Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26

Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26

^*Centre d'Immunologie de Marseille Luminy, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique Case 906, Parc Scientifique de Luminy, 13288 Marseille Cedex 9, France; ^†Department of Medicine, Toronto General Hospital, Banting and Best Diabetes Centre, University of Toronto, 200 Elizabeth Street CCRW3–838, Toronto, ON M5G 2C4, Canada; ^‡Department of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-82, Japan; and Departments of ^§Biochemistry, ^¶Pharmacological Research I, and ^‖Molecular Genetics, Health Care Discovery, Novo Nordisk, Novo Allé, DK-2880 Bagsvaerd, Denmark

Edited by Donald F. Steiner, The University of Chicago, Chicago, IL, and approved April 11, 2000 (received for review February 16, 2000)

Abstract

A subset of prolyl oligopeptidases, including dipeptidyl-peptidase IV (DPP IV or CD26, EC 3.4.14.5), specifically cleave off N-terminal dipeptides from substrates having proline or alanine in amino acid position 2. This enzyme activity has been implicated in the regulation of the biological activity of multiple hormones and chemokines, including the insulinotropic peptides glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Targeted inactivation of the CD26 gene yielded healthy mice that have normal blood glucose levels in the fasted state, but reduced glycemic excursion after a glucose challenge. Levels of glucose-stimulated circulating insulin and the intact insulinotropic form of GLP-1 are increased in CD26^−/− mice. A pharmacological inhibitor of DPP IV enzymatic activity improved glucose tolerance in wild-type, but not in CD26^−/−, mice. This inhibitor also improved glucose tolerance in GLP-1 receptor^−/− mice, indicating that CD26 contributes to blood glucose regulation by controlling the activity of GLP-1 as well as additional substrates. These data reveal a critical role for CD26 in physiological glucose homeostasis, and establish it as a potential target for therapy in type II diabetes.

Footnotes

↵ ** To whom reprint requests should be addressed. E-mail: wagt{at}novo.dk.
This paper was submitted directly (Track II) to the PNAS office.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.120069197.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.120069197
Abbreviations:

DPP,

dipeptidyl-peptidase;

GLP-1,

glucagon-like peptide 1;

GLP-1R,

GLP-1 receptor;

GIP,

glucose-dependent insulinotropic polypeptide;

pNA,

p-nitroanilide