title: Differential hypoglycaemic, anorectic, autonomic and emetic effects of the glucagon-like peptide receptor agonist, exendin-4, in the conscious telemetered ferret.
abstract: BACKGROUND
  Rodents are incapable of emesis and consequently the emetic potential of glucagon-like peptide-1 receptor (GLP-1R) agonists in studies designed to assess a potential blood glucose lowering action of the compound was missed. Therefore, we investigated if the ferret, a carnivore with demonstrated translation capability in emesis research, would identify the emetic potential of the GLP-1R agonist, exendin-4, and any associated effects on gastric motor function, appetite and cardiovascular homeostasis.
  
  
  METHODS
  The biological activity of the GLP-1R ligands was investigated in vivo using a glucose tolerance test in pentobarbitone-anesthetised ferrets and in vitro using organ bath studies. Radiotelemetry was used to investigate the effect of exendin-4 on gastric myoelectric activity (GMA) and cardiovascular function in conscious ferrets; behaviour was also simultaneously assessed. Western blot was used to characterize GLP-1R distribution in the gastrointestinal and brain tissues.
  
  
  RESULTS
  In anesthetised ferrets, exendin-4 (30 nmol/kg, s.c.) reduced experimentally elevated blood glucose levels by 36.3%, whereas the GLP-1R antagonist, exendin (9-39) (300 nmol/kg, s.c.) antagonised the effect and increased AUC0-120 by 31.0% when injected alone (P < 0.05). In animals with radiotelemetry devices, exendin-4 (100 nmol/kg, s.c.) induced emesis in 1/9 ferrets, but inhibited food intake and decreased heart rate variability (HRV) in all animals (P < 0.05). In the animals not exhibiting emesis, there was no effect on GMA, mean arterial blood pressure, heart rate, or core body temperature. In the ferret exhibiting emesis, there was a shift in the GMA towards bradygastria with a decrease in power, and a concomitant decrease in HRV. Western blot revealed GLP-1R throughout the gastrointestinal tract but exendin-4 (up to 300 nM) and exendin (9-39), failed to contract or relax isolated ferret gut tissues. GLP-1R were found in all major brain regions and the levels were comparable those in the vagus nerve.
  
  
  CONCLUSIONS
  Peripherally administered exendin-4 reduced blood glucose and inhibited feeding with a low emetic potential similar to that in humans (11% vs 12.8%). A disrupted GMA only occurred in the animal exhibiting emesis raising the possibility that disruption of the GMA may influence the probability of emesis occurring in response to treatment with GLP-1R agonists.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, China. zengbinglu.jack@gmail.com.
authors.forename: Zengbing
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Division of Biomedical Sciences, St George's University of London, London, UK. nathalie.perciedusert@nc3rs.org.uk.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Percie Du Sert
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, China. stellacsw@gmail.com.
authors.forename: Sze Wa
authors.initials: SW
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, China. yeungck@rocketmail.com.
authors.forename: Chi-Kong
authors.initials: CK
authors.lastname: Yeung
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, China. linge@cuhk.edu.hk.
authors.forename: Ge
authors.initials: G
authors.lastname: Lin
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, China. david-yew@cuhk.edu.hk.
authors.forename: David T W
authors.initials: DT
authors.lastname: Yew
authors.affiliation: Division of Biomedical Sciences, St George's University of London, London, UK. pandrews@sgul.ac.uk.
authors.forename: Paul L R
authors.initials: PL
authors.lastname: Andrews
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR, China. jar@cuhk.edu.hk.
authors.forename: John A
authors.initials: JA
authors.lastname: Rudd
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D004639:Emetics / Q000494:pharmacology*; D000077270:Exenatide; D005289:Ferrets; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology*
chemical_list: D001067:Appetite Depressants; D001786:Blood Glucose; D004639:Emetics; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide