title: Effects of the DPP-4 inhibitor, linagliptin, in diet-induced obese rats: a comparison in naive and exenatide-treated animals.
abstract: BACKGROUND
  To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats.
  
  
  METHODS
  Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period. In a subsequent study, rats received exenatide (either 3 or 30 microg/kg/day) or vehicle by osmotic mini-pump for 28 days. In addition, groups of animals were dosed orally with linagliptin either alone or in combination with a 3 microg/kg/day exenatide dose for the study duration. In a final study, rats were administered exenatide (30 microg/kg/day) or vehicle by osmotic mini-pump for eleven days. Subsequently, exenatide-treated animals were transferred to vehicle or continued exenatide infusion for a further ten days. Animals transferred from exenatide to vehicle were also dosed orally with either vehicle or linagliptin. In all studies, body weight, food and water intake were recorded daily and relevant plasma parameters and carcass composition were determined.
  
  
  RESULTS
  In contrast to exenatide, linagliptin did not significantly reduce body weight or carcass fat in DIO rats versus controls. Linagliptin augmented the effect of exenatide to reduce body fat when given in combination but did not affect the body weight response. In rats withdrawn from exenatide, weight regain was observed such that body weight was not significantly different to controls. Linagliptin reduced weight regain after withdrawal of exenatide such that a significant difference from controls was evident.
  
  
  CONCLUSIONS
  These data demonstrate that linagliptin does not significantly alter body weight in either untreated or exenatide-treated DIO rats, although it delays weight gain after exenatide withdrawal. This finding may suggest the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain.
authors.affiliation: RenaSci Ltd, BioCity Nottingham, Pennyfoot Street, Nottingham, UK.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Vickers
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Cheetham
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Birmingham
authors.forename: Helen L
authors.initials: HL
authors.lastname: Rowley
authors.forename: Katie R
authors.initials: KR
authors.lastname: Headland
authors.forename: Keith
authors.initials: K
authors.lastname: Dickinson
authors.forename: Rolf
authors.initials: R
authors.lastname: Grempler
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
mesh_terms: D000818:Animals; D004032:Diet; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005260:Female; D000069476:Linagliptin; D009765:Obesity / Q000188:drug therapy*; D011687:Purines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin