Publications by authors named "Katrin Nagl"

15 Publications

  • Page 1 of 1

Randomized Trial of Closed-Loop Control in Very Young Children with Type 1 Diabetes.

N Engl J Med 2022 01;386(3):209-219

From the Wellcome Trust-Medical Research Council (MRC) Institute of Metabolic Science (J.W., J.M.A., C.K.B., M.E.W., R.H.) and the Department of Paediatrics (J.W., M.E.W., A.T., R.H.), University of Cambridge, and the Wolfson Diabetes and Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust (S.H.), Cambridge, the Department of Paediatric Diabetes, Leeds Children's Hospital, Leeds (F.M.C., J.Y.), and Usher Institute, University of Edinburgh, Edinburgh (J.L.) - all in the United Kingdom; Diabetes and Endocrine Care Clinique Pédiatrique, Clinique Pédiatrique, Centre Hospitalier de Luxembourg, Luxembourg (C.B., U.S.); the Department of Pediatric Endocrinology, Universitair Ziekenhuis Brussel-Vrije Universiteit Brussel, Brussels (C.B.); the Department of Pediatric and Adolescent Medicine (E.F.-R.), and the Division of Endocrinology and Diabetology, Department of Internal Medicine (J.K.M.), Medical University of Graz, Graz, the Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna (B.R.-M., M.T., K.N.), and the Department of Pediatrics I, Medical University of Innsbruck, Innsbruck (S.E.H.) - all in Austria; the Hospital for Children and Adolescents, University of Leipzig, Leipzig, and the Hospital for Children and Adolescents "am Nicolausholz," Bad Kösen - both in Germany (T.M.K.); the Division of Pediatric Endocrinology, Stanford University, Stanford, CA (K.K.H.); Vyoo Agency, Lyon, France (S.R.); and the Jaeb Center for Health Research, Tampa, FL (J.S., L.E.B., C.K.).

Background: The possible advantage of hybrid closed-loop therapy (i.e., artificial pancreas) over sensor-augmented pump therapy in very young children with type 1 diabetes is unclear.

Methods: In this multicenter, randomized, crossover trial, we recruited children 1 to 7 years of age with type 1 diabetes who were receiving insulin-pump therapy at seven centers across Austria, Germany, Luxembourg, and the United Kingdom. Participants received treatment in two 16-week periods, in random order, in which the closed-loop system was compared with sensor-augmented pump therapy (control). The primary end point was the between-treatment difference in the percentage of time that the sensor glucose measurement was in the target range (70 to 180 mg per deciliter) during each 16-week period. The analysis was conducted according to the intention-to-treat principle. Key secondary end points included the percentage of time spent in a hyperglycemic state (glucose level, >180 mg per deciliter), the glycated hemoglobin level, the mean sensor glucose level, and the percentage of time spent in a hypoglycemic state (glucose level, <70 mg per deciliter). Safety was assessed.

Results: A total of 74 participants underwent randomization. The mean (±SD) age of the participants was 5.6±1.6 years, and the baseline glycated hemoglobin level was 7.3±0.7%. The percentage of time with the glucose level in the target range was 8.7 percentage points (95% confidence interval [CI], 7.4 to 9.9) higher during the closed-loop period than during the control period (P<0.001). The mean adjusted difference (closed-loop minus control) in the percentage of time spent in a hyperglycemic state was -8.5 percentage points (95% CI, -9.9 to -7.1), the difference in the glycated hemoglobin level was -0.4 percentage points (95% CI, -0.5 to -0.3), and the difference in the mean sensor glucose level was -12.3 mg per deciliter (95% CI, -14.8 to -9.8) (P<0.001 for all comparisons). The time spent in a hypoglycemic state was similar with the two treatments (P = 0.74). The median time spent in the closed-loop mode was 95% (interquartile range, 92 to 97) over the 16-week closed-loop period. One serious adverse event of severe hypoglycemia occurred during the closed-loop period. One serious adverse event that was deemed to be unrelated to treatment occurred.

Conclusions: A hybrid closed-loop system significantly improved glycemic control in very young children with type 1 diabetes, without increasing the time spent in hypoglycemia. (Funded by the European Commission and others; number, NCT03784027.).
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January 2022

Psychological Well-Being of Parents of Very Young Children With Type 1 Diabetes - Baseline Assessment.

Front Endocrinol (Lausanne) 2021 12;12:721028. Epub 2021 Aug 12.

Wellcome Trust-Medical Research Council (MRC) Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.

Background: Type 1 diabetes in young children is a heavy parental burden. As part of pilot phase of the KIDSAP01 study, we conducted a baseline assessment in parents to study the association between hypoglycemia fear, parental well-being and child behavior.

Methods: All parents were invited to fill in baseline questionnaires: hypoglycemia fear survey (HFS), WHO-5, Epworth Sleepiness Scale and Strength and Difficulties Questionnaire (SDQ).

Results: 24 children (median age: 5-year, range 1-7 years, 63% male, mean diabetes duration: 3 ± 1.7 years) participated. 23/24 parents filled out the questionnaires. We found a higher score for the hypoglycemia fear behavior 33.9 ± 5.6 compared to hypoglycemia worry 34.6 ± 12.2. Median WHO-5 score was 16 (8 - 22) with poor well-being in two parents. Median daytime sleepiness score was high in five parents (>10). For six children a high total behavioral difficulty score (>16) was reported. Pro social behavior score was lower than normal in six children (<6). Parental well-being was negatively associated with HFS total ( = - 0.50, <.05) and subscale scores ( = - 0.44, <.05 for HFS-Worry and HFS-Behavior), child behavior ( = - 0.45, = .05) and positively with child age and diabetes duration ( = 0.58, <.01, = 0.6, <.01). HFS, parental well-being nor daytime sleepiness are associated with the HbA1c.

Conclusion: Regular screening of parental well-being, hypoglycemia fear and child behavior should be part of routine care to target early intervention.
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August 2021

Glycemic Outcome Associated With Insulin Pump and Glucose Sensor Use in Children and Adolescents With Type 1 Diabetes. Data From the International Pediatric Registry SWEET.

Diabetes Care 2021 05 2;44(5):1176-1184. Epub 2021 Mar 2.

The Department of Paediatrics and Endocrinology, Cork University Hospital, Cork, Ireland.

Objective: Insulin delivery methods, glucose-monitoring modalities, and related outcomes were examined in a large, international, diverse cohort of children and adolescents with type 1 diabetes from the Better Control in Pediatric and Adolescent Diabetes: Working to Create Centers of Reference (SWEET) -Registry.

Research Design And Methods: Participants with type 1 diabetes of ≥1 year, aged ≤18 years, and who had documented pump or sensor usage during the period August 2017-July 2019 were stratified into four categories: injections-no sensor (referent); injections + sensor; pump-no sensor; and pump + sensor. HbA and proportion of patients with diabetic ketoacidosis (DKA) or severe hypoglycemia (SH) were analyzed; linear and logistic regression models adjusted for demographics, region, and gross domestic product per capita were applied.

Results: Data of 25,654 participants were analyzed. The proportions of participants (adjusted HbA data) by study group were as follows: injections-no sensor group, 37.44% (8.72; 95% CI 8.68-8.75); injections + sensor group, 14.98% (8.30; 95% CI 8.25-8.35); pump-no sensor group, 17.22% (8.07; 95% CI 8.03-8.12); and pump + sensor group, 30.35% (7.81; 95% CI 7.77-7.84). HbA was lower in all categories of participants who used a pump and/or sensor compared with the injections-no sensor treatment method ( < 0.001). The proportion of DKA episodes was lower in participants in the pump + sensor (1.98%; 95% CI 1.64-2.48; < 0.001) and the pump-no sensor (2.02%; 95% CI 1.64-2.48; < 0.05) groups when compared with those in the injections-no sensor group (2.91%; 95% CI 2.59-3.31). The proportion of participants experiencing SH was lower in pump-no sensor group (1.10%; 95% CI 0.85-1.43; < 0.001) but higher in the injections + sensor group (4.25%; 95% CI 3.65-4.95; < 0.001) compared with the injections-no sensor group (2.35%; 95% CI 2.04-2.71).

Conclusions: Lower HbA and fewer DKA episodes were observed in participants using either a pump or continuous glucose monitoring (CGM) or both. Pump use was associated with a lower rate of SH. Across SWEET centers, use of pumps and CGM is increasing. The concomitant use of pump and CGM was associated with an additive benefit.
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May 2021

Early versus delayed insulin pump therapy in children with newly diagnosed type 1 diabetes: results from the multicentre, prospective diabetes follow-up DPV registry.

Lancet Child Adolesc Health 2021 01 27;5(1):17-25. Epub 2020 Nov 27.

ZIBMT, Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany; German Center for Diabetes Research, Munich, Germany.

Background: Although continuous subcutaneous insulin infusion therapy (ie, insulin pump therapy) is associated with improved metabolic control compared with multiple daily insulin injections in children with type 1 diabetes, it is unclear when it is best to start it after diagnosis. In this study, we aimed to compare the outcomes between early and delayed start of insulin pump therapy in young patients with type 1 diabetes.

Methods: We based the current study on data from the multicentre, prospective diabetes follow-up registry (ie, Diabetes-Patienten-Verlaufsdokumentation [DPV]). The DPV registry comprises 501 diabetes centres from Germany, Austria, Switzerland, and Luxembourg. We included patients diagnosed with type 1 diabetes between 2004 and 2014, who were aged between 6 months and 15 years at the time of diagnosis, who had started insulin pump therapy either within the first 6 months (ie, the early treatment group) or in the second to third year (ie, the delayed treatment group) after diabetes diagnosis, and who were treated with insulin pump therapy for at least 1 year. The outcome parameters included the glycated haemoglobin (HbA) values, the cardiovascular risk profile, and rates of acute complications and diabetes-associated hospital admissions (ie, hospitalisation) during the most recent documented treatment year with insulin pump therapy. Statistical models were adjusted for age at diabetes diagnosis, year of diagnosis, sex, immigrant background, use of continuous glucose monitoring, centre size, and the German Index of Socioeconomic Deprivation 2012 terciles.

Findings: Our study sample comprised 8332 patients from 311 diabetes centres in Germany, Austria, Switzerland, and Luxembourg. The early treatment group consisted of 4004 (48·1%) of 8332 patients, and the delayed treatment group consisted of 4328 (51·9%). The median diabetes duration during follow-up was 6·7 years (IQR 5·1-8·7 in the early group; 5·0-8·7 in the delayed group) in both groups. Patients with early initiation of insulin pump therapy compared with those with delayed initiation of insulin pump therapy had significantly lower estimated mean HbA values (7·9% [95% CI 7·8-7·9] and 62·6 mmol/mol [95% CI 62·1-63·2] vs 8·0% [8·0-8·1] and 64·1 mmol/mol [63·6-64·6]; p=0·0006), and lower rates of hypoglycaemic coma (incidence risk ratio 0·44 [95% CI 0·24-0·79]; p=0·0064) and hospitalisation (0·86 [95% CI 0·78-0·94]; p=0·0016). A better cardiovascular risk profile was observed in patients with early initiation of insulin pump therapy than in those with delayed initiation: an estimated mean systolic blood pressure of 117·6 mm Hg (95% CI 117·2-117·9) versus 118·5 mm Hg (118·2-118·9), p=0·0007; and HDL cholesterol of 62·8 mg/dL (95% CI 62·2-63·5) versus 60·6 mg/dL (60·0-61·2), p<0·0001; however, diastolic blood pressure; concentrations of LDL cholesterol, non-HDL cholesterol, and triglycerides; and estimated body-mass index standard deviation scores during follow-up did not differ significantly between both groups.

Interpretation: Our findings provide evidence for improved clinical outcomes associated with the early initiation of insulin pump therapy in children with type 1 diabetes.

Funding: The German Center for Diabetes Research (Deutsches Zentrum für Diabetesforschung), German Robert Koch Institute, German Diabetes Association, and Diabetes Agenda 2010.
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January 2021

Performance of three different continuous glucose monitoring systems in children with type 1 diabetes during a diabetes summer camp.

Pediatr Diabetes 2021 03 4;22(2):271-278. Epub 2020 Dec 4.

Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria.

The aim of this study was to assess accuracy of the three most commonly used continuous glucose monitoring (CGM) systems in almost real-life situation during a diabetes camp in children with type 1 diabetes (T1D) aged 9-14 years. Data was gathered during a 2-week summer camp under physicians' supervision. Out of 38 participating children with T1D (aged: 11.0 [9.9; 12.1] years; 57% girls, mean HbA1c 7.2 [6.9; 7.7] %,) 37 wore a CGM system (either Abbott FreeStyle Libre (FSL), Dexcom G6 (DEX) or Medtronic Enlite (ENL)) throughout the camp. All concomitantly available data pairs of capillary glucose measurements and sensor values were used for the analysis. Mean absolute relative difference (MARD) was calculated and Parkes Error Grid analyses were done for all three systems used. In total 2079 data pairs were available for analysis. The overall MARDs of CGM systems used at the camp was FSL: 13.3% (6.7;21.6). DEX: 10.3% (5.8; 16.7) and ENL 8.5% (3.6; 15.6). During eu-, hypo- and hyperglycemia MARDs were lowest in ENL. Highest MARDs were seen in hypoglycemia, where all three systems exhibited MARDs above 15%. Overnight MARDs of all systems was higher than during daytime. All sensors performed worst in hypoglycemia. Performance of the adequately calibrated Medtronic system outperformed the factory-calibrated sensors. For clinical practice, it is important to adequately train children with T1D and families in the correct procedures for sensors that require calibrations.
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March 2021

A Cyanotic Newborn with a Pink Right Upper Extremity.

Case Rep Pediatr 2020 29;2020:8873156. Epub 2020 Jun 29.

Division of Pediatric Cardiology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Aberrant origin of the subclavian artery (SCA) is a well-known vascular anomaly as part of congenital heart diseases with the left subclavian artery (LSCA) being more frequently affected than the right subclavian artery (RSCA). Complete isolation of the SCA is an even more infrequent aortic arch anomaly, occurring in less than 1% for the LSCA and even less for the RSCA. Isolation of the RSCA in patients with d-transposition of the great arteries (D-TGA) is even scanter with only a hand full of cases being reported in the literature. However, isolation of the RSCA has important implications on hemodynamics and surgical strategies. In this case report, we present a newborn patient with D-TGA which presented with distinct differential cyanosis. While the right upper extremity appeared pink with an oxygen saturation of 100%, the rest of the body was cyanotic. At first, this appearance was interpreted as the Harlequin phenomenon during primary care. However, detailed echocardiography revealed an aberrant origin of the RSCA from the right pulmonary artery, which led to the differential cyanosis. The patient underwent arterial switch operation on day of life two including dissection and reimplantation of the RSCA. The special hemodynamic situation of this is discussed in terms of pathophysiology and as well as its impact on perioperative and surgical management.
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June 2020

Children with onset-ketoacidosis are admitted to the nearest hospital available, regardless of center size.

J Pediatr Endocrinol Metab 2020 May 24;33(6):751-759. Epub 2020 May 24.

German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany.

Background To investigate longitudinal trends of admissions with diabetic ketoacidosis (DKA) in new-onset type 1 diabetes (T1D) and subsequent duration of hospitalization in association with structural health care properties, such as size of treatment facility, population density and linear distance between home and treatment centers. Methods Data from 24,321 German and Austrian pediatric patients with newly-diagnosed T1D between 2008 and 2017 within the DPV registry were analyzed. Results Onset-DKA rates fluctuated at around 19% and slightly increased over the observation period (p<0.001). Compared to children without onset-DKA, children with onset-DKA were more frequently treated at centers located closer to their homes, independent of center size or urbanity. Annual median duration of hospitalization decreased from 13.1 (12.6;13.6) to 12.7 (12.3;13.2) days (p<0.001). It was highest in patients younger than 5 years, with migration background, and in severe DKA. Conclusion Patients with onset-DKA are admitted to the nearest hospital, independent of center size. Facilities close to patients' homes therefore play an important role in the acute management of T1D onset. In Germany and Austria, diabetes education at diagnosis is mainly performed in inpatient settings. This is reflected by a long duration of hospitalization, which has decreased only slightly over the past decade.
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May 2020

Lower HbA1c in patients with type 1 diabetes and celiac disease who reached celiac-specific antibody-negativity-A multicenter DPV analysis.

Pediatr Diabetes 2019 12 26;20(8):1100-1109. Epub 2019 Aug 26.

Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany.

Objectives: To study celiac-specific antibody status over 3 years in patients with type 1 diabetes and biopsy-proven celiac disease (T1D + CD). Furthermore, to determine clinical differences after diagnosis between patients reaching constant antibody-negativity (Ab-neg) and staying antibody-positive (Ab-pos).

Methods: A total of 608 pediatric T1D + CD patients from the multicenter DPV registry were studied longitudinally regarding their CD specific antibody-status. Differences between Ab-neg (n = 218) and Ab-pos (n = 158) patients 3 years after biopsy were assessed and compared with 26 833 T1D patients without CD by linear and logistic regression adjusted for age, gender, diabetes duration and migration background.

Results: Thirty-six percent of T1D + CD patients reached and sustained antibody-negativity 3 years after CD diagnosis. The median time until patients returned to Ab-neg was 0.86 (0.51;1.16) years. Three years after diagnosis, HbA1c was lowest in Ab-neg and highest in Ab-pos patients compared to T1D-only patients (adjusted mean (95%CI): 7.72 (7.51-7.92) % vs 8.44 (8.20-8.68) % vs 8.19 (8.17-8.21) %, adjusted P < 0.001, respectively). Total cholesterol, LDL-cholesterol and frequency of dyslipidemia were significantly lower in Ab-neg compared to T1D-only patients (167 (161-173) mg/dl vs 179 (178-179) mg/dl, P < .001; 90 (84-96) mg/dl vs 99 (98-99) mg/dl, P = .005; 15.7 (10.5-22.9) % vs 25.9 (25.2-26.6) %, P = .017). In longitudinal analyses over 6 years after diagnosis, a constantly higher HbA1c (P < .001) and a lower height-SDS (P = .044) was observed in Ab-pos compared to Ab-neg patients.

Conclusion: Only one third of T1D + CD patients reached constant Ab-negativity after CD diagnosis. Achieving Ab-negativity after diagnosis seems to be associated with better metabolic control and growth, supposedly due to a higher adherence to therapy in general.
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December 2019

Reduced burden of diabetes and improved quality of life: Experiences from unrestricted day-and-night hybrid closed-loop use in very young children with type 1 diabetes.

Pediatr Diabetes 2019 09 13;20(6):794-799. Epub 2019 Jun 13.

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Objective: To evaluate the experiences of families with very young children aged 1 to 7 years (inclusive) with type 1 diabetes using day-and-night hybrid closed-loop insulin delivery.

Methods: Parents/caregivers of 20 children aged 1 to 7 years with type 1 diabetes completed a closed-loop experience survey following two 3-week periods of unrestricted day-and-night hybrid closed-loop insulin therapy using Cambridge FlorenceM system at home. Benefits, limitations, and improvements of closed-loop technology were explored.

Results: Responders reported reduced burden of diabetes management, less time spent managing diabetes, and improved quality of sleep with closed-loop. Ninety percent of the responders felt less worried about their child's glucose control using closed-loop. Size of study devices, battery performance and connectivity issues were identified as areas for improvement. Parents/caregivers wished for more options to input information to the system such as temporary glucose targets.

Conclusions: Parents/caregivers of very young children reported important quality of life benefits associated with using closed-loop, supporting adoption of this technology in this population.
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September 2019

Home Use of Day-and-Night Hybrid Closed-Loop Insulin Delivery in Very Young Children: A Multicenter, 3-Week, Randomized Trial.

Diabetes Care 2019 04 28;42(4):594-600. Epub 2019 Jan 28.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Objective: We aimed to assess the feasibility and safety of hybrid closed-loop insulin delivery in children with type 1 diabetes aged 1-7 years as well as evaluate the role of diluted insulin on glucose control.

Research Design And Methods: In an open-label, multicenter, multinational, randomized crossover study, 24 children with type 1 diabetes on insulin pump therapy (median age 5 years [interquartile range 3-6] and mean ± SD HbA 7.4 ± 0.7% [57 ± 8 mmol/mol] and total insulin 13.2 ± 4.8 units/day) underwent two 21-day periods of unrestricted living and we compared hybrid closed-loop with diluted insulin (U20) and hybrid closed-loop with standard strength insulin (U100) in random order. During both interventions, the Cambridge model predictive control algorithm was used.

Results: The proportion of time that sensor glucose was in the target range between 3.9 and 10 mmol/L (primary end point) was not different between interventions (mean ± SD 72 ± 8% vs. 70 ± 7% for closed-loop with diluted insulin vs. closed-loop with standard insulin, respectively; = 0.16). There was no difference in mean glucose levels (8.0 ± 0.8 vs. 8.2 ± 0.6 mmol/L; = 0.14), glucose variability (SD of sensor glucose 3.1 ± 0.5 vs. 3.2 ± 0.4 mmol/L; = 0.16), or the proportion of time spent with sensor glucose <3.9 mmol/L (4.5 ± 1.7% vs. 4.7 ± 1.4%; = 0.47) or <2.8 mmol/L (0.6 ± 0.5% vs. 0.6 ± 0.4%; > 0.99). Total daily insulin delivery did not differ (17.3 ± 5.6 vs. 18.9 ± 6.9 units/day; = 0.07). No closed-loop-related severe hypoglycemia or ketoacidosis occurred.

Conclusions: Unrestricted home use of day-and-night closed-loop in very young children with type 1 diabetes is feasible and safe. The use of diluted insulin during closed-loop does not provide additional benefits compared with standard strength insulin.
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April 2019

Factors contributing to partial remission in type 1 diabetes: analysis based on the insulin dose-adjusted HbA1c in 3657 children and adolescents from Germany and Austria.

Pediatr Diabetes 2017 Sep 15;18(6):428-434. Epub 2016 Jul 15.

Epidemiology and Medical Biometry, University of Ulm, Germany.

Objective: Insulin dose-adjusted hemoglobin A1c (HbA1C, IDAA1c) correlates well with stimulated C-peptide levels, but has not yet been evaluated in a large cohort of patients with Type 1 diabetes (T1D).

Methods: We investigated prevalence of partial remission (PREM) defined by IDAA1c ≤9 in 3657 in children with new-onset T1D who were continuously followed over 6 years. We evaluated the predictors of PREM using the multicenter database from the DPV (Diabetes Patienten Verlaufsdokumentation) registry.

Results: PREM occurred in 71% of patients. Median duration was 9 (0-21) months. Compared to children <5 years at T1D onset, those aged 5-10 and ≥10 years had twice the chance of developing PREM (OR: 2.08, CI: 1.67-2.60; P < .001 and OR: 2.16, CI: 1.70-2.75; P < .001). Boys were more likely to develop PREM than girls (OR 1.41, CI: 1.18-1.69; P = .0002). Further predictors for PREM were: ketoacidosis, autoantibodies, and HbA1c at T1D onset. These results were confirmed by quantile regression analysis with duration of PREM as dependent variable.

Conclusion: This research on a large cohort provides insight into epidemiologic characteristics of PREM in T1D defined by IDAA1c. As IDAA1c does not discriminate between insulin sensitivity and secretion, available data cannot resolve whether the sex-difference in PREM reflects innate higher insulin resistance in girls, or better beta-cell recovery in boys. Further research is needed to clarify the usefulness and performance of IDAA1c in clinical practice.
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September 2017

Leptin but not adiponectin is related to type 2 diabetes mellitus in obese adolescents.

Pediatr Diabetes 2016 06 16;17(4):281-8. Epub 2015 Apr 16.

Institute of Epidemiology and Medical Biometry, ZIBMT, German Center for Diabetes Research (DZD), University of Ulm, Ulm, Germany.

Background: Adipokines have been suggested to be involved in the development of type 2 diabetes mellitus (T2DM). However, studies in humans are controversial and analyzes at the onset of disease are scarce.

Methods: We compared adiponectin and leptin levels between 74 predominately Caucasian adolescents with T2DM and 74 body mass index (BMI)-, age-, and gender-matched controls without T2DM. Adiponectin and leptin were correlated to age, BMI, hemoglobin A1c (HbA1c), blood pressure, and lipids.

Results: Adolescents with T2DM showed significant lower leptin levels as compared with controls (18 ± 12 vs. 37 ± 23 ng/mL, p < 0.001), whereas the adiponectin levels did not differ between the adolescents with and without T2DM (5.0 ± 2.5 vs. 4.9 ± 2.5 µg/mL, p = 0.833). The associations between adiponectin and high-density lipoprotein (HDL) cholesterol (r = 0.42), systolic (r = -0.15), and diastolic blood pressure (r = -0.20) were stronger as the associations of leptin to these parameters (all r < 0.07). In multiple linear regression analysis, leptin was significantly and positively associated with BMI [β-coefficient: 1.3 (95% confidence interval (95% CI): ±0.5), p < 0.001] and female sex [β-coefficient: 9.7 (95% CI: ±6.7), p = 0.005], and negatively with age [β-coefficient: -2.3 (95% CI: ±2.1), p < 0.001] and HbA1c [β-coefficient -3.1 (95% CI: ±2.1), p = 0.011]. Adiponectin was not significantly associated with BMI, HbA1c, age, or gender in multiple linear regression analysis.

Conclusions: Because adiponectin levels did not differ between obese adolescents with and without T2DM, hypoadiponectinemia as observed in obesity seems not to be involved in the genesis of T2DM. The relative hypoleptinemia in obese adolescents with T2DM as compared with obese adolescents without T2DM may contribute to the development of T2DM. Future longitudinal studies in humans are necessary to prove this hypothesis.
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June 2016

Gender, metabolic control and carotid intima-media-thickness in children and adolescents with type 1 diabetes mellitus.

Wien Klin Wochenschr 2015 Feb 21;127(3-4):116-23. Epub 2014 Nov 21.

Department of Medicine II, Division of Angiology, Medical University & General Hospital Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria,

Background: Despite a marked improvement in the overall prognosis of patients with type 1 diabetes mellitus (T1DM), cardiovascular morbidity/mortality is still increased. Since cellular and microvascular aberrations have been demonstrated already in children with T1DM, albeit a good glycemic control (CO), we hypothesized that early macrovascular changes can be detected by common carotid artery intima-media thickness (CCA-IMT).

Methods: We included 73 children/adolescents with T1DM (34 boys, 39 girls; mean age, 14.8 ± 2 years) and 243 sex- and age-matched healthy CO. In T1DM mean HbA1c was 7.9 ± 1.1 rel.%, and duration of disease 7.5 ± 3.1 years. High-resolution ultrasonography was used to assess CCA-IMT, defined as the mean of 24 measurements of the near and far wall on both right and left CCA.

Results: CCA-IMT was not different in the total of children and adolescents with T1DM compared with CO (0.302 ± 0.057 vs. 0.301 ± 0.054 mm; p = 0.88). Analysis according to gender, however, revealed higher CCA-IMT values in girls than in boys in the diabetic cohort (0.315 ± 0.055 vs. 0.288 ± 0.058 mm; p = 0.047), whereas CCA-IMT was higher in boys than in girls in the CO group (0.321 ± 0.057 vs. 0.284 ± 0.045 mm; p < 0.001). Multiple stepwise backward regression showed that in the T1DM group only HbA1c remained significantly associated with CCA-IMT (Beta = - 0.307, p = 0.008). In CO, gender (Beta = - 0.302, p < 0.001), body mass index (Beta = 0.226, p < 0.001) and systolic blood pressure (Beta = 0.213, p < 0.001) were predictive of CCA-IMT.

Conclusion: Our data suggest that in children/adolescents with T1DM the quality of metabolic CO (HbA1c) is the most important predictor of CCA-IMT and outweighs the effect of gender.
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February 2015

Endothelial progenitor cells are related to glycemic control in children with type 1 diabetes over time.

Diabetes Care 2013 Jun 22;36(6):1647-53. Epub 2013 Jan 22.

Department of Pediatric and Adolescent Medicine, Medical University of Vienna and Vienna General Hospital, Vienna, Austria.

Objective: The risk of cardiovascular death before the age of 40 is 20-fold higher in patients with type 1 diabetes mellitus (T1DM). Endothelial progenitor cells (EPCs) predict cardiovascular morbidity and mortality in patients without diabetes. We hypothesized that EPCs are modified in children with T1DM and are related to characteristics of T1DM such as glycemic control.

Research Design And Methods: Children (n = 190; 156 T1DM subjects and 34 control subjects) were included in an observational cohort study and matched for age and sex. EPCs were enumerated by flow cytometry at the beginning (cross-sectional) and 1 year later (longitudinal). To analyze changes of variables during the observation, Δ values were calculated.

Results: EPCs were significantly reduced in T1DM children versus control subjects (609 ± 359 vs. 1,165 ± 484, P < 0.001). Multivariate regression modeling revealed that glycated hemoglobin A1c (HbA1c) was the strongest independent predictor of EPCs (β = -0.355, P < 0.001). Overall glycemic control at the beginning and end of study did not differ (7.8 ± 1.2 vs. 7.8 ± 1.2 relative %, P = NS), but we observed individual HbA1c changes of -4.30/+3.10 relative %. The strongest EPC increase was observed in the patients with the most favorable HbA1c lowering during the 1-year follow-up. Accordingly, the strongest EPC decrease was demonstrated in the patients with the strongest HbA1c worsening during the time period.

Conclusions: This is the first prospective study demonstrating diminished EPCs in children with T1DM. The association of better glycemic control with an increase in EPC numbers within 1 year suggests that a reduction of the high cardiovascular disease burden might be mediated likewise.
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June 2013

Voltage-gated ion channel dysfunction precedes cardiomyopathy development in the dystrophic heart.

PLoS One 2011 23;6(5):e20300. Epub 2011 May 23.

Center for Physiology and Pharmacology, Department of Neurophysiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

Background: Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology.

Methodology/principal Findings: To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged.

Conclusions/significance: Ion channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers.
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September 2011