title: The insulinotropic effect of pulsatile compared with continuous intravenous delivery of GLP-1.
abstract: OBJECTIVE
  In healthy individuals, both insulin and glucagon-like peptide 1 (GLP-1) are secreted in a pulsatile fashion. Insulin has greater glucose-lowering properties when administered in pulses compared with a constant i.v. infusion. The primary aim of this randomised double-dummy cross-over study was to compare the insulinotropic response to pulsatile and continuous i.v. infusions of equivalent doses of GLP-1.
  
  
  METHODS
  Twelve healthy participants aged 18-35 years were randomised to three different treatments on separate days: a continuous infusion day (GLP-1 at 0.6 pmol kg(-1) min(-1) [1 ml/min] and a 1 ml placebo bolus every 6 min); a pulsatile infusion day (placebo at 1 ml/min and a 3.6 pmol/kg GLP-1 bolus every 6 min); and a placebo day (placebo at 1 ml/min and a 1 ml placebo bolus every 6 min). Between 45 and 120 min, a hyperglycaemic clamp was used to maintain blood glucose at 9 mmol/l. Venous blood glucose and plasma insulin concentrations were measured every 5 min from 0 to 45 min and every 1 min from 45 to 120 min; plasma glucagon was measured every 15 min. The order of treatment was randomised by the Pharmacy Department and both study investigators and participants were blinded to the treatment arm. The dextrose requirement and glucagon data were analysed using repeated measures ANOVA and insulin data were analysed with a linear mixed effects maximum likelihood model.
  
  
  RESULTS
  Continuous and pulsatile infusions of GLP-1 increased the dextrose requirement by ~threefold (p < 0.001) and increased insulin secretion by ~ninefold (p < 0.001). There was no difference in the effect of both treatments. Although hyperglycaemia reduced plasma glucagon concentrations, there was no difference between the treatment days.
  
  
  CONCLUSIONS
  In healthy individuals, pulsatile and continuous administration of i.v. GLP-1 appears to have comparable insulinotropic effects.
  
  
  BACKGROUND
  ACTRN12612001040853 FUNDING: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia.
authors.affiliation: Discipline of Acute Care Medicine, University of Adelaide, Adelaide, SA, Australia. mark.plummer@adelaide.edu.au.|Intensive Care Research Unit, Level 4 Emergency Block, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia. mark.plummer@adelaide.edu.au.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Plummer
authors.affiliation: Discipline of Acute Care Medicine, University of Adelaide, Adelaide, SA, Australia.|Intensive Care Research Unit, Level 4 Emergency Block, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.
authors.forename: Palash
authors.initials: P
authors.lastname: Kar
authors.affiliation: Intensive Care Research Unit, Level 4 Emergency Block, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Cousins
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Kylie
authors.initials: K
authors.lastname: Lange
authors.affiliation: Discipline of Acute Care Medicine, University of Adelaide, Adelaide, SA, Australia.|Intensive Care Research Unit, Level 4 Emergency Block, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.
authors.forename: Marianne J
authors.initials: MJ
authors.lastname: Chapman
authors.affiliation: Division of Diabetes and GI Endocrinology, University Hospital St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nauck
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Horowitz
authors.affiliation: Division of Diabetes and GI Endocrinology, University Hospital St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Juris J
authors.initials: JJ
authors.lastname: Meier
authors.affiliation: Discipline of Acute Care Medicine, University of Adelaide, Adelaide, SA, Australia.|Intensive Care Research Unit, Level 4 Emergency Block, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Deane
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000627:therapeutic use*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007262:Infusions, Intravenous / Q000379:methods*; D007328:Insulin / Q000378:metabolism; D008297:Male; D055815:Young Adult
chemical_list: D007328:Insulin; D052216:Glucagon-Like Peptide 1
keywords: Glucagon; Glucagon-like peptide 1; Insulin; Pulsatile
references.citation: Diabetes. 2003 Feb;52(2):380-6
references.pmid: 12540611
references.citation: Diabetologia. 2002 Jan;45(1):3-20
references.pmid: 11845219
references.citation: Endocr Rev. 2008 Dec;29(7):823-64
references.pmid: 18940916
references.citation: Rev Diabet Stud. 2011 Fall;8(3):293-306
references.pmid: 22262068
references.citation: Diabetes Care. 2000 Jun;23(6):807-12
references.pmid: 10841001
references.citation: J Clin Endocrinol Metab. 1997 Mar;82(3):786-90
references.pmid: 9062483
references.citation: J Clin Endocrinol Metab. 1988 Jun;66(6):1220-6
references.pmid: 3286673
references.citation: Eur J Intern Med. 2014 Jun;25(5):407-14
references.pmid: 24694879
references.citation: Diabetes Care. 2015 Jun;38(6):1123-9
references.pmid: 25784665
references.citation: Pharmacol Rev. 2002 Jun;54(2):323-74
references.pmid: 12037145