Double Incretin Receptor Knockout (DIRKO) Mice Reveal an Essential Role for the Enteroinsular Axis in Transducing the Glucoregulatory Actions of DPP-IV Inhibitors

• Published in: Diabetes (New York, N.Y.) Vol. 53; no. 5; pp. 1326 - 1335
• Main Authors: Hansotia, Tanya, Baggio, Laurie L., Delmeire, Dominique, Hinke, Simon A., Yamada, Yuichiro, Tsukiyama, Katsushi, Seino, Yutaka, Holst, Jens J., Schuit, Frans, Drucker, D.J.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2004
• Subjects: Animals; Associated diseases and complications; Biological and medical sciences; Care and treatment; Dextrose; Diabetes; Diabetes. Impaired glucose tolerance; Dipeptidyl Peptidase 4 - drug effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - pharmacology; Exenatide; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose - metabolism; Health aspects; Homeostasis; House mouse; Insulin; Insulin - metabolism; Insulin Secretion; Intestines - physiology; Islets of Langerhans - physiology; Medical sciences; Mice; Mice as laboratory animals; Mice, Inbred C57BL; Mice, Knockout; Organic Chemicals - pharmacology; Pancreatic beta cells; Peptides; Peptides - pharmacology; Plasma; Pyrroles - pharmacology; Receptors, Gastrointestinal Hormone - agonists; Receptors, Gastrointestinal Hormone - deficiency; Receptors, Gastrointestinal Hormone - physiology; Receptors, Glucagon - agonists; Receptors, Glucagon - deficiency; Receptors, Glucagon - physiology; Type 2 diabetes; Valine - pharmacology; Venoms - pharmacology; United States; Endocrinopathy; Vertebrata; Mammalia; Mouse; Enteroinsular axis; Animal; Diabetes mellitus; Rodentia; Mutation
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.53.5.1326

Double Incretin Receptor Knockout (DIRKO) Mice Reveal an Essential Role for the Enteroinsular Axis in Transducing the Glucoregulatory Actions of DPP-IV Inhibitors Tanya Hansotia 1 , Laurie L. Baggio 1 , Dominique Delmeire 2 , Simon A. Hinke 2 , Yuichiro Yamada 3 , Katsushi Tsukiyama 3 , Yutaka Seino 3 , Jens J. Holst 4 , Frans Schuit 2 and D.J. Drucker 1 1 Banting and Best Diabetes Centre, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Canada 2 Molecular Pharmacology Unit, Diabetes Research Center, Faculty of Medicine, Free University of Brussels, Brussels, Belgium 3 Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan 4 Department of Medical Physiology, Panum Institute, Copenhagen, Denmark Address correspondence and reprint requests to Daniel J. Drucker, MD, Banting and Best Diabetes Centre, Toronto General Hospital, 200 Elizabeth St., MBRW4R-402, Toronto, Ontario, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca Abstract Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived incretins that potentiate glucose clearance following nutrient ingestion. Elimination of incretin receptor action in GIPR −/− or GLP-1R −/− mice produces only modest impairment in glucose homeostasis, perhaps due to compensatory upregulation of the remaining incretin. We have now studied glucose homeostasis in double incretin receptor knockout (DIRKO) mice. DIRKO mice exhibit normal body weight and fail to exhibit an improved glycemic response after exogenous administration of GIP or the GLP-1R agonist exendin-4. Plasma glucagon and the hypoglycemic response to exogenous insulin were normal in DIRKO mice. Glycemic excursion was abnormally increased and levels of glucose-stimulated insulin secretion were decreased following oral but not intraperitoneal glucose challenge in DIRKO compared with GIPR −/− or GLP-1R −/− mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin in wild-type and single incretin receptor knockout mice, the glucose-lowering actions of DPP-IV inhibitors were eliminated in DIRKO mice. These findings demonstrate that glucose-stimulated insulin secretion is maintained despite complete absence of both incretin receptors, and they delineate a critical role for incretin receptors as essential downstream targets for the acute glucoregulatory actions of DPP-IV inhibitors. DIRKO, double incretin receptor knockout DPP-IV, dipeptidyl peptidase-IV GIP, glucose-dependent insulinotropic polypeptide GLP, glucagon-like peptide 1 Val-Pyr, valine pyrrolidide Footnotes F.S. is currently affiliated with the Gene Expression Unit, Afdeling Biochimie, Katholieke Universiteit Leuven, Leuven, Belgium. D.J.D. has received consulting fees from Merck, Syrrx, and Triad. Accepted February 4, 2004. Received November 25, 2003. DIABETES