Responses to the Strengths and Difficulties Questionnaire predict HbA1c trajectories in children and adolescents with type 1 diabetes: a population-based study.

INTRODUCTION: We aimed to determine whether caregiver responses to the Strengths and Difficulties Questionnaire (SDQ) are predictive of HbA1c trajectory membership in children and adolescents with type 1 diabetes, when adjusting for covariates. RESEARCH DESIGN AND METHODS: For a Danish 2009 national cohort of children and adolescents with type 1 diabetes, we analyzed yearly HbA1c follow-up data during 2010-2020 including sociodemographic data from Danish national registries. Using group-based trajectory modeling and multinomial logistic regression, we tested whether caregiver SDQ scores predicted HbA1c trajectory membership when adjusting for sex, age at diabetes diagnosis, diabetes duration, family structure, and caregiver education. RESULTS: In total, 835 children and adolescents (52% females) with a mean (SD) age of 12.5 (3.3) years, and a mean diabetes duration of 5.2 (3.1) years, were included. Based on 7247 HbA1c observations, four HbA1c trajectories were identified: (1) 'on target, gradual decrease' (26%), (2) 'above target, mild increase then decrease' (41%), (3) 'above target, moderate increase then decrease' (24%), and (4) 'well above target, large increase then decrease' (9%). Higher SDQ total difficulties scores predicted trajectories 3 and 4 (p=0.0002 and p<0.0001, respectively). Regarding the SDQ subscale scores, emotional symptoms predicted trajectories 3 and 4, and conduct problems and hyperactivity/inattention predicted trajectories 2, 3, and 4. Single-parent family and low caregiver education level both predicted trajectories 3 and 4. CONCLUSIONS: Caregiver SDQ responses and sociodemographic information may help detect children and adolescents with type 1 diabetes, who need intensive multidisciplinary medical and psychological interventions.

Associations between disordered eating behaviors and HbA1c in young people with type 1 diabetes: a systematic review and meta-analysis.

BACKGROUND: In type 1 diabetes, disordered eating behaviors (DEBs) can adversely impact HbA1c. Diabetes-adapted DEB questionnaires assess intentional insulin omission, whereas generic questionnaires do not. Given the number of studies describing DEB-HbA1c associations published over the past decade, an updated systematic review is warranted. OBJECTIVE: The study aimed to examine the associations between disordered eating behaviors (DEBs) assessed by generic and diabetes-adapted questionnaires (and subscales) and HbA1c among young people (<29 years) with type 1 diabetes. METHODS: A systematic search was conducted in PubMed, Embase, PsycInfo, and CINAHL databases. Observational studies examining associations between DEB as assessed by questionnaires and HbA1c were included. Publication information, DEB and HbA1c characteristics, and DEB-HbA1c associations were extracted. Hedges' g was calculated for mean HbA1c differences between groups with and without DEB. RESULTS: The systematic search yielded 733 reports, of which 39 reports representing 35 unique studies met the inclusion criteria. Nineteen studies assessing DEB by diabetes-adapted questionnaires (n=5,795) and seven using generic questionnaires (n=2,162) provided data for meta-analysis. For diabetes-adapted questionnaires, DEB was associated with higher HbA1c (g=0.62 CI=0.52; 0.73) with a similar effect size when restricted to validated questionnaires (g=0.61; CI=0.50; 0.73). DEB was not associated with HbA1c for generic questionnaires (g=0.19; CI=-0.17; 0.55), but significantly associated with higher HbA1c for validated generic questionnaires (g=0.32; 95% CI=0.16-0.48). Participant and HbA1c collection characteristics were often inadequately described. CONCLUSION: Diabetes-adapted DEB questionnaires should be used in youth with type 1 diabetes because they capture intentional insulin omission and are more strongly associated with HbA1c than generic DEB questionnaires.

Adherence in Diabetes Questionnaire (ADQ) score as predictor of 11-year HbA1c trajectories in children and adolescents with type 1 diabetes: A population-based longitudinal study.

AIMS: To identify 11-year HbA1c trajectories in children/adolescents with type 1 diabetes and determine whether baseline caregiver- and/or child/adolescent-reported Adherence in Diabetes Questionnaire (ADQ) scores and multiple covariates predict HbA1c trajectory membership. METHODS: For a 2009 population-based cohort of children/adolescents with type 1 diabetes, we analyzed HbA1c follow-up (2010-2020) data from Danish diabetes registries. HbA1c trajectories were identified with group-based trajectory modeling. Using multinomial logistic regression, we tested whether ADQ scores predicted trajectory membership when adjusting for sex, age at diabetes diagnosis, diabetes duration, family structure, and caregiver education. RESULTS: For 671 children/adolescents (10-17 years at baseline) with 5644 HbA1c observations over 11 years, four trajectories/groups were identified: 1) "on target, gradual decrease" (27%), 2) "above target, mild increase then decrease" (39%), 3) "above target, moderate increase then decrease" (25%), and 4) "well above target, large increase then decrease" (9%). Using group one as the reference, lower caregiver-reported ADQ scores predicted group 2, 3, and 4 membership. Lower child/adolescent-reported ADQ scores predicted group 3 and 4 membership. Low caregiver education predicted group 3 and 4 membership. Single-parent status predicted group 4 membership. CONCLUSIONS: ADQ scores and socio-demographics may serve as tools to predict glycemic control in youth with type 1 diabetes.

Effects of lifestyle intervention on IGF-1, IGFBP-3, and insulin resistance in children with obesity with or without metabolic-associated fatty liver disease.

Obesity is a strong predictor for metabolic associated fatty liver disease (MAFLD), which has been associated with decreased insulin like growth factor 1 (IGF-1). In obesity, weight loss increases growth hormone secretion, but this is not unequivocally associated with increases in serum IGF-1 and IGF binding protein-3 (IGFBP-3). We studied the changes in the IGF axis in relation to weight loss and improvement in insulin resistance in children with or without MALFD after 10 weeks of lifestyle intervention at a weight loss camp (WLC). We investigated 113 (66 females) Caucasian children with obesity, median age 12.4 (range 7.3-14.6) years, before and after 10 weeks of lifestyle intervention at a WLC. We investigated children who was either MAFLD positive (n = 54) or negative (n = 59) before and after WLC. Children with MAFLD had lower baseline IGF-1 (249 ± 112 vs 278 ± 107 µg/l, P = 0.048), whereas the IGF-1/IGFBP-3 molar ratio was similar to children without MAFLD (19.4 ± 6.6 vs. 21.8 ± 6.6%, P = 0.108). When all children were considered as one group, WLC decreased SDS-BMI and HOMA-IR (P < 0.001, both) and increased IGF-1 (264 ± 110 vs 285 ± 108 µg/l, P < 0.001) and the IGF/IGFBP-3 molar ratio (20.7 ± 6.7 vs 22.4 ± 6.1%, P < 0.001). When categorized according to liver status, IGF-1 increased significantly in children with MAFLD (P = 0.008) and tended to increase in children without MAFLD (P = 0.052).   Conclusions: Ten weeks of lifestyle intervention decreased insulin resistance and improved the IGF axis. We observed slight differences in the IGF axis in relation to MAFLD status. This suggests that the IGF axis is primarily influenced by insulin resistance rather than MAFLD status. What is New: • Weight loss decreases insulin resistance and subsequently increases the IGF axis in children with obesity. • Children with MAFLD had an aberration in the IGF axis compared to their MAFLD negative counter parts and the IGF axis was primarily influenced by the decreased BMI-SDS and insulin resistance, rather than MAFLD status. What is Known: • NAFLD has previously been associated with reduced serum IGF-1 concentrations. • Data on the impact of MAFLD and aberrations in the growth hormone and IGF axis and the effects of lifestyle interventions in children are limited.

Impact of the COVID-19 pandemic on long-term trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes: an international multicentre study based on data from 13 national diabetes registries.

BACKGROUND: An increased prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in children was observed in various diabetes centres worldwide during the COVID-19 pandemic. We aimed to evaluate trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes before and during the COVID-19 pandemic, and to identify potential predictors of changes in diabetic ketoacidosis prevalence during the pandemic. METHODS: For this international multicentre study, we used data from 13 national diabetes registries (Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA [Colorado], and Wales). The study population comprised 104 290 children and adolescents aged 6 months to younger than 18 years, who were diagnosed with type 1 diabetes between Jan 1, 2006, and Dec 31, 2021. The observed diabetic ketoacidosis prevalence in 2020 and 2021 was compared to predictions based on trends over the pre-pandemic years 2006-19. Associations between changes in diabetic ketoacidosis prevalence and the severity of the COVID-19 pandemic and containment measures were examined with excess all-cause mortality in the whole population and the Stringency Index from the Oxford COVID-19 Government Response Tracker. FINDINGS: 87 228 children and adolescents were diagnosed with type 1 diabetes between 2006 and 2019, 8209 were diagnosed in 2020, and 8853 were diagnosed in 2021. From 2006 to 2019, diabetic ketoacidosis at diagnosis of type 1 diabetes was present in 23 775 (27·3%) of 87 228 individuals and the mean annual increase in the prevalence of diabetic ketoacidosis in the total cohort from 2006 to 2019 was 1·6% (95% CI 1·3 to 1·9). The adjusted observed prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes was 39·4% (95% CI 34·0 to 45·6) in 2020 and 38·9% (33·6 to 45·0) in 2021, significantly higher than the predicted prevalence of 32·5% (27·8 to 37·9) for 2020 and 33·0% (28·3 to 38·5) for 2021 (p<0·0001 for both years). The prevalence of diabetic ketoacidosis was associated with the pandemic containment measures, with an estimated risk ratio of 1·037 (95% CI 1·024 to 1·051; p<0·0001) per ten-unit increase in the Stringency Index for 2020 and 1·028 (1·009 to 1·047; p=0·0033) for 2021, but was not significantly associated with excess all-cause mortality. INTERPRETATION: During the COVID-19 pandemic, there was a marked exacerbation of the pre-existing increase in diabetic ketoacidosis prevalence at diagnosis of type 1 diabetes in children. This finding highlights the need for early and timely diagnosis of type 1 diabetes in children and adolescents. FUNDING: German Federal Ministry for Education and Research, German Robert Koch Institute, German Diabetes Association, German Diabetes Foundation, Slovenian Research Agency, Welsh Government, Central Denmark Region, and Swedish Association of Local Authorities and Regions.

Increased prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes and hypertension: The SWEET international database.

AIMS: To investigate the prevalence of modifiable cardiovascular risk factors (CVRFs), including dyslipidaemia, obesity and high glycated haemoglobin (HbA1c) concentration, in patients with type 1 diabetes (T1D), and to evaluate their association with blood pressure (BP) categories. METHODS: We analysed 21 634 children and adolescents with T1D from the SWEET international database with office BP values assessed at a three or more visits within a year from 2010 to 2021. Participants were classified into a normotensive group, a group with elevated BP (90 to 94th percentile) or a hypertensive group (≥95th percentile), based on the median BP for the visits within the last treatment year. The prevalences of dyslipidaemia [cholesterol ≥ 5.18 mmol/L (200 mg/dL)  and/or HDL cholesterol ≤ 1.036 mmol/L (40 mg/dL)  and/or LDL cholesterol ≥ 2.59 mmol/L (100 mg/dL)], obesity (body mass index ≥2 standard deviation score) and elevated HbA1c [≥ 75 mmol/mol (9%)] were evaluated in patients within each BP group. RESULTS: Patients with hypertension/elevated BP had less favourable lipid profiles, and a higher prevalence of obesity and HbA1c ≥ 75 mmol/mol than normotensive patients. A total of 38.4% of hypertensive patients and 36.0% of those with elevated BP had one CVRF, 15.1% and 10.1%, respectively, had two CVRFs, and 2.3% and 0.8%, respectively, had three CVRFs. Patients with hypertension/elevated BP had a higher prevalence of one or more CVRFs versus normotensive patients (P < 0.001). Obesity was the CVRF most strongly related to hypertension. Girls had a higher prevalence of one or more CVRFs than boys. Similar results were found in patients aged ≥13 years with hypertension compared to those aged <13 years. CONCLUSIONS: The prevalence of modifiable CVRFs is higher in children and adolescents with T1D who have elevated BP/hypertension than in those with normotension, suggesting that they are more vulnerable to future morbidity and mortality requiring early detection and intervention.

Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). DESIGN: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. PATIENTS: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. MEASUREMENTS: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). RESULTS: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m2 /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R2 = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R2 = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2 /day for every 1 point increase in weight standard deviation score. DISCUSSION: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.

The Importance of Office Blood Pressure Measurement Frequency and Methodology in Evaluating the Prevalence of Hypertension in Children and Adolescents With Type 1 Diabetes: The SWEET International Database.

OBJECTIVE: The prevalence of hypertension is higher in children and adolescents with type 1 diabetes (T1D) compared with those without. This retrospective analysis of a large cohort of children and adolescents with T1D from the SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) international consortium of pediatric diabetes centers aimed to 1) estimate the prevalence of elevated office blood pressure (BP) and hypertension and 2) investigate the influence of BP measurement methodology on the prevalence of hypertension. RESEARCH DESIGN AND METHODS: A total of 27,120 individuals with T1D, aged 5-18 years, were analyzed. Participants were grouped into those with BP measurements at three or more visits (n = 10,440) and fewer than 3 visits (n = 16,680) per year and stratified by age and sex. A subgroup analysis was performed on 15,742 individuals from centers providing a score indicating BP measurement accuracy. RESULTS: Among participants with BP measurement at three or more visits, the prevalence of hypertension was lower compared with those with fewer than three visits (10.8% vs. 17.5% P < 0.001), whereas elevated BP and normotension were higher (17.5% and 71.7% vs. 15.3% and 67.1%, respectively; both P < 0.001). The prevalence of hypertension and elevated BP was higher in individuals aged ≥13 years than in younger ones (P < 0.001) and in male than female participants (P < 0.001). In linear regression models, systolic and diastolic BP was independently determined by the BP measurement methodology. CONCLUSIONS: The estimated prevalence of elevated BP and hypertension in children and adolescents with T1D is ∼30% and depends on the BP measurement methodology. Less frequent BP evaluation may overestimate the prevalence of hypertension.

Trajectory and predictors of HbA1c in children and adolescents with type 1 diabetes-A Danish nationwide cohort study.

OBJECTIVES: Poor glycemic control in type 1 diabetes increases the risk of chronic complications and it is essential to identify life periods and predictors associated with deteriorating HbA1c . The aim was to describe specific HbA1c trajectories in Danish children and adolescents with type 1 diabetes and study associations with clinical and sociodemographic factors. RESEARCH DESIGN AND METHODS: 5889 children with type 1 diabetes were included from the nationwide Danish Registry of Childhood and Adolescent Diabetes with annual visits during 1996-2019. Trajectories of HbA1c were modeled with linear mixed-effects models (using age as time scale, included as cubic spline) and with an individual-specific random intercept and slope. The following cofactors were included stepwise into the model: sex, age at diagnosis, calendar year, parental education, immigrant status, health care region, blood glucose monitoring (BGM) frequency, treatment modalities: continuous subcutaneous insulin infusion (pump) versus multiple daily insulin injection therapy (pen) and continuous glucose monitoring. RESULTS: HbA1c overall increased during age while there was a significant decreasing secular trend. Older age at diagnosis was associated with a steeper trajectory, and non-Danish origin and shorter parental education were each associated with higher levels of HbA1c across age. A lower BGM frequency was associated with a markedly poorer HbA1c trajectory, while no significant differences were shown for different treatment modalities. CONCLUSIONS: Glycemic outcome worsened with age during childhood and adolescence, which is of clinical concern. Important predictors for a poorer glycemic trajectory were later age at diabetes diagnosis, shorter parental education, non-Danish origin and, in particular low BGM frequency.

Overeating, binge eating, quality of life, emotional difficulties, and HbA1c in adolescents with type 1 diabetes: A Danish national survey.

AIMS: To determine 1) the prevalence of symptoms of overeating (OE), subclinical binge eating (SBE) and clinical binge eating (CBE), in adolescents with type 1 diabetes (T1D), and 2) their associations with quality of life (QoL), anxiety, depression, HbA1c, and body mass index standard deviation score (BMISDS). METHODS: In total 506 adolescents (age 12-17 years; mean 14.7 years; girls 49%) from the Danish Registry for Diabetes in Childhood and Adolescence (DanDiabKids) were included. Participants completed questionnaires on disordered eating, QoL, and emotional difficulties. A blood sample was sent for HbA1c determination. BMISDS was determined from the DanDiabKids data. RESULTS: Prevalence rates of OE, SBE, and CBE were 8.4%, 18% and 7.9% respectively. Youth with CBE symptoms scored lowest on generic and diabetes specific QoL, highest on anxiety and depression symptoms, and had a higher HbA1c. Youth with CBE had borderline increased BMISDS. CONCLUSIONS: In a Danish national survey of adolescents with T1D, approximately one-third of participants had overeating or binge eating symptoms, comparable with the numbers in a U.S T2D population. Increased binge eating symptoms associated with lower QoL, higher depression scores, higher anxiety scores, and poorer clinical outcomes. Binge eating symptoms were markers for poor mental and somatic health.

Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children With Congenital Adrenal Hyperplasia.

BACKGROUND: Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear. METHODS: Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC. RESULTS: A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P < 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (P = 0.43), respectively. CONCLUSIONS: The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.

Blood pressure measurement methodology and technology in the SWEET diabetes centers: An international SWEET database survey.

INTRODUCTION: The accuracy of blood pressure (BP) measurement is a prerequisite for the reliable diagnosis and management of hypertension. OBJECTIVES: This survey evaluated the use of office and out-of-office BP measurements and the antihypertensive pharmacological treatment in expert pediatric diabetes centers. METHODS: A questionnaire was distributed in 78 reference pediatric diabetes centers of the SWEET international consortium. The methodology, devices, indications, and interpretation of office BP measurements (OBPM), 24-hour ambulatory BP monitoring (ABPM) and home BP monitoring (HBPM), and the preference for antihypertensive drug treatment was assessed. A grading score was developed to evaluate centers for overall BP measurement performance. RESULTS: Fifty-two centers responded. The average score for OBPM methodology was 72.5%, for technology 77.5% and the overall center score was 74.75%.The majority of the centers used appropriate methodology and technology, however, there was heterogeneity among them. Manual auscultatory or automated devices specifically validated for children were used by 26/52 centers. ABPM was recommended by 35/52 centers (27/35 had health insurance coverage) and HBPM by 18/52 centers. The BP measurement methodology and devices used for ABPM and HBPM were frequently inadequate. Angiotensin converting enzyme inhibitors were the most frequently prescribed drugs for treating hypertension. CONCLUSIONS: The majority of SWEET pediatric diabetes centers use adequate methodology and devices for BP measurement. ABPM is recommended by two thirds of the centers, whereas HBPM is less widely used. Further improvement in the quality of office and out-of-office BP measurements and harmonization among centers is necessary according to current guidelines.

Temporal trends in diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes between 2006 and 2016: results from 13 countries in three continents.

AIMS/HYPOTHESIS: The aim of this work was to evaluate geographical variability and trends in the prevalence of diabetic ketoacidosis (DKA), between 2006 and 2016, at the diagnosis of childhood-onset type 1 diabetes in 13 countries over three continents. METHODS: An international retrospective study on DKA at diagnosis of diabetes was conducted. Data on age, sex, date of diabetes diagnosis, ethnic minority status and presence of DKA at diabetes onset were obtained from Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA and the UK (Wales). Mean prevalence was estimated for the entire period, both overall and by country, adjusted for sex and age group. Temporal trends in annual prevalence of DKA were estimated using logistic regression analysis for each country, before and after adjustment for sex, age group and ethnic minority status. RESULTS: During the study period, new-onset type 1 diabetes was diagnosed in 59,000 children (median age [interquartile range], 9.0 years [5.5-11.7]; male sex, 52.9%). The overall adjusted DKA prevalence was 29.9%, with the lowest prevalence in Sweden and Denmark and the highest in Luxembourg and Italy. The adjusted DKA prevalence significantly increased over time in Australia, Germany and the USA while it decreased in Italy. Preschool children, adolescents and children from ethnic minority groups were at highest risk of DKA at diabetes diagnosis in most countries. A significantly higher risk was also found for females in Denmark, Germany and Slovenia. CONCLUSIONS/INTERPRETATION: DKA prevalence at type 1 diabetes diagnosis varied considerably across countries, albeit it was generally high and showed a slight increase between 2006 and 2016. Increased awareness of symptoms to prevent delay in diagnosis is warranted, especially in preschool children, adolescents and children from ethnic minority groups.

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.

International benchmarking in type 1 diabetes: Large difference in childhood HbA1c between eight high-income countries but similar rise during adolescence-A quality registry study.

OBJECTIVES: To identify differences and similarities in HbA1c levels and patterns regarding age and gender in eight high-income countries. SUBJECTS: 66 071 children and adolescents below18 years of age with type 1 diabetes for at least 3 months and at least one HbA1c measurement during the study period. METHODS: Pediatric Diabetes Quality Registry data from Austria, Denmark, England, Germany, Norway, Sweden, the United States, and Wales were collected between 2013 and 2014. HbA1c, gender, age, and duration were used in the analysis. RESULTS: Distribution of gender and age groups was similar in the eight participating countries. The mean HbA1c varied from 60 to 73 mmol/mol (7.6%-8.8%) between the countries. The increase in HbA1c between the youngest (0-9 years) to the oldest (15-17 years) age group was close to 8 mmol/mol (0.7%) in all countries (P < .001). Females had a 1 mmol/mol (0.1%) higher mean HbA1c than boys (P < .001) in seven out of eight countries. CONCLUSIONS: In spite of large differences in the mean HbA1c between countries, a remarkable similarity in the increase of HbA1c from childhood to adolescence was found.

Screening for retinopathy in children with type 1 diabetes in Denmark.

BACKGROUND/OBJECTIVE: Children with type 1 diabetes (T1D) are screened regularly for retinopathy with fundus photography to prevent visual impairment. According to Danish national guidelines, screening should take place at age 12, 15, and 18 years after minimum 3 years of diabetes. As glycemic control has improved, prevalence of retinopathy is expected to be decreased. The aim of this study is to investigate the prevalence, degree, and progression of retinopathy in children with T1D and to explore if screening at 12 years is currently indicated in Denmark. METHODS: Data on all Danish children with onset of T1D from 2003 to 2013 (n = 2943) were collected from the "DanDiabKids" registry. For children with registered screenings (n = 2382), prevalence of retinopathy at 12, 15, and 18 years was determined. In children with retinopathy, subsequent screenings were studied to reveal if retinopathy was persistent or temporary. RESULTS: Prevalence of retinopathy at 12, 15, and 18 years was 0.9%, 2.3%, and 3.1%, respectively. Minimal background retinopathy was seen in over 90% and 100% at 12 years. In available re-screenings, retinopathy resolved spontaneously in 87.5% of all cases and 100% of cases at 12 years. CONCLUSIONS: The prevalence of retinopathy in Danish children with T1D was low. At 12 years, prevalence was 0.9% and exclusively minimal background retinopathy with 100% remission in re-screenings. Thus, screening at this age does not seem to have significant clinical relevance. We propose more individualized screening selection before the age of 15.

Geographical variation in the incidence of type 1 diabetes in the Nordic countries: A study within NordicDiabKids.

BACKGROUND: The incidence of type 1 diabetes (T1D) is high in the Nordic countries with geographic differences between as well as within countries. OBJECTIVE: To describe the geographical distribution of the incidence of T1D among children in four Nordic countries, an area where the population is considered genetically similar. METHODS: Data on children 0 to 14 years of age and diagnosed with T1D 2006 to 2011 was collected from four Nordic national pediatric quality diabetes registries. Data included year of diagnosis (2006-2011), sex, and age at diagnosis. Figures for number of children at risk during 2006 to 2011-as well as total population, proportion with foreign background and size of populated areas of geographic regions-were collected from official statistics. RESULTS: The total incidence during the study period for all four countries was 35.7/100 000 person years but differed between the countries (range 18.2-44.1; P < .001). The incidence difference between the countries was most obvious in the highest age group, 10 to 14 years of age, whereas there was no difference in the youngest age group 0 to 5 years of age. Iceland had similar incidence in the entire country, whereas the other countries had areas with different incidence. Densely populated areas, such as major cities, had the lowest incidence. CONCLUSION: The incidence of T1D differed between the Nordic countries and also between the neighboring countries and generally decreased with population density. This indicates that environmental factors may contribute to the level of incidence of T1D.

A placebo-controlled randomized study with testosterone in Klinefelter syndrome: beneficial effects on body composition.

CONTEXT AND OBJECTIVE: Males with Klinefelter syndrome (KS) are typically hypogonadal with a high incidence of metabolic disease, increased body fat and mortality. Testosterone treatment of hypogonadal patients decrease fat mass, increase lean body mass and improve insulin sensitivity, but whether this extends to patients with KS is presently unknown. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, BMI-matched cross-over study, 13 males with KS (age: 34.8 years; BMI: 26.7 kg/m2) received testosterone (Andriol®) 160 mg per day (testosterone) or placebo treatment for 6 months. Thirteen age- and BMI-matched healthy controls were recruited. DEXA scan, abdominal computed tomography (CT) scan and a hyperinsulinemic-euglycemic clamp, muscle strength and maximal oxygen uptake measurement were performed. RESULTS: Total lean body mass and body fat mass were comparable between testosterone-naïve KS and controls using DEXA, whereas visceral fat mass, total abdominal and intra-abdominal fat by CT was increased (P < 0.05). Testosterone decreased total body fat (P = 0.01) and abdominal fat by CT (P = 0.04). Glucose disposal was similar between testosterone-naïve KS and controls (P = 0.3) and unchanged during testosterone (P = 0.8). Free fatty acid suppression during the clamp was impaired in KS and maximal oxygen uptake was markedly lower in KS, but both were unaffected by treatment. Testosterone increased hemoglobin and IGF-I. CONCLUSION: Testosterone treatment in adult males with KS for 6 months leads to favorable changes in body composition with reductions in fat mass, including abdominal fat mass, but does not change measures of glucose homeostasis.

Proportion of Basal to Total Insulin Dose Is Associated with Metabolic Control, Body Mass Index, and Treatment Modality in Children with Type 1 Diabetes-A Cross-Sectional Study with Data from the International SWEET Registry.

OBJECTIVES: To investigate in a large population the proportion of daily basal insulin dose (BD) to daily total insulin dose (TD) (BD/TD) and its association with glycated hemoglobin A1c (HbA1c), body mass index (BMI)- SDS, and treatment modality in children with type 1 diabetes. STUDY DESIGN: Cross-sectional study in subjects with type 1 diabetes, age ≤18 years, and ≥2 years of diabetes duration, registered in the international multicenter Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference registry in March 2018. Variables included region, sex, age, diabetes duration, treatment modality (multiple daily injections [MDI] or continuous subcutaneous insulin infusion [CSII]), self-monitoring blood glucose, HbA1c, BD/TD, and BMI-SDS. BMI was converted to BMI-SDS using World Health Organization charts as reference. Hierarchic linear regression models were applied with adjustment for age, sex, and diabetes duration. RESULTS: A total of 19 687 children with type 1 diabetes (49% female, 49% CSII users) with median age 14.8 (11.5; 17.2) years and diabetes duration 6.0 (3.9; 9.0) years were included. HbA1c was 63 (55; 74) mmol/mol (7.9 [7.2; 8.9]%), and BMI-SDS 0.55 (-0.13; 1.21). Unadjusted, a lower BD/TD was associated with lower HbA1c, male sex, younger age, shorter diabetes duration, lower BMI-SDS, higher numbers of self-monitoring blood glucose and CSII (all P < .01). After adjustment for confounders, lower BD/TD was associated with lower HbA1c (P < .01) and lower BMI-SDS (P < .01) in children on CSII, but not on MDI. CONCLUSIONS: Lower BD/TD is positively associated with lower HbA1c and lower BMI-SDS in children with type 1 diabetes on CSII. It remains to be investigated in a prospective study whether reducing BD/TD insulin will improve metabolic control and normalize body weight in children with type 1 diabetes.