 diabetes, and outlines the gaps in our knowledge where further research is needed. The paper draws on both mechanistic studies, large scale intervention trials, epidemiological studies and international consensus statements.Expert opinion: Type 2 diabetes in pediatric patients is an increasing health care problem, and the current treatment strategies do not successfully meet the many challenges and obstacles in this patient group. Treatments must be early, intensive, multifaceted and durable. Also, prevention of obesity and type 2 diabetes in at-risk children should be addressed and prioritized on all levels.

Reference intervals in Danish children and adolescents for bone turnover markers carboxy-terminal cross-linked telopeptide of type I collagen (ß-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP).

PURPOSE: Bone turnover markers (BTM) are gaining ground in clinical practice but to fully use their potential there is a need for establishing valid reference intervals (RI). Consequently, the purpose of the study was to establish general RI as well as suggested clinical RI for carboxy-terminal cross-linked telopeptide of type I collagen (ß-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP) in children and adolescents. METHOD: BTM were measured on Danish children and adolescents participating in the CHAMPS-study DK. A total of 762 participants were included (8-18 years, 50.4% girls) contributing a total of 1410 study visits. The RI was calculated based on 2-years age spans. Participants with biochemical signs of metabolic bone disease were excluded. RESULTS: The differences in RI between age groups clearly reflect changes in growth with an initial increase in BTM, greatest in boys, and a subsequent decrease most pronounced in girls. ß-CTX and PINP are markers most affected by these changes, compared to OC and bone ALP. The suggested clinical 95% RI included participants with vitamin D insufficiency but no biochemical signs of metabolic bone disease which did not markedly alter the RI. CONCLUSION: RI for ß-CTX, PINP, OC and bone ALP varies with age and sex. ß-CTX and PINP which reflect bone resorption and formation processes are mostly affected by these changes. We suggest a set of clinically applicable 95% RI for the four BTM to heighten the usefulness and generalizability of the RI.

Systemic TNFα correlates with residual ß-cell function in children and adolescents newly diagnosed with type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is caused by immune-mediated destruction of the ß-cells. After initiation of insulin therapy many patients experience a period of improved residual ß-cell function leading to partial disease remission. Cytokines are important immune-modulatory molecules and contribute to ß-cell damage in T1D. The patterns of systemic circulating cytokines during T1D remission are not clear but may constitute biomarkers of disease status and progression. In this study, we investigated if the plasma levels of various pro- and anti-inflammatory cytokines around time of diagnosis were predictors of remission and residual ß-cell function in children with T1D followed for one year after disease onset. METHODS: In a cohort of 63 newly diagnosed children (33% females) with T1D with a mean age of 11.3 years (3.3-17.7), ten cytokines were measured of which eight were detectable in plasma samples by Mesoscale Discovery multiplex technology at study start and after 6 and 12 months. Linear regression models were used to evaluate association of cytokines with stimulated C-peptide. RESULTS: Systemic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2 and IL-6 inversely correlated with stimulated C-peptide levels over the entire study (P < 0.05). The concentrations of TNFα and IL-10 at study start predicted stimulated C-peptide level at 6 months (P = 0.011 and P = 0.043, respectively, adjusted for sex, age, HbA1c and stage of puberty). CONCLUSIONS: In recent-onset T1D, systemic cytokine levels, and in particular that of TNFα, correlate with residual ß-cell function and may serve as prognostic biomarkers of disease remission and progression to optimize treatment strategies. TRIAL REGISTRATION: The study was performed according to the criteria of the Helsinki II Declaration and was approved by the Danish Capital Region Ethics Committee on Biomedical Research Ethics (journal number H-3-2014-052). The parents of all participants gave written consent.

[Feedback loops in medical education].

Feedback is in demand by medical students, supervisors, educational researchers and universities, but clinicians' theoretical knowledge about feedback and learning is limited. In this review, we 1) present various feedback forms and learning theories such as peer feedback, formative and summative feedback, feedback loops, feedforward and self-regulated learning, 2) exemplify how feedback loops can be used in medical education activities, and 3) provide insight into how medical students perceive feedback loops with peer, and how supervisor feedback affects their learning in a paediatric outpatient clinic.

Fluispotter, a novel automated and wearable device for accurate volume serial dried blood spot sampling.

Aim: A novel automated serial dried blood spot (DBS) sampler, 'Fluispotter', was tested for its sampling performance. Materials & methods: An LC-MS/MS method was developed for the analysis of cortisol in DBS samples serially spotted by Fluispotter. The cortisol concentrations in 148 paired DBS and plasma samples were compared across a hematocrit (HCT) range of 22-55%. Results: The interassay accuracy and precision were <10%. Overall assay bias was negligible across the HCTs tested when analyzing the whole-spot DBS samples. The accuracy and precision of the blood volume in 10 µl DBS samples spotted by Fluispotters and micropipettes were within 3%. Deming regression and Bland-Altman analysis showed a good agreement of DBS-predicted and measured plasma cortisol. Conclusion: The Fluispotter performed serial sampling with high accuracy and precision of the sample blood volume.

High prevalence of disordered eating behavior in Danish children and adolescents with type 1 diabetes.

OBJECTIVE: A higher prevalence of disordered eating behavior (DEB) has been demonstrated in children and adolescents with type 1 diabetes (T1D) compared to healthy aged-matched peers. DEB is associated with higher HbA1c levels and increased risk of developing complications to T1D. The aim of this study was to determine the prevalence of DEB in a Danish cohort of children and adolescents with T1D aged 11 to 19 years and to characterize them regarding metabolic control and relevant clinical data. RESEARCH DESIGN AND METHODS: In a cross-sectional study, we determined the prevalence of DEB using the revised Diabetes Eating Problem Survey (DEPS-R) questionnaire. HbA1c and relevant clinical data were obtained at the time they filled in the questionnaire. RESULTS: Hundred and ninety-two children and adolescents (46% girls) aged 11 to 19 years with T1D were included from the pediatric diabetes outpatient clinic. A total of 40 participants (21%) had DEB. The prevalence was higher among girls compared with boys (34.1% vs 8.9%) and those who had DEB were older (16.7 vs 15.0 years, P < .001), had longer duration of T1D (7.5 vs 4.9 years, P < .001), higher BMI Z-scores (1.2 vs 0.3, P < .001), higher HbA1c (72.8 (8.8%) vs 62.0 (7.8%) mmol/mol, P < .001), higher total cholesterol (4.6 mmol/L vs 4.2 mmol/L, P = .0048), and LDL (2.7 vs 2.3, P = .001) compared with those with no signs of DEB. CONCLUSION: As in other countries, the prevalence of DEB is high in Danish adolescents with T1D. Early detection of DEB is essential to prevent short- and long-term complications to T1D.

Episodes of severe hypoglycemia is associated with a progressive increase in hemoglobin A1c in children and adolescents with type 1 diabetes.

OBJECTIVE: To investigate the trajectory in glycemic control following episodes of severe hypoglycemia (SH) among children and adolescents with type 1 diabetes (T1D). METHODS: A Danish national population-based study comprising data from 2008-17. SH was defined according to the 2014 ISPAD guidelines. A mixed model was applied with HbA1c as outcome and SH episodes and time since first episode as explanatory variables. Data were adjusted for age, gender and diabetes duration. RESULTS: A total of 4244 children (51.6% boys) with 18 793 annual outpatient visits were included. Mean (SD) age at diabetes onset was 9.0 (4.1) years. Median diabetes duration at inclusion in the study was 1.2 (Q1 = 0.9, Q3 = 3.0) years, and median diabetes duration at last visit was 5.0 (Q1 = 2.7, Q3 = 8.1) years. A total of 506 children experienced at least one episode of SH during the nine-year follow-up; 294 children experienced one episode, 115 two episodes and 97 three or more episodes of SH. HbA1c increased with episodes of SH and in the years following the first episode. The glycemic trajectory peaked 2 to 3 years after an SH episode. The accumulated deterioration in glycemic control was in the range of 5% in patients with two or more episodes equivalent to an increase in HbA1c of 4 mmol/mol (HbA1c ~0.4%). CONCLUSION: SH was followed by a progressive and lasting increase in HbA1c among Danish children and adolescents with T1D. Thus, in addition to the known risk of new episodes of hypoglycemia and cognitive impairment, SH contributes to long-term diabetes complications.