title: Divergent effects of liraglutide, exendin-4, and sitagliptin on beta-cell mass and indicators of pancreatitis in a mouse model of hyperglycaemia.
abstract: OBJECTIVE
  Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4 inhibitor, sitagliptin, in the mouse.
  
  
  METHODS
  C57BL6 mice were maintained for 131 days on a normal diet (ND) or a diet comprising 60% fat (HFD) before measurements of fasting blood glucose and insulin, and intraperitoneal glucose tolerance. Beta- and alpha- cell volume, and Reg3b immunoreactivity, were measured by immunohistochemical analysis of pancreatic slices.
  
  
  RESULTS
  Whereas liraglutide (200 µg/kg) and exendin-4 (10 µg/kg) treatment reduced body weight and/or improved glucose tolerance, sitagliptin (10 mg/kg) was without effect on either parameter. Liraglutide caused a sharp reduction in beta-cell mass in both ND and HFD mice, whereas exendin-4 exerted no effect. By contrast, sitagliptin unmasked an action of high fat diet to increase beta-cell mass. Reg3B positive area was augmented by all three agents in normal chow-fed mice, whilst sitagliptin and exendin-4, but not liraglutide, affected this parameter in HFD animals. Correspondingly sitagliptin, but not the GLP-1 analogues, increased circulating amylase levels in ND and HFD mice.
  
  
  CONCLUSIONS
  Liraglutide improves glucose tolerance in the mouse whilst exerting relatively modest effects on pancreatitis risk. Conversely, exendin-4 and sitagliptin, at doses which exert, respectively, minor or no effects on metabolic parameters, lead to signs of pancreatitis.
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Angeles
authors.initials: A
authors.lastname: Mondragon
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Davidsson
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Styliana
authors.initials: S
authors.lastname: Kyriakoudi
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Annika
authors.initials: A
authors.lastname: Bertling
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Rosa
authors.initials: R
authors.lastname: Gomes-Faria
authors.affiliation: Imperial College Healthcare NHS Trust, Department of Pathology, St. Mary's Hospital, London, United Kingdom.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cohen
authors.affiliation: FILM, Imperial College London, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rothery
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chabosseau
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Gabriela
authors.initials: G
authors.lastname: da Silva Xavier
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D000077270:Exenatide; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000069450:Liraglutide / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000009:adverse effects* / Q000627:therapeutic use; D000068900:Sitagliptin Phosphate / Q000009:adverse effects* / Q000627:therapeutic use; D014688:Venoms / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000069450:Liraglutide; D000077270:Exenatide; D000068900:Sitagliptin Phosphate