title: Safety, efficacy and glucose turnover of reduced prandial boluses during closed-loop therapy in adolescents with type 1 diabetes: a randomized clinical trial.
abstract: OBJECTIVE
  To evaluate safety, efficacy and glucose turnover during closed-loop with meal announcement using reduced prandial insulin boluses in adolescents with type 1 diabetes (T1D).
  
  
  METHODS
  We conducted a randomized crossover study comparing closed-loop therapy with standard prandial insulin boluses versus closed-loop therapy with prandial boluses reduced by 25%. Eight adolescents with T1D [3 males; mean (standard deviation) age 15.9 (1.5) years, glycated haemoglobin 74 (17) mmol/mol; median (interquartile range) total daily dose 0.9 (0.7, 1.1) IU/kg/day] were studied on two 36-h-long visits. In random order, subjects received closed-loop therapy with either standard or reduced insulin boluses administered with main meals (50-80 g carbohydrates) but not with snacks (15-30 g carbohydrates). Stable-label tracer dilution methodology measured total glucose appearance (Ra_total) and glucose disposal (Rd).
  
  
  RESULTS
  The median (interquartile range) time spent in target (3.9-10 mmol/l) was similar between the two interventions [74 (66, 84)% vs 80 (65, 96)%; p = 0.87] as was time spent above 10 mmol/l [21.8 (16.3, 33.5)% vs 18.0 (4.1, 34.2)%; p = 0.87] and below 3.9 mmol/l [0 (0, 1.5)% vs 0 (0, 1.8)%; p = 0.88]. Mean plasma glucose was identical during the two interventions [8.4 (0.9) mmol/l; p = 0.98]. Hypoglycaemia occurred once 1.5 h post-meal during closed-loop therapy with standard bolus. Overall insulin delivery was lower with reduced prandial boluses [61.9 (55.2, 75.0) vs 72.5 (63.6, 80.3) IU; p = 0.01] and resulted in lower mean plasma insulin concentration [186 (171, 260) vs 252 (198, 336) pmol/l; p = 0.002]. Lower plasma insulin was also documented overnight [160 (136, 192) vs 191 (133, 252) pmol/l; p = 0.01, pooled nights]. Ra_total was similar [26.3 (21.9, 28.0) vs 25.4 (21.0, 29.2) µmol/kg/min; p = 0.19] during the two interventions as was Rd [25.8 (21.0, 26.9) vs 25.2 (21.2, 28.8) µmol/kg/min; p = 0.46].
  
  
  CONCLUSIONS
  A 25% reduction in prandial boluses during closed-loop therapy maintains similar glucose control in adolescents with T1D whilst lowering overall plasma insulin levels. It remains unclear whether closed-loop therapy with a 25% reduction in prandial boluses would prevent postprandial hypoglycaemia.
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK.|Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: D
authors.initials: D
authors.lastname: Elleri
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK.|Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Biagioni
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK.|Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Allen
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: K
authors.initials: K
authors.lastname: Kumareswaran
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: L
authors.initials: L
authors.lastname: Leelarathna
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: K
authors.initials: K
authors.lastname: Caldwell
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Nodale
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK.|Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: M E
authors.initials: ME
authors.lastname: Wilinska
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Haidar
authors.affiliation: The Jaeb Center for Health Research, Tampa, FL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Calhoun
authors.affiliation: The Jaeb Center for Health Research, Tampa, FL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kollman
authors.affiliation: Diabetes and Metabolic Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
authors.forename: N C
authors.initials: NC
authors.lastname: Jackson
authors.affiliation: Diabetes and Metabolic Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Umpleby
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK.|Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: C L
authors.initials: CL
authors.lastname: Acerini
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK.|Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: D B
authors.initials: DB
authors.lastname: Dunger
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK.|Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors.forename: R
authors.initials: R
authors.lastname: Hovorka
mesh_terms: D000293:Adolescent; D000465:Algorithms; D001786:Blood Glucose / Q000032:analysis*; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D004739:England / Q000453:epidemiology; D005260:Female; D000067940:Glycemic Load; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control; D007003:Hypoglycemia / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D007332:Insulin Infusion Systems; D007333:Insulin Resistance; D008297:Male; D062407:Meals; D008991:Monitoring, Physiologic; D012306:Risk
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin
keywords: closed-loop insulin delivery; postprandial hypoglycaemia; type 1 diabetes