Divergent effects of liraglutide, exendin-4, and sitagliptin on beta-cell mass and indicators of pancreatitis in a mouse model of hyperglycaemia

• Published in: PloS one 2014-08, Vol.9 (8), p.e104873
• Main Authors: Mondragon, Angeles, Davidsson, Daniel, Kyriakoudi, Styliana, Bertling, Annika, Gomes-Faria, Rosa, Cohen, Patrizia, Rothery, Stephen, Chabosseau, Pauline, Rutter, Guy A, da Silva Xavier, Gabriela
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Antidiabetics; Beta cells; Biology; Biology and Life Sciences; Blood glucose; Blood Glucose - metabolism; Body weight; Body Weight - drug effects; Cancer therapies; Cell size; Diabetes; Diet; Dipeptidyl-peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - adverse effects; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Endocrinology; Exenatide; GLP-1 receptor agonists; Glucagon; Glucagon-like peptide 1; Glucose; Glucose tolerance; High fat diet; Hyperglycemia; Hyperglycemia - complications; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Hyperglycemia - pathology; Hypoglycemic agents; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Immunoreactivity; Insulin; Insulin - metabolism; Insulin resistance; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Kinases; Liraglutide - adverse effects; Liraglutide - therapeutic use; Male; Medicine; Medicine and Health Sciences; Metabolism; Mice; Mice, Inbred C57BL; Pancreas; Pancreas - drug effects; Pancreas - metabolism; Pancreas - pathology; Pancreatic beta cells; Pancreatic cancer; Pancreatitis; Pancreatitis - chemically induced; Pancreatitis - complications; Pancreatitis - metabolism; Pancreatitis - pathology; Parameters; Peptidase; Peptides; Peptides - adverse effects; Peptides - therapeutic use; Sitagliptin Phosphate - adverse effects; Sitagliptin Phosphate - therapeutic use; Venoms - adverse effects; Venoms - therapeutic use; Weight reduction
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0104873

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. 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. 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. 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.