title: The novel GLP-1-gastrin dual agonist, ZP3022, increases β-cell mass and prevents diabetes in db/db mice.
abstract: OBJECTIVE
  Diabetes is characterized by β-cell deficiency, and therefore restoration of β-cell function has been suggested as a potential therapy. We hypothesized that a novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist, ZP3022, improves glycaemic control via improvement of β-cell status in db/db mice.
  
  
  METHODS
  Diabetic mice were studied following short- or long-term treatment with either the GLP-1-gastrin dual agonist or the commercially available GLP-1 agonists (exendin-4 and liraglutide). The effects on glycaemic control were addressed by repeated glucose tolerance tests and/or measurements of HbA1c levels, and pancreatic islet and β-cell masses were determined by stereology.
  
  
  RESULTS
  ZP3022 and the pure GLP-1 agonists improved glycaemic control after both short- and long-term treatment compared with vehicle. Interestingly, the effect was sustainable only in mice treated with ZP3022. Stereology data displayed a dose-dependent increase of β-cell mass (p < 0.05) following treatment with ZP3022, whereas no significant effect of liraglutide was observed (β-cell mass: vehicle 3.7 ± 0.2 mg; liraglutide (30 nmol/kg) 3.4 ± 0.5 mg; ZP3022 (30 nmol/kg) 4.3 ± 0.4 mg and ZP3022 (100 nmol/kg) 5.2 ± 0.4 mg).
  
  
  CONCLUSIONS
  The novel GLP-1-gastrin dual agonist, ZP3022, improved glycaemic control in db/db mice, and pancreatic islet and β-cell mass increased significantly following treatment with ZP3022 compared with vehicle.
authors.affiliation: Research and Development, Zealand Pharma A/S, Glostrup, Denmark. kfo@zealandpharma.com
authors.forename: K
authors.initials: K
authors.lastname: Fosgerau
authors.forename: L
authors.initials: L
authors.lastname: Jessen
authors.forename: J
authors.initials: J
authors.lastname: Lind Tolborg
authors.forename: T
authors.initials: T
authors.lastname: Østerlund
authors.forename: K
authors.initials: K
authors.lastname: Schæffer Larsen
authors.forename: K
authors.initials: K
authors.lastname: Rolsted
authors.forename: M
authors.initials: M
authors.lastname: Brorson
authors.forename: J
authors.initials: J
authors.lastname: Jelsing
authors.forename: T
authors.initials: T
authors.lastname: Skovlund Ryge Neerup
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D000077270:Exenatide; D005755:Gastrins / Q000819:agonists* / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000031:analogs & derivatives / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology
chemical_list: D005755:Gastrins; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; C581977:ZP3022; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide