title: The anti-diabetic effects of GLP-1-gastrin dual agonist ZP3022 in ZDF rats.
abstract: OBJECTIVE
  Combination treatment with exendin-4 and gastrin has proven beneficial in treatment of diabetes and preservation of beta cell mass in diabetic mice. Here, we examined the chronic effects of a GLP-1-gastrin dual agonist ZP3022 on glycemic control and beta cell dysfunction in overtly diabetic Zucker Diabetic Fatty (ZDF) rats.
  
  
  METHODS
  ZDF rats aged 11 weeks were dosed s.c., b.i.d. for 8 weeks with vehicle, ZP3022, liraglutide, exendin-4, or gastrin-17 with or without exendin-4. Glycemic control was assessed by measurements of HbA1c and blood glucose levels, as well as glucose tolerance during an oral glucose tolerance test (OGTT). Beta cell dynamics were examined by morphometric analyses of beta and alpha cell fractions.
  
  
  RESULTS
  ZP3022 improved glycemic control as measured by terminal HbA1c levels (6.2±0.12 (high dose) vs. 7.9±0.07% (vehicle), P<0.001), as did all treatments, except gastrin-17 monotherapy. In contrast, only ZP3022, exendin-4 and combination treatment with exendin-4 and gastrin-17 significantly improved glucose tolerance and increased insulin levels during an OGTT. Moreover, only ZP3022 significantly enhanced the beta cell fraction in ZDF rats, a difference of 41%, when compared to the vehicle group (0.31±0.03 vs. 0.22±0.02%, respectively, P<0.05).
  
  
  CONCLUSIONS
  These data suggest that ZP3022 may have therapeutic potential in the prevention/delay of beta cell dysfunction in type 2 diabetes.
authors: Research and Development, Zealand Pharma A/S, Glostrup, Denmark. Electronic address: jsk@zealandpharma.com.
authors: Jolanta
authors: J
authors: Skarbaliene
authors: Gubra ApS, Hørsholm, Denmark.
authors: Thomas
authors: T
authors: Secher
authors: Gubra ApS, Hørsholm, Denmark.
authors: Jacob
authors: J
authors: Jelsing
authors: The Sanford Project, Children Health Research Center, Sanford Research/USD, Sioux Falls, SD, United States.
authors: Ansarullah
authors: Research and Development, Zealand Pharma A/S, Glostrup, Denmark.
authors: Trine S R
authors: TS
authors: Neerup
authors: Department of Biomedical Sciences, University of Copenhagen, Denmark.
authors: Nils
authors: N
authors: Billestrup
authors: Research and Development, Zealand Pharma A/S, Glostrup, Denmark.
authors: Keld
authors: K
authors: Fosgerau
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005755:Gastrins / Q000819:agonists / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects; D051379:Mice; D010455:Peptides / Q000008:administration & dosage*; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D005755:Gastrins; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007328:Insulin; D010455:Peptides; C581977:ZP3022
keywords: Dual agonist; Gastrin; Glucagon-like peptide-1; Pancreatic beta cell; Type 2 diabetes; Zucker diabetic fatty rats