Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26

A subset of prolyl oligopeptidases, including dipeptidyl-peptidase IV (DPP IV or CD26, EC 3.4.14.5), specifically cleave off N-terminal dipeptides fro m substrates having proline or alanine in amino acid position 2, This enzym e 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 polyp eptide (GIP), Targeted inactivation of the CD26 gene yielded healthy mice t hat have normal blood glucose levels in the fasted state, but reduced glyce mic excursion after a glucose challenge. Levels of glucose-stimulated circu lating insulin and the intact insulinotropic form of GLP-1 are increased in CD26(-/-) mice. A pharmacological inhibitor of DPP IV enzymatic activity i mproved glucose tolerance in wildtype, but not in CD26(-/-), mice. This inh ibitor also improved glucose tolerance in GLP-1 receptor(-/-) mice, indicat ing that CD26 contributes to blood glucose regulation by controlling the ac tivity of GLP-1 as well as additional substrates. These data reveal a criti cal role for CD26 in physiological glucose homeostasis, and establish it as a potential target for therapy in type II diabetes.