First year national Swedish paediatric Hba1c data are at the level of several intervention studies: Results from a Swedish nationwide diabetes register study.

AIMS/HYPOTHESIS: To study the progression of HbA1c after diagnosis of type 1 diabetes in children and adolescents during 2010-2019 with emphasis on HbA1c nadir 3-6 months after onset. METHODS: Partial funding was secured for this study. The Swedish paediatric diabetes quality register SWEDIABKIDS has >95 % coverage of type 1 diabetes up to 18 years. A mixed model for repeated measurements was used to estimate differences in HbA1c between onset year periods. RESULTS: We followed 6,891 patients over two years from onset (48,292 HbA1c values). We found a gradual decrease in mean HbA1c 24 months after onset from 56.0 mmol/mol (7.28 %) in 2010/11 to 50.5 mmol/mol (6.77 %) in 2018/19, which is at the level of several recent intervention studies. The initial drop in HbA1c from onset until 3 and 6 months has become more pronounced in recent years. There was a significant positive correlation between HbA1c at 3 and 6 months with 12, 18 and 24 months. Percentage of severe hypoglycaemic coma was higher (5.1 % vs 3.4 %; p = 0.023) in 2010/2011 than 2018/2019, but the absolute risk of ketoacidosis was essentially unchanged, (1.5 % to 0.8 %, p = 0.110) CONCLUSIONS/INTERPRETATION: There was a continuous decrease in HbA1c over the study period 2010-2019, which coincides in time with an increased use of diabetes technology and lowering the HbA1c target to 48 mmol/mol (6.5 %). The decrease in 2-year HbA1c was preceded by a lower HbA1c nadir, which may set the trajectories for coming HbA1c and be a modifiable factor for a long-term improvement in metabolic control.

Automated Insulin Delivery Systems in Pediatric Type 1 Diabetes: A Narrative Review.

This narrative review assesses the use of automated insulin delivery (AID) systems in managing persons with type 1 diabetes (PWD) in the pediatric population. It outlines current research, the differences between various AID systems currently on the market and the challenges faced, and discusses potential opportunities for further advancements within this field. Furthermore, the narrative review includes various expert opinions on how different AID systems can be used in the event of challenges with rapidly changing insulin requirements. These include examples, such as during illness with increased or decreased insulin requirements and during physical activity of different intensities or durations. Case descriptions give examples of scenarios with added user-initiated actions depending on the type of AID system used. The authors also discuss how another AID system could have been used in these situations.

Current Management of Type 1 Diabetes in Children: Guideline-based Expert Opinions and Recommendations

Successful management of type 1 diabetes (T1D) requires not only optimal glycemic outcomes, but also a holistic approach that encompasses all aspects of life and recommendations to address needs. Current goals include optimal glycemic values, quality of life and life expectancy similar to peers, prevention of long-term complications, prevention of severe hypoglycemia as far as possible and facilitation of glucose management. The International Society for Pediatric and Adolescent Diabetes (ISPAD) has been updating its guidelines for diabetes care every four years since 1995, covering more and more topics. For optimal metabolic outcomes, diabetes teams need to follow these current recommendations, adapt them to their clinical practice and provide guidance to people with T1D and their families. In this review, in the light of ISPAD 2018-2022 guidelines and clinical experiences, "10 Key Recommendations", emphasizing the importance of teamwork and the use of technology, current T1D treatment is described for practical applications.

Relative poverty is associated with increased risk of diabetic ketoacidosis at onset of type 1 diabetes in children. A Swedish national population-based study in 2014-2019.

AIMS: The aim of the study was to estimate the effect of household relative poverty on the risk of diabetic ketoacidosis at diagnosis of children with type 1 diabetes using an international standard measurement of relative poverty. METHODS: A national population-based retrospective study was conducted. The Swedish National Diabetes Register (NDR) was linked with data from Sweden's public statistical agency (Statistics Sweden). Children who were diagnosed with new-onset type 1 diabetes in the period of 2014-2019 were common identifiers. The definition of diabetic ketoacidosis was venous pH <7.30 or a serum bicarbonate level <18 mmol/L. The exposure variable was defined according to the standard definition of the persistent at-risk-of-poverty rate used by the statistical office of the European Union (Eurostat) and several other European public statistical agencies. Univariate and multi-variable analyses were used to calculate the effect of relative poverty on the risk of diabetic ketoacidosis. RESULTS: Children from households with relative poverty had a 41% higher risk of diabetic ketoacidosis (1.41, CI 1.12-1.77, p = 0.004) and more than double the risk of severe diabetic ketoacidosis (pH <7.10) (RR 2.10, CI 1.35-3.25, p = 0.001), as compared to children from households without relative poverty. CONCLUSIONS: Relative poverty significantly increases the risk of diabetic ketoacidosis at onset of type 1 diabetes in children, even in a high-income country with publicly reimbursed health care.

Autoimmune comorbidity in type 1 diabetes and its association with metabolic control and mortality risk in young people: a population-based study.

AIMS/HYPOTHESIS: This register-based study aimed to describe autoimmune comorbidity in children and young adults from type 1 diabetes onset, and to investigate whether such comorbidity was associated with a difference in HbA1c or mortality risk compared with children/young adults with type 1 diabetes without autoimmune comorbidity. METHODS: A total of 15,188 individuals from the Swedish National Diabetes Register, registered with type 1 diabetes before 18 years of age between 2000 and 2019, were included. Five randomly selected control individuals from the Swedish population (Statistics Sweden) were matched to each individual with type 1 diabetes (n=74,210 [346 individuals with type 1 diabetes were not found in the Statistics Sweden register at the date of type 1 diabetes diagnosis, so could not be matched to control individuals]). The National Patient Register was used to attain ICD-10 codes on autoimmune diseases and the Cause of Death Register was used to identify deceased individuals. RESULTS: In the total type 1 diabetes cohort, mean±SD age at onset of type 1 diabetes was 9.5±4.4 years and mean disease duration at end of follow-up was 8.8±5.7 years. Of the individuals with type 1 diabetes, 19.2% were diagnosed with at least one autoimmune disease vs 4.0% of the control group. The HRs for comorbidities within 19 years from onset of type 1 diabetes were 11.6 (95% CI 10.6, 12.6) for coeliac disease, 10.6 (95% CI 9.6, 11.8) for thyroid disease, 1.3 (95% CI 1.1, 1.6) for psoriasis, 4.1 (95% CI 3.2, 5.3) for vitiligo, 1.7 (95% CI 1.4, 2.2) for rheumatic joint disease, 1.0 (95% CI 0.8, 1.3) for inflammatory bowel disease, 1.0 (95% CI 0.7, 1.2) for systemic connective tissue disorder, 1.4 (95% CI 1.1, 1.9) for uveitis, 18.3 (95% CI 8.4, 40.0) for Addison's disease, 1.8 (95% CI 0.9, 3.6) for multiple sclerosis, 3.7 (95% CI 1.6, 8.7) for inflammatory liver disease and 19.6 (95% CI 4.2, 92.3) for atrophic gastritis. Autoimmune disease in addition to type 1 diabetes had no statistically significant effect on HbA1c or mortality risk. CONCLUSIONS/INTERPRETATION: To our knowledge, this is the first comprehensive study where young individuals with type 1 diabetes were followed regarding development of a wide spectrum of autoimmune diseases, from onset of type 1 diabetes. In this nationwide and population-based study, there was already a high prevalence of autoimmune diseases in childhood, especially coeliac and thyroid disease. The presence of autoimmune comorbidity did not have a statistically significant effect on metabolic control or mortality risk.

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.

Intralymphatic GAD-Alum (Diamyd®) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2.

AIMS: Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). METHODS: DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 µg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. RESULTS: We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. CONCLUSIONS: Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

Insulin pump therapy is associated with higher rates of mild diabetic ketoacidosis compared to injection therapy: A 2-year Swedish national survey of children and adolescents with type 1 diabetes.

OBJECTIVES: Diabetic ketoacidosis (DKA) in type 1 diabetes (T1D) can occur during both insulin pump therapy (continuous subcutaneous insulin infusion, CSII) and insulin injection therapy (multiple daily injections, MDI). The primary aim of this study was to compare CSII and MDI regarding DKA frequency. A secondary aim was to compare metabolic derangement between CSII and MDI at hospital admission for DKA. RESEARCH DESIGN AND METHODS: Children 0-17.99 years with established T1D admitted for DKA in Sweden from February 1, 2015 to January 31, 2017 were invited to participate. Data regarding demographics, laboratory data, CSII or MDI, and access to ketone meters and CGM were provided through questionnaires and medical records. The Swedish National Diabetes Registry (SWEDIABKIDS) was used to compare the distribution of CSII and MDI in the national population with the population admitted for DKA, using the chi-square goodness-of-fit test. Distribution of CSII and MDI was then categorized in clinical severity grades for mild (pH 7.20-7.29), moderate (pH 7.10-7.29) and severe DKA (pH <7.10). RESULTS: The distribution of CSII at DKA admission was significantly larger than in the national pediatric population with T1D (74.7% vs. 59.7%, p = 0.002). CSII was overrepresented in mild DKA (85.2% vs. with CSII, p < 0.001), but not in moderate/severe DKA (57.9% with CSII, p = 0.82). Mean HbA1c at hospital admission was 73.9 mmol/mol with CSII and 102.7 mmol/mol with MDI. CONCLUSIONS: CSII was associated with higher risk of mild DKA than MDI. MDI was associated with markedly higher HbA1c levels than CSII at hospital admission for DKA.

A Lifestyle Intervention During Pregnancy and Its Effects on Child Weight 2.5 Years Later.

AIM: The aim of this study was to evaluate if overweight and obesity in the offspring is reduced by a low-intensity antenatal primary care intervention with focus on diet and physical activity for pregnant women with obesity, comparing children to mothers receiving the intervention with children to mothers who did not. METHODS: This study is a follow-up of children 2.5 years of age after their mothers' participation in a non-randomised controlled intervention intending to limit gestational weight gain. All study participants received standard antenatal care. The intervention group received lifestyle support via motivational talks with midwife and support from dietician. Data on child weight were collected by medical records, letter and phone. RESULTS: There was no significant difference between the groups 2.5 years after intervention (International Obesity Task Force ISO-BMI 25 (child BMI corresponding to adult BMI of 25): 20% vs. 21%; ISO-BMI 30: 4.6% vs. 1.3%). The mother's BMI at the beginning of pregnancy significantly influenced child BMI at 2.5 years (r = 0.13, p = 0.014, r2 = 0.017). For each unit of increase in maternal BMI at enrollment, the probability of child ISO-BMI ≥ 25 increased by 7.5% (p = 0.021) and of ≥ 30, by 12.9% (p = 0.017). CONCLUSION: The frequency of overweight and obesity of the children at 2.5 years of age was significantly correlated to the mother's BMI, but not correlated to the mothers' participation in the antenatal lifestyle intervention. Thus, it seems important to address obesity and lifestyle issues before and between pregnancies. Trial registration The study has been registered at ClinicalTrials.gov, Identifier: NCT03147079.

Hemoglobin A1c trajectories in the first 18 months after diabetes diagnosis in the SWEET diabetes registry.

AIM: A majority of youth with type 1 diabetes do not meet recommended hemoglobin A1c (HbA1c) targets. The SWEET diabetes registry is a multi-national registry of youth with diabetes. We used data from this registry to identify characteristics associated with glycemic control. METHODS: Patients in the SWEET diabetes registry with at least one HbA1c value within 10 days of diagnosis and three follow up measurements in the first 18 months of diagnosis were included (~10% of the SWEET diabetes registry). Locally weighted scatterplot smoothing was used to generate curves of HbA1c. Wilcoxon, Kruskal-Wallis, or χ2-tests were used to calculate differences between groups. RESULTS: The mean HbA1c of youth in the SWEET diabetes registry is highest at diagnosis and lowest between months 4 and 5 post-diabetes diagnosis. HbA1c continues to increase steadily through the first 18 months of diagnosis. There are no differences in HbA1c trajectories based on sex or use of diabetes technology. Youth in North America/Australia/New Zealand had the highest HbA1c throughout the first 18 months of diagnosis. The trajectory of youth from countries with nationalized health insurance was lower than those countries without nationalized health insurance. Youth from countries with the highest gross domestic product (GDP) had the highest HbA1c throughout the first 18 months of diagnosis. CONCLUSIONS: In this subset of patients, the trajectory of youth from countries with nationalized health insurance was lower than those countries without nationalized health insurance. High GDP and high use of technology did not seem to protect from a higher trajectory.

Changes in HbA1c Between 2011 and 2017 in Germany/Austria, Sweden, and the United States: A Lifespan Perspective.

Aims: This study assessed hemoglobin A1c (HbA1c) across the lifespan in people with type 1 diabetes (T1D) in Germany/Austria, Sweden, and the United States between 2011 and 2017 to ascertain temporal and age-related trends. Methods: Data from the Diabetes-Patienten-Verlaufsdokumentation (DPV) (n = 25,651 in 2011, n = 29,442 in 2017); Swedish Pediatric Diabetes Quality Registry (SWEDIABKIDS)/National Diabetes Register (NDR), (n = 44,474 in 2011, n = 53,690 in 2017); and T1D Exchange (n = 16,198 in 2011, n = 17,087 in 2017) registries were analyzed by linear regression to compare mean HbA1c overall and by age group. Results: Controlling for age, sex, and T1D duration, HbA1c increased in the United States between 2011 and 2017, decreased in Sweden, and did not change in Germany/Austria. Controlling for sex and T1D duration, mean HbA1c decreased between 2011 and 2017 in all age cohorts in Sweden (P < 0.001). In the United States, HbA1c stayed the same for participants <6 years and 45 to <65 years and increased in all other age groups (P < 0.05). In Germany/Austria, HbA1c stayed the same for participants <6 to <13 years and 18 to <25 years; decreased for participants ages 13 to <18 years (P < 0.01); and increased for participants ≥25 years (P < 0.05). Conclusions: The comparison of international trends in HbA1c makes it possible to identify differences, explore underlying causes, and share quality improvement processes. National quality improvement initiatives are well accepted in Europe but have yet to be implemented systematically in the United States. However, disparities created by the lack of universal access to health care coverage, unequal access to diabetes technologies (e.g., continuous glucose monitoring) regardless of insurance status, and high out-of-pocket cost for the underinsured ultimately limit the potential of quality improvement initiatives.

Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial.

OBJECTIVE: To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup. RESEARCH DESIGN AND METHODS: In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12-24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7-193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 µg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months. RESULTS: Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845-1.408]; P = 0.5009). However, GAD-alum-treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126-2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose-adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported. CONCLUSION: Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

Delayed referral is common even when new-onset diabetes is suspected in children. A Swedish prospective observational study of diabetic ketoacidosis at onset of Type 1 diabetes.

OBJECTIVE: Delayed treatment for new-onset diabetes Type 1 (T1D) can lead to diabetic ketoacidosis (DKA) with potentially devastating consequences. This prospective observational study aimed to characterize pediatric patients with DKA at hospital admission, regarding parental awareness of diabetes-related symptoms and delayed referrals from primary health care providers to pediatric emergency wards. RESEARCH DESIGN AND METHODS: Patients 0-18 years admitted to hospital with new-onset T1D and DKA between 2015 and 2017 were invited to participate. Questionnaires were filled out separately by the caregivers and by the attending hospital staff. Data from the Swedish National Diabetes Registry (SWEDIABKIDS) were used for comparison. Delayed referral was defined as a primary healthcare contact due to diabetes-related symptoms 0-4 weeks before hospital admission without immediate referral, or registered elevated glucose levels at primary healthcare centers without immediate referral. RESULTS: The study included 237 patients, among which parental suspicion of new-onset diabetes before healthcare contacts was reported in 39%. Parental suspicion of diabetes was associated with higher pH values at diagnosis. Patients in contact with primary health care providers before hospital admission had a delayed referral in 43% of the cases. Delayed referral was associated with lower pH values at hospital admission. Symptoms leading to primary healthcare contacts were similar regardless of whether delay occurred or not. CONCLUSIONS: Parental suspicion of diabetes was associated with milder DKA at hospital admission. Delayed referral was seen in a considerable proportion of children with primary healthcare contacts for symptoms associated with diabetes. Increased awareness of diabetes symptoms is of paramount importance.

Combined Etanercept, GAD-alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes.

AIM: We aimed to study the feasibility and tolerability of a combination therapy consisting of glutamic acid decarboxylase (GAD-alum), Etanercept and vitamin D in children and adolescents with newly diagnosed with type 1 diabetes (T1D), and evaluate preservation of beta cell function. MATERIAL AND METHODS: Etanercept Diamyd Combination Regimen is an open-labelled multi-centre study pilot trial which enrolled 20 GAD antibodies positive T1D patients (7 girls and 13 boys), aged (mean ±SD): 12.4 ± 2.3 (8.3-16.1) years, with a diabetes duration of 81.4 ± 22.1 days. Baseline fasting C-peptide was 0.24 ± 0.1 (0.10-0.35) nmol/l. The patients received Day 1-450 Vitamin D (Calciferol) 2000 U/d per os, Etanercept sc Day 1-90 0.8 mg/kg once a week and GAD-alum sc injections (20 µg, Diamyd™) Day 30 and 60. They were followed for 30 months. RESULTS: No treatment related serious adverse events were observed. After 6 months 90-min stimulated C-peptide had improved in 8/20 patients and C-peptide area under the curve (AUC) after Mixed Meal Tolerance Test in 5 patients, but declined thereafter, while HbA1c and insulin requirement remained close to baseline. Administration of Etanercept did not reduce tumour necrosis factor (TNF) spontaneous secretion from peripheral blood mononuclear cells, but rather GAD65-induced TNF-α increased. Spontaneous interleukin-17a secretion increased after the administration of Etanercept, and GAD65-induced cytokines and chemokines were also enhanced following 1 month of Etanercept administration. CONCLUSIONS: Combination therapy with parallel treatment with GAD-alum, Etanercept and vitamin D in children and adolescents with type 1 diabetes was feasible and tolerable but had no beneficial effects on the autoimmune process or beta cell function.

Combined vitamin D, ibuprofen and glutamic acid decarboxylase-alum treatment in recent onset Type I diabetes: lessons from the DIABGAD randomized pilot trial.

AIM: Double-blind placebo-controlled intervention using glutamic acid decarboxylase (GAD)-alum, vitamin D and Ibuprofen in recent onset Type I diabetes (T1D). METHODS: 64 patients (T1D since <4 months, age 10-17.99, fasting sC-peptide ≥0.12 nmol/l, GADA-positive) were randomized into Day(D) 1-90 400 mg/day Ibuprofen, D1-450 vitamin D 2000 IU/day, D15, 45 sc. 20 µg GAD-alum; as A but placebo instead of Ibuprofen; as B but 40 µg GAD-alum D15, 45; placebo. RESULTS: Treatment was safe and tolerable. No C-peptide preservation was observed. We observed a linear correlation of baseline C-peptide, HbA1c and insulin/per kilogram/24 h with change in C-peptide AUC at 15 months (r = -0.776, p < 0.0001). CONCLUSION: Ibuprofen, vitamin D + GAD-alum did not preserve C-peptide. Treatment efficacy was influenced by baseline clinical and immunological factors and vitamin D concentration. Clinical Trial Registration: NCT01785108 (ClinicalTrials.gov).

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.

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.

Is Age a Risk Factor for Cerebral Edema in Children With Diabetic Ketoacidosis? A Literature Review.

Cerebral edema (CE) is a rare but potentially fatal complication of diabetic ketoacidosis (DKA) in children with type 1 diabetes. CE is frequently mentioned as being more common in young children. The primary objective of this study was to review the evidence suggesting that younger age is a risk factor for the development of CE during DKA. The secondary objective was to assess if younger children are at a higher risk of DKA and severe DKA. A literature review was performed, and studies which reported the frequency of CE, DKA and severe DKA in children <3 and 3 to 5 years of age were included. Among the 6 studies reporting the frequency of CE that were identified, 5 good-quality studies found no significant association between younger age and higher risk of CE. Twenty-seven studies (DKA frequency: 11.3% to 54%) reported DKA frequency as a function of age. Most published studies found a higher frequency of DKA in children <5 years of age (20/25 studies), and in particular in those in the first 2 to 3 years of life (8/8 studies). There was inconclusive evidence to determine whether the severity of DKA was influenced by age. In conclusion, the commonly held view that CE is more common in younger children is not supported by the existing literature. Published data suggest that DKA (and possibly severe DKA) is more common in very young children. Regardless of age, all children with DKA should be monitored carefully for the development of CE.