Glycated hemoglobin A1c as a risk factor for severe hypoglycemia in pediatric type 1 diabetes.

OBJECTIVE: To assess the risk of severe hypoglycemia related to glycated hemoglobin A1c (HbA1c) levels in a population-based cohort of pediatric type 1 diabetes patients during two time periods since 1995. METHODS: The association between HbA1c levels and severe hypoglycemia (defined as requiring assistance from another person) or hypoglycemic coma (loss of consciousness or seizures) was analyzed by multivariable regression analysis in children and adolescents with type 1 diabetes from the DPV Diabetes Prospective Follow-up in Germany and Austria in 1995-2003 (n = 15 221 patients) and 2004-2012 (n = 22 318 patients). RESULTS: Mean adjusted rates of severe hypoglycemia and hypoglycemic coma decreased from 19.18 [95% confidence interval (CI), 17.95-20.48] and 4.36 (3.93-4.83) per 100 patient-years in 1995-2003 to 15.01 (14.18-15.88) and 2.15 (1.94-2.39) in 2004-2012, respectively (p < 0.001). From the first to the second period, the relative risk (RR) for severe hypoglycemia and hypoglycemic coma per 1% lower HbA1c decreased from 1.22 (1.15-1.30) to 1.06 (1.01-1.12) and from 1.27 (1.15-1.40) to 1.04 (0.94-1.16), respectively. Risk of severe hypoglycemia and coma declined most in patients with HbA1c levels of 6-6.9% (RR 0.70 and 0.43, respectively) and with HbA1c of 7-7.9% (RR 0.63 and 0.38, respectively). Mean HbA1c levels fell from 8.4% in 1995-2003 to 8.2% in 2004-2012, while the use of insulin pumps, short- and long-acting insulin analogs, and glucose monitoring increased (p < 0.001). CONCLUSIONS: In contrast to 1995-2003, low HbA1c has become a minor risk factor for severe hypoglycemia and coma in pediatric patients with type 1 diabetes in the 2004-2012 period.

Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus - A randomized clinical trial.

It is unknown if cholecalciferol is able to modify defects in regulatory T cells (Tregs) in type 1 diabetes (T1D). In this randomized, double-blind, placebo controlled trial 30 young patients with new-onset T1D were assigned to cholecalciferol (70IU/kgbodyweight/day) or placebo for 12months. Tregs were determined by FACS-analysis and functional tests were assessed with ex vivo suppression co-cultures at months 0, 3, 6 and 12. Suppressive capacity of Tregs increased (p<0.001) with cholecalciferol from baseline (-1.59±25.6%) to 3 (30.5±39.4%), 6 (44.6±23.8%) and 12months (37.2±25.0%) and change of suppression capacity from baseline to 12months was significantly higher (p<0.05) with cholecalciferol (22.2±47.2%) than placebo (-16.6±21.1%). Serum calcium and parathormone stayed within normal range. This is the first study, which showed that cholecalciferol improved suppressor function of Tregs in patients with T1D and vitamin D could serve as one possible agent in the development of immunomodulatory combination therapies for T1D.

Comparison of BMI and HbA1c changes before and during the COVID-19 pandemic in type 1 diabetes: a longitudinal population-based study.

Purpose: To compare the changes in body weight and glycemic control before and during the COVID-19 pandemic in people with type 1 diabetes (T1D). Methods: In 47,065 individuals with T1D from the German Diabetes Prospective Follow-up Registry (DPV), we compared the adjusted mean changes in BMI-Z-scores and HbA1c as well as the distribution of individual changes between four periods from March 2018 to February 2022, by sex and age group (4- < 11, 11- < 16, 16-50 years). Results: At population level, the only significant pandemic effects were a slight increase in BMI Z-score in prepubertal children (girls: + 0.03 in the first COVID year vs. before, P < 0.01; boys: + 0.04, P < 0.01) as well as a stabilization of HbA1c in all subgroups or even improvement in women (- 0.08%, P < 0.01). At individual level, however, heterogeneity increased significantly (p < 0.01), especially in children. More prepubertal children gained weight (girls: 45% vs. 35% before COVID; boys: 39% vs. 33%). More pubertal girls lost weight (30% vs. 21%) and fewer gained weight (43% vs. 54%). More children had a decreasing HbA1c (prepubertal group: 29% vs. 22%; pubertal girls: 33% vs. 28%; pubertal boys: 32% vs. 25%) and fewer had increasing values. More women had stable HbA1c and fewer had increasing values (30% vs. 37%). In men, no significant changes were observed. Conclusion: This real-world analysis shows no detrimental consequences of the two first COVID years on weight and HbA1c in T1D on average, but reveals, beyond the mean trends, a greater variability at the individual level.

Continuous glucose monitoring versus blood glucose monitoring for risk of severe hypoglycaemia and diabetic ketoacidosis in children, adolescents, and young adults with type 1 diabetes: a population-based study.

BACKGROUND: The effect of continuous glucose monitoring on the risk of severe hypoglycaemia and ketoacidosis in patients with diabetes is unclear. We investigated whether rates of acute diabetes complications are lower with continuous glucose monitoring, compared with blood glucose monitoring, and which metrics predict its risk in young patients with type 1 diabetes. METHODS: In this population-based cohort study, patients were identified from 511 diabetes centres across Austria, Germany, Luxembourg, and Switzerland participating in the Diabetes Prospective Follow-up initiative. We included people with type 1 diabetes aged 1·5-25·0 years, with a diabetes duration of more than 1 year, who had been treated between Jan 1, 2014, and June 30, 2021, and had an observation time of longer than 120 days in the most recent treatment year. Severe hypoglycaemia and ketoacidosis rates during the most recent treatment year were examined in people using continuous glucose monitoring and in those using blood glucose monitoring. Adjustments of statistical models included age, sex, diabetes duration, migration background, insulin therapy (pump or injections), and treatment period. Rates of severe hypoglycaemia and diabetic ketoacidosis were evaluated by several continuous glucose monitoring metrics, including percentage of time below target glucose range (<3·9 mmol/L), glycaemic variability (measured as the coefficient of variation), and mean sensor glucose. FINDINGS: Of 32 117 people with type 1 diabetes (median age 16·8 years [IQR 13·3-18·1], 17 056 [53·1%] males), 10 883 used continuous glucose monitoring (median 289 days per year), and 21 234 used blood glucose monitoring. People using continuous glucose monitoring had lower rates of severe hypoglycaemia than those using blood glucose monitoring (6·74 [95% CI 5·90-7·69] per 100 patient-years vs 8·84 [8·09-9·66] per 100 patient-years; incidence rate ratio 0·76 [95% CI 0·64-0·91]; p=0·0017) and diabetic ketoacidosis (3·72 [3·32-4·18] per 100 patient-years vs 7·29 [6·83-7·78] per 100 patient-years; 0·51 [0·44-0·59]; p<0·0001). Severe hypoglycaemia rates increased with percentage of time below target glucose range (incidence rate ratio 1·69 [95% CI 1·18-2·43]; p=0·0024, for 4·0-7·9% vs <4·0% and 2·38 [1·51-3·76]; p<0·0001, for ≥8·0% vs <4·0%) and glycaemic variability (coefficient of variation ≥36% vs <36%; incidence rate ratio 1·52 [95% CI 1·06-2·17]; p=0·022). Diabetic ketoacidosis rates increased with mean sensor glucose (incidence rate ratio 1·77 [95% CI 0·89-3·51], p=0·13, for 8·3-9·9 mmol/L vs <8·3 mmol/L; 3·56 [1·83-6·93], p<0·0001, for 10·0-11·6 mmol/L vs <8·3 mmol/L; and 8·66 [4·48-16·75], p<0·0001, for ≥11·7 mmol/L vs <8·3 mmol/L). INTERPRETATION: These findings provide evidence that continuous glucose monitoring can reduce severe hypoglycaemia and ketoacidosis risk in young people with type 1 diabetes on insulin therapy. Continuous glucose monitoring metrics might help to identify those at risk for acute diabetes complications. FUNDING: German Center for Diabetes Research, German Federal Ministry of Education and Research, German Diabetes Association, and Robert Koch Institute.

Prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes in Austria.

Mortality of cardiovascular diseases in patients with type 1 diabetes is increased 2- to 20-fold compared to non-diabetic individuals. In young adults with type 1 diabetes, cardiovascular events are more often the cause of premature death than nephropathy. The aim of this study was to evaluate the prevalence and extent of cardiovascular risk factors in children and adolescents with type 1 diabetes in Austria. In a cross sectional study data of children with type 1 diabetes <18 years of age treated at the Children's department of the University Hospitals of Vienna and Graz were collected. We recorded body mass index, waist circumference, blood pressure, HbA1c, triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol according to age, sex, age at manifestation, diabetes duration, and insulin requirement. From 264 patients (49.4% male) complete data were available. Of all patients, 76.1% had one or more risk factors, 20.8% had two or more, 10.2% had three or more, and 4.9% had four or more risk factors. Insufficient glycemic control was the most frequent risk factor, present in 60.6% of our patients, followed by elevated triglycerides (22.7%) and increased body mass index (20.1%). Higher prevalence of risk factors was correlated with increasing age, diabetes duration, HbA1c, and insulin requirement. In conclusion, children and adolescents with type 1 diabetes have a much higher prevalence of cardiovascular risk factors compared to non-diabetic individuals. To prevent future cardiovascular events, achieving the best possible glycemic control, early detection of further risk factors, and adequate intervention are highly important.

Transatlantic Comparison of Pediatric Continuous Glucose Monitoring Use in the Diabetes-Patienten-Verlaufsdokumentation Initiative and Type 1 Diabetes Exchange Quality Improvement Collaborative.

Achieving glycemic targets in youth and young adults with type 1 diabetes (T1D) is challenging. Diabetes devices, including continuous glucose monitors (CGM) may impact glycemic control. We analyzed the proportion of CGM use in youth and young adults with T1D at nine U.S. T1D Exchange Quality Improvement (T1DX-QI) Collaborative centers and 402 European diabetes prospective follow-up registry (Diabetes-Patienten-Verlaufsdokumentation [DPV]) sites from 2017 to 2020 and examined the association of CGM use to glycemic control as measured by hemoglobin A1c (HbA1c). CGM use increased each year from 2017 to 2020 across all age ranges (<6, 6-<12, 12-<18, 18-<25 years) in both registries and lower mean HbA1c was observed in CGM users compared with nonusers regardless of insulin delivery method for all years analyzed. CGM use appeared to increase more so in the European DPV than the U.S. T1DX-QI, which may be due to transatlantic differences in health care systems, insurance coverage, and prescriber habits.

The Role of Protein and Fat Intake on Insulin Therapy in Glycaemic Control of Paediatric Type 1 Diabetes: A Systematic Review and Research Gaps.

Carbohydrate counting (CHC) is the established form of calculating bolus insulin for meals in children with type 1 diabetes (T1DM). With the widespread use of continuous glucose monitoring (CGM) observation time has become gapless. Recently, the impact of fat, protein and not only carbohydrates on prolonged postprandial hyperglycaemia have become more evident to patients and health-care professionals alike. However, there is no unified recommendation on how to calculate and best administer additional bolus insulin for these two macronutrients. The aim of this review is to investigate: the scientific evidence of how dietary fat and protein influence postprandial glucose levels; current recommendations on the adjustment of bolus insulin; and algorithms for insulin application in children with T1DM. A PubMed search for all articles addressing the role of fat and protein in paediatric (sub-)populations (<18 years old) and a mixed age population (paediatric and adult) with T1DM published in the last 10 years was performed. Conclusion: Only a small number of studies with a very low number of participants and high degree of heterogeneity was identified. While all studies concluded that additional bolus insulin for (high) fat and (high) protein is necessary, no consensus on when dietary fat and/or protein should be taken into calculation and no unified algorithm for insulin therapy in this context exists. A prolonged postprandial observation time is necessary to improve individual metabolic control. Further studies focusing on a stratified paediatric population to create a safe and effective algorithm, taking fat and protein into account, are necessary.

Longitudinal trajectories of BMI z-score: an international comparison of 11,513 Australian, American and German/Austrian/Luxembourgian youth with type 1 diabetes.

BACKGROUND: BMI fluctuations during puberty are common. Data on individual change in BMI from childhood to young adulthood are limited in youth with type 1 diabetes. OBJECTIVES: To compare longitudinal trajectories of body mass index z score (BMIz) from childhood to adolescence across three registries spanning five countries. METHODS: Data sources: T1DX (USA), DPV (Germany/Austria/Luxembourg) and ADDN (Australia). The analysis included 11,513 youth with type 1 diabetes, duration >1 year, at least one BMI measure at baseline (age 8-10 years) and >5 aggregated BMI measures by year of age during follow-up until age 17 years. BMIz was calculated based on WHO charts. Latent class growth modelling was used to identify subgroups following a similar trajectory of BMIz over time. RESULTS: Five distinct trajectories of BMIz were present in the T1DX and ADDN cohorts, while six trajectories were identified in the DPV cohort. Boys followed more often a low/near-normal pattern while elevated BMIz curves were more likely in girls (ADDN; DPV). For T1DX cohort, no sex differences were observed. Comparing the reference group (BMIz ~0) with the other groups during puberty, higher BMIz was significantly associated with older age at T1D onset, racial/ethnic minority and elevated HbA1c (all p<0.05). CONCLUSION: This multinational study presents unique BMIz trajectories in youth with T1D across three continents. The prevalence of overweight and the longitudinal persistence of overweight support the need for close monitoring of weight and nutrition in this population. The international and individual differences likely result from diverse genetic, environmental and therapeutic factors.

Diabetes care in pediatric refugees from Africa or Middle East: experiences from Germany and Austria based on real-world data from the DPV registry.

OBJECTIVE: With increasing migration to Europe, diabetes diagnosis and treatment of refugees became challenging. To describe the current experience with pediatric refugees in Germany and Austria. DESIGN AND METHODS: 43,137 patients (<21 years) with type 1 diabetes from the diabetes patient follow-up registry (DPV) were studied and divided by refugee status into patients born in Middle East (n = 365) or Africa (n = 175) and native patients (child and parents born in Germany/Austria; G/A: n = 42,597). Groups were compared using multivariable regression adjusted for age, sex and diabetes duration (SAS 9.4). In refugees the first year after arrival was studied, and for native children the most recent year of care. RESULTS: After adjustment, HbA1c was highest in refugees (1. ME and 2. AFR vs 3. G/A: 72.3 ± 1.0 and 75.0 ± 1.4 vs 66.0 ± 0.1 mmol/mol, 1 vs 3: P < 0.001 and 2 vs 3: P < 0.001) and microalbuminuria (9.9 and 13.6 vs 6.5%, 1 vs 3: P = 0.039 and 2 vs 3: P = 0.002) was more prevalent. African children experienced severe hypoglycemia (17.8 ± 4.3 and 25.4 ± 8.7 vs 11.5 ± 0.3 per 100 patient years, 1 vs 3: P > 0.05 and 2 vs 3: P = 0.045) significantly more often, whereas hypoglycemia with coma (5.1 ± 1.1 and 4.1 ± 1.6 vs 2.6 ± 0.1 per 100 patient years, 1 vs 3: P = 0.006 and 2 vs 3: P > 0.05) and retinopathy (2.1 and n/a vs 0.2%, 1 vs 3: P < 0.001) were significantly more common in children from Middle East compared to natives. Insulin pumps were used in a markedly larger proportion of native patients (7.4 and 13.2 vs 43.0%, 1 vs 3: P < 0.001 and 2 vs 3: P < 0.001). CONCLUSIONS: A relevant number of pediatric refugees with type 1 diabetes are treated in German/Austrian diabetes clinics. Refugee children, parents and caregivers are faced with several problems in diabetes therapy and outcome that should be addressed more intensively by pediatric diabetes teams.

Seasonal Variation in Blood Pressure in 162,135 Patients With Type 1 or Type 2 Diabetes Mellitus.

Seasonal variation in blood pressure (BP) has been observed in different populations. However, only few studies have focused on BP seasonality in diabetic patients. This study examined the seasonal patterns in BP in 62,589 patients with type 1 diabetes mellitus (T1DM) and in 99,546 patients with type 2 diabetes mellitus (T2DM) from the German/Austrian Diabetes Follow-up Registry. Adjusted mean BP values revealed seasonal cycles of 12 months, with higher BP in colder months. Using harmonic regression models, the estimated systolic BP difference throughout the year was 2.28/2.48 mm Hg in T1DM/T2DM (both P<.001). Interestingly, seasonal variation in diastolic BP was larger in T1DM than in T2DM (1.24/0.64 mm Hg, P<.001). A sex difference was observed in T1DM only, while age differences occurred in both types of diabetes. Correlations between BP and potentially related factors such as outdoor temperature indicated that reasons underlying BP seasonality are likely to be complex and vary by subgroup.

Rates of diabetic ketoacidosis: international comparison with 49,859 pediatric patients with type 1 diabetes from England, Wales, the U.S., Austria, and Germany.

OBJECTIVE: Diabetic ketoacidosis (DKA) in children and adolescents with established type 1 diabetes is a major problem with considerable morbidity, mortality, and associated costs to patients, families, and health care systems. We analyzed data from three multinational type 1 diabetes registries/audits with similarly advanced, yet differing, health care systems with an aim to identify factors associated with DKA admissions. RESEARCH DESIGN AND METHODS: Data from 49,859 individuals <18 years with type 1 diabetes duration ≥1 year from the Prospective Diabetes Follow-up Registry (DPV) initiative (n = 22,397, Austria and Germany), the National Paediatric Diabetes Audit (NPDA; n = 16,314, England and Wales), and the T1D Exchange (T1DX; n = 11,148, U.S.) were included. DKA was defined as ≥1 hospitalization for hyperglycemia with a pH <7.3 during the prior year. Data were analyzed using multivariable logistic regression models. RESULTS: The frequency of DKA was 5.0% in DPV, 6.4% in NPDA, and 7.1% in T1DX, with differences persisting after demographic adjustment (P < 0.0001). In multivariable analyses, higher odds of DKA were found in females (odds ratio [OR] 1.23, 99% CI 1.10-1.37), ethnic minorities (OR 1.27, 99% CI 1.11-1.44), and HbA1c ≥7.5% (≥58 mmol/mol) (OR 2.54, 99% CI 2.09-3.09 for HbA1c from 7.5 to <9% [58 to <75 mmol/mol] and OR 8.74, 99% CI 7.18-10.63 for HbA1c ≥9.0% [≥75 mmol/mol]). CONCLUSIONS: These multinational data demonstrate high rates of DKA in childhood type 1 diabetes across three registries/audits and five nations. Females, ethnic minorities, and HbA1c above target were all associated with an increased risk of DKA. Targeted DKA prevention programs could result in substantial health care cost reduction and reduced patient morbidity and mortality.