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Ludvigsson J.,Linköping University | Krisky D.,Diamyd Medical | Casas R.,Linköping University | Battelino T.,University of Ljubljana | And 8 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixedmeal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P = 0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.) Copyright © 2012 Massachusetts Medical Society.


Phillip M.,Jesse Z And Sara Lea Shafer Institute For Endocrinology And Diabetes | Phillip M.,Tel Aviv University | Battelino T.,University of Ljubljana | Atlas E.,Jesse Z And Sara Lea Shafer Institute For Endocrinology And Diabetes | And 8 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Recent studies have shown that an artificial-pancreas system can improve glucose control and reduce nocturnal hypoglycemia. However, it is not known whether such results can be replicated in settings outside the hospital. METHODS: In this multicenter, multinational, randomized, crossover trial, we assessed the short-term safety and efficacy of an artificial pancreas system for control of nocturnal glucose levels in patients (10 to 18 years of age) with type 1 diabetes at a diabetes camp. In two consecutive overnight sessions, we randomly assigned 56 patients to receive treatment with an artificial pancreas on the first night and a sensor-augmented insulin pump (control) on the second night or to the reverse order of therapies on the first and second nights. Thus, all the patients received each treatment in a randomly assigned order. The primary end points were the number of hypoglycemic events (defined as a sensor glucose value of <63 mg per deciliter [3.5 mmol per liter] for at least 10 consecutive minutes), the time spent with glucose levels below 60 mg per deciliter (3.3 mmol per liter), and the mean overnight glucose level for individual patients. RESULTS: On nights when the artificial pancreas was used, versus nights when the sensor-augmented insulin pump was used, there were significantly fewer episodes of nighttime glucose levels below 63 mg per deciliter (7 vs. 22) and significantly shorter periods when glucose levels were below 60 mg per deciliter (P=0.003 and P=0.02, respectively, after adjustment for multiplicity). Median values for the individual mean overnight glucose levels were 126.4 mg per deciliter (interquartile range, 115.7 to 139.1 [7.0 mmol per liter; interquartile range, 6.4 to 7.7]) with the artificial pancreas and 140.4 mg per deciliter (interquartile range, 105.7 to 167.4 [7.8 mmol per liter; interquartile range, 5.9 to 9.3]) with the sensor-augmented pump. No serious adverse events were reported. CONCLUSIONS: Patients at a diabetes camp who were treated with an artificial-pancreas system had less nocturnal hypoglycemia and tighter glucose control than when they were treated with a sensor-augmented insulin pump. (Funded by Sanofi and others; ClinicalTrials.gov number, NCT01238406.) Copyright © 2013 Massachusetts Medical Society.


Pozzilli P.,Biomedical University of Rome | Battelino T.,University of Ljubljana | Danne T.,Diabetes Center for Children and Adolescents | Hovorka R.,University of Cambridge | And 2 more authors.
Diabetes/Metabolism Research and Reviews | Year: 2016

Summary: The level of glycaemic control necessary to achieve optimal short-term and long-term outcomes in subjects with type 1 diabetes mellitus (T1DM) typically requires intensified insulin therapy using multiple daily injections or continuous subcutaneous insulin infusion. For continuous subcutaneous insulin infusion, the insulins of choice are the rapid-acting insulin analogues, insulin aspart, insulin lispro and insulin glulisine. The advantages of continuous subcutaneous insulin infusion over multiple daily injections in adult and paediatric populations with T1DM include superior glycaemic control, lower insulin requirements and better health-related quality of life/patient satisfaction. An association between continuous subcutaneous insulin infusion and reduced hypoglycaemic risk is more consistent in children/adolescents than in adults. The use of continuous subcutaneous insulin infusion is widely recommended in both adult and paediatric T1DM populations but is limited in pregnant patients and those with type 2 diabetes mellitus. All available rapid-acting insulin analogues are approved for use in adult, paediatric and pregnant populations. However, minimum patient age varies (insulin lispro: no minimum; insulin aspart: ≥2 years; insulin glulisine: ≥6 years) and experience in pregnancy ranges from extensive (insulin aspart, insulin lispro) to limited (insulin glulisine). Although more expensive than multiple daily injections, continuous subcutaneous insulin infusion is cost-effective in selected patient groups. This comprehensive review focuses on the European situation and summarises evidence for the efficacy and safety of continuous subcutaneous insulin infusion, particularly when used with rapid-acting insulin analogues, in adult, paediatric and pregnant populations. The review also discusses relevant European guidelines; reviews issues that surround use of this technology; summarises the effects of continuous subcutaneous insulin infusion on patients' health-related quality of life; reviews relevant pharmacoeconomic data; and discusses recent advances in pump technology, including the development of closed-loop 'artificial pancreas' systems. © 2015 The Authors.


Nimri R.,Jesse Z And Sara Lea Shafer Institute For Endocrinology And Diabetes | Muller I.,Jesse Z And Sara Lea Shafer Institute For Endocrinology And Diabetes | Atlas E.,Jesse Z And Sara Lea Shafer Institute For Endocrinology And Diabetes | Miller S.,Jesse Z And Sara Lea Shafer Institute For Endocrinology And Diabetes | And 7 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: We evaluated the effect of the MD-Logic system on overnight glycemic control at patients' homes. RESEARCH DESIGN AND METHODS: Twenty-four patients (aged 12-43 years; averageA1c 7.5±0.8%, 58.1±8.4mmol/mol) were randomly assigned to participate in two overnight crossover periods, each including 6 weeks of consecutive nights: one under closed loop and the second under sensor-augmented pump (SAP) therapy at patients' homes in real-life conditions. The primary end point was time spent with sensor glucose levels below 70 mg/dL (3.9 mmol/L) overnight. RESULTS: Closed-loop nights significantly reduced time spent in hypoglycemia (P = 0.02) and increased the percentage of time spent in the target range of 70-140 mg/dL (P = 0.003) compared with nights when the SAP therapy was used. The time spent in substantial hyperglycemia above 240 mg/dL was reduced by a median of 52.2% (interquartile range [IQR] 4.8, 72.9%; P = 0.001) under closed-loop control compared with SAP therapy. Overnight total insulin doses were lower in the closedloop nights compared with the SAP nights (P = 0.04). The average daytime glucose levels after closed-loop operation were reduced by a median of 10.0 mg/dL (IQR-2.7, 19.2; P = 0.017) while lower total insulin doses were used (P = 0.038). No severe adverse events occurred during closed-loop control; there was a single event of severe hypoglycemia during a control night. CONCLUSIONS: The long-term home use of automated overnight insulin delivery by the MD-Logic system was found to be a feasible, safe, and an effective tool to reduce nocturnal hypoglycemia and improve overnight glycemic control in subjects with type 1 diabetes. © 2014 by the American Diabetes Association.


Kordonouri O.,Diabetes Center for Children and Adolescents | Hartmann R.,Diabetes Center for Children and Adolescents | Pankowska E.,Medical University of Warsaw | Rami B.,The Institute of Mother and Child | And 4 more authors.
Pediatric Diabetes | Year: 2012

Aim: To evaluate the metabolic control and β-cell function 1 yr after the end of the European multicentre randomized Pediatric Onset Study. Methods: Of 154 study patients, 131 were re-examined 24months after type 1 diabetes onset (49.6% boys, age at onset 8.9±4.3yrs). Of which, 62 patients belonged to the primary group of the main study applying a sensor-augmented pump system during the first yr and 69 patients to the control group performing conventional insulin pump therapy with self-monitoring blood glucose. HbA1c, fasting blood glucose, and C-peptide were centrally measured (Clinical Trail Registration Number: ISRCTN05450731). Results: At 24months, i.e., 1 yr after the end of the interventional study, 52.4% of the patients used the sensor-augmented pump system, 46.0% conventional pump, and 1.6% multiple daily injections. HbA1c was 7.6±1.3% in the primary and 7.7±1.2% in the control group (p=0.493). Frequent sensor use during the first yr was associated with statistically insignificant lowering of the HbA1c at 24months (p=0.236) as compared with irregular or no sensor use (7.4±1.0% vs. 7.7±1.3%). Although fasting C-peptide was not clearly different between the primary and control group (0.13±0.17 vs. 0.09±0.10nmol/L, p=0.121), patients with frequent sensor use had significantly less C-peptide loss within 24months (C-peptide reduction 0.02±0.18 vs. 0.07±0.11nmol/L, p=0.046). There was no difference between the groups regarding daily insulin requirements. Conclusion: Sensor-augmented pump therapy from onset of diabetes may lead to better long-term glycemic control and help to preserve endogenous β-cell function, if patients comply with frequent use of continuous glucose monitoring. © 2012 John Wiley & Sons A/S.


Martin D.,University of Paris Pantheon Sorbonne | Lange K.,Hannover Medical School | Sima A.,Foundation Cristian Serban | Kownatka D.,Roche Holding AG | And 3 more authors.
Pediatric Diabetes | Year: 2012

Education is the keystone of diabetes care, and structured self-management education is the key to a successful outcome. Existing guidelines provide comprehensive guidance on the various aspects of education and offer general and organizational principles of education, detailed curricula at different ages and stages of diabetes, and recommendations on models, methods, and tools to attain educative objectives. The International Society for Pediatric and Adolescent Diabetes guidelines give the most elaborate and detailed descriptions and recommendations on the practice of education, which other national guidelines address on specific aspects of education and care. The aim of the work package on education developed by Better Control in Paediatric and Adolescent Diabetes in the European Union: Working to Create Centers of Reference (SWEET) project was not to generate new guidelines but to evaluate how the existing guidelines were implemented in some pediatric diabetes reference centers. The SWEET members have completed a questionnaire that elaborates on the many aspects of delivery of education. This survey highlights a profound diversity of practices across centers in Europe, in terms of organization as well as the practices and the content of initial and continuing education. A toolbox is being developed within SWEET to facilitate exchanges on all aspects of education and to establish a process of validation of materials, tools, written structured age-adjusted programs, and evaluation procedures for the education of children and adolescents with diabetes. © 2012 John Wiley & Sons A/S.


O'Riordan S.M.P.,University College London | Danne T.,Diabetes Center for Children and Adolescents | Hanas R.,Uddevalla Hospital | Peters C.J.,University College London | Hindmarsh P.,University College London
Diabetic Medicine | Year: 2014

Aim: Estimated average glucose has been used to transform HbA1c into a glucose measure that might better inform patients of their glycaemic control. The data set used to obtain the estimated average glucose equation was derived in adults with Type 1 and Type 2 diabetes, along with normal healthy control subjects, and requires testing in children. Methods: This was a cross-sectional study of 234 children and young people (106 male) with Type 1 diabetes aged 4.0-23.5 years who underwent continuous glucose monitoring over a 5-day period along with a measure of HbA1c. Regression analysis was used to determine estimated average glucose and agreement was assessed with the average glucose estimated from the Nathan equation: Nathan average glucose equation = 1.59 (HbA1c%) - 2.59. Results: Mean HbA1c was 76 mmol/mol (25.1) [9.1 (2.3)%] and mean continuous glucose monitoring tissue glucose was 10.4 (2.6) mmol/l. The relationship between continuous glucose monitoring tissue glucose and HbA1c was described by the paediatric equation: paediatric estimated average glucose = 0.49 (HbA1c%) + 5.95 (r = 0.45; P < 0.001). The mean paediatric estimated average glucose was 10.4 (1.1) mmol/l compared with that from the Nathan average glucose equation of 11.9 (3.7) mmol/l (P < 0.001). Overall, the paediatric estimated average glucose was 2.7 mmol/l lower than the Nathan estimated average glucose, with a 95% limit of agreement of ± 0.5 mmol/l. The agreement was very close with HbA1c values below 80 mmol/mol (9.5%). Conclusion: These data suggest that the Nathan estimated average glucose could be used in children and young people with Type 1 diabetes. Caution should still be exercised in the estimates derived for average glucose as the data set is skewed in both Nathan and paediatric average glucose estimates in opposite directions because of the differences in average HbA1c. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.


Biester T.,Diabetes Center for Children and Adolescents | Blaesig S.,Diabetes Center for Children and Adolescents | Remus K.,Diabetes Center for Children and Adolescents | Aschemeier B.,Diabetes Center for Children and Adolescents | And 6 more authors.
Pediatric Diabetes | Year: 2014

Insulin degludec (IDeg) is a basal insulin with an ultra-long pharmacokinetic profile in adults that at steady-state produces remarkably flat and stable insulin levels; however, no studies have yet reported on the pharmacokinetic properties of IDeg in subjects younger than 18years of age. This was a single-centre, randomised, single-dose, double-blind, two-period crossover trial conducted in children (6-11years), adolescents (12-17years), and adults (18-65years) with type 1 diabetes. Subjects received a single subcutaneous dose of 0.4U/kg IDeg or insulin glargine (IGlar), respectively, on two separate dosing visits, with pharmacokinetic blood sampling up to 72-h postdose. A total of 37 subjects (12 children, 13 adolescents, and 12 adults) completed the trial. Total exposure of IDeg after a single dose (AUCIDeg,0-∞,SD) was higher in children compared to adults [estimated ratio children/adults 1.48 (95% confidence interval, CI: 0.98; 2.24)] and in adolescents compared to adults [estimated ratio adolescents/adults 1.33 (95% CI: 1.08; 1.64)]; however, the difference was only statistically significant for the latter comparison. No statistically significant difference in maximum concentration of IDeg (Cmax,IDeg,SD) was observed. Estimated ratios for Cmax,IDeg,SD were (children/adults) 1.20 (95% CI: 0.90; 1.60) and (adolescents/adults) 1.23 (95% CI: 1.00; 1.51). Simulated mean steady state pharmacokinetic profiles supported a flat and stable IDeg exposure across a 24-h dosing interval. IDeg was detectable in serum for at least 72h (end of blood sampling period) in all subjects following single dose. In conclusion, the ultra-long pharmacokinetic properties of IDeg observed in adults are preserved in children and adolescents with type 1 diabetes. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Danne T.,Diabetes Center for Children and Adolescents | Tsioli C.,Diabetes Center for Children and Adolescents | Kordonouri O.,Diabetes Center for Children and Adolescents | Blaesig S.,Diabetes Center for Children and Adolescents | And 5 more authors.
Diabetes Technology and Therapeutics | Year: 2014

Background: Predictive low glucose management (PLGM) may help prevent hypoglycemia by stopping insulin pump delivery based on predicted sensor glucose values. Materials and Methods: Hypoglycemic challenges were simulated using the Food and Drug Administration- accepted glucose simulatorwith 100 virtual patients. PLGMwas then testedwith a system composed of a Paradigm® insulin pump (Medtronic, Northridge, CA), an Enlite™ glucose sensor (Medtronic), and a BlackBerry® (Waterloo, ON, Canada)-based controller. Subjects (n = 22) on continuous subcutaneous insulin infusion (five females, 17 males; median [range] age, 15 [range, 14-20] years; median [range] diabetes duration, 7 [2-14] years; median [range] glycated hemoglobin, 8.0% [6.7-10.4%]) exercised until the PLGM system suspended insulin delivery or until the reference blood glucose value (HemoCue®; HemoCue GmbH, Großostheim, Germany) reached the predictive suspension threshold setting. Results: PLGM reduced hypoglycemia (< 70 mg/dL) in silico by 26.7% compared with no insulin suspension, as opposed to a 5.3% reduction in hypoglycemia with use of low glucose suspend (LGS). The median duration of hypoglycemia (time spent <70 mg/dL) with PLGM was significantly less than with LGS (58 min vs. 101 min, respectively; P < 0.001). In the clinical trial the hypoglycemic threshold during exercise was reached in 73% of the patients, and hypoglycemia was prevented in 80% of the successful experiments. The mean (± SD) sensor glucose at predictive suspension was 92 ± 7 mg/dL, resulting in a postsuspension nadir (by HemoCue) of 77 ± 22 mg/dL. The suspension lasted for 90 ± 35 (range, 30-120) min, resulting in a sensor glucose level at insulin resumption of 97 ± 19 mg/dL. Conclusions: In silico modeling and early feasibility data demonstrate that PLGM may further reduce the severity of hypoglycemia beyond that already established for algorithms that use a threshold-based suspension. © 2014 Mary Ann Liebert, Inc.


Kordonouri O.,Diabetes Center for Children and Adolescents | Hartmann R.,Diabetes Center for Children and Adolescents | Remus K.,Diabetes Center for Children and Adolescents | Blasig S.,Diabetes Center for Children and Adolescents | And 2 more authors.
Pediatric Diabetes | Year: 2012

Objective: To investigate carbohydrate (CARB) and supplementary fat/protein (CFP) counting using normal and dual-wave bolus in pump therapy of children and young people with type 1 diabetes (T1D). Study design and methods: A randomized clinical trial was conducted in 42 patients (age 6-21 yr) with T1D for at least 1 yr (5.2 ± 3.1 yr, mean ± SD) and pump therapy for at least 3 months (3.3 ± 1.8 yr). Standardized test meals (pizza-salami; 50% carbohydrate, 34% fat, 16% protein; corresponding to 33% of age-adjusted daily energy requirement) were given at lunch time on four different days with normal and dual-wave bolus using CARB and CFP counting in a randomized sequence. Sensor-augmented pumps were used for continuous glucose monitoring of 6-h postprandial glucose profiles. Intra-individual comparisons of glucose parameters [area under the curve (AUC) mg/dL ×6 h; average glucose, AV mg/dL] were performed. Results: Using CFP counting, 6-h postprandial glucose AUC (805 ± 261) and AV (137.8 ± 46.2) were significantly lower than AUC (926 ± 285) and AV (160.5 ± 51.9) by CARB counting (p < 0.001, each). CFP counting led to significantly lower postprandial glucose parameters independently from the kind of bolus (normal bolus: ΔAUC 169, p < 0.001; ΔAV 30.6, p < 0.001/dual-wave bolus: ΔAUC 73, p = 0.045, ΔAV 14.8, p = 0.033). Postprandial hypoglycemia episodes (<70 mg/dL) occurred more frequently in CFP than in CARB counting (35.7% vs. 9.5%, p < 0.001). No severe hypoglycemia was reported. Conclusion: In patients with long-term T1D, meal-related insulin dosing based on carbohydrate plus fat/protein counting reduces the postprandial glucose levels (ClinicalTrials.gov NCT01400659). © 2012 John Wiley & Sons A/S.

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