Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26

摘要

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 regu- lation of the biological activity of multiple hormones and chemo- kines, 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 contrib- utes 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.