title: Incretin actions and consequences of incretin-based therapies: lessons from complementary animal models.
abstract: The two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1), were discovered 45 and 30 years ago. Initially, only their insulinotropic effect on pancreatic β cells was known. Over the years, physiological and pharmacological effects of GIP and GLP1 in numerous extrapancreatic tissues were discovered which partially overlap, but may also be specific for GIP or GLP1 in certain target tissues. While the insulinotropic effect of GIP was found to be blunted in patients with type 2 diabetes, the function of GLP1 is preserved and GLP1 receptor agonists and dipeptidyl-peptidase 4 (DPP4) inhibitors, which prolong the half-life of incretins, are widely used in diabetes therapy. Wild-type and genetically modified rodent models have provided important mechanistic insights into the incretin system, but may have limitations in predicting the clinical efficacy and safety of incretin-based therapies. This review summarizes insights from rodent and non-rodent models (pig, non-human primate) into physiological and pharmacological incretin effects, with a focus on the pancreas. Similarities and differences between species are discussed and the increasing potential of genetically engineered pig models for translational incretin research is highlighted.
authors.affiliation: Gene Centre, Centre for Innovative Medical Models (CiMM) and German Centre for Diabetes Research (DZD), Ludwig-Maximilians-Universität München, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Renner
authors.affiliation: Institute of Veterinary Pathology, Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Blutke
authors.affiliation: Gene Centre, Centre for Innovative Medical Models (CiMM) and German Centre for Diabetes Research (DZD), Ludwig-Maximilians-Universität München, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Streckel
authors.affiliation: Institute of Veterinary Pathology, Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Wanke
authors.affiliation: Gene Centre, Centre for Innovative Medical Models (CiMM) and German Centre for Diabetes Research (DZD), Ludwig-Maximilians-Universität München, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D005749:Gastric Inhibitory Polypeptide / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D054795:Incretins / Q000494:pharmacology / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D000069450:Liraglutide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011323:Primates; D011964:Receptors, Gastrointestinal Hormone / Q000502:physiology; D012377:Rodentia; D013552:Swine
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor
keywords: GIP; GIP receptor; GLP1; GLP1 receptor; GLP1 receptor agonist; human; liraglutide; mouse; non-human primate; pig