Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice

We explored whether inhibition of the enzyme dipeptidyl peptidase IV (DPP I V) increases endogenous levels of glucagon-like peptide-1 (GLP-1) and impro ves glucose tolerance and insulin secretion in mice. Glucose (150 mg) was a dministered through a gastric gavage with or without the inhibitor of dipep tidyl peptidase IV, valine-pyrrolidide (100 mu mol/kg). in high-fat fed glu cose intolerant or control C57BL/6J mice. The increase in plasma GLP-1 afte r gastric glucose was potentiated by dipeptidyl peptidase IV inhibition (P < 0.05). Valine-pyrrolidide also potentiated the plasma insulin response to gastric glucose and improved the glucose tolerance in both groups of mice (P < 0.001). In contrast, valine-pyrrolidide did not affect glucose-stimula ted insulin secretion from isolated islets. This suggests that valine-pyrro lidide improves insulin secretion and glucose tolerance through indirect ac tion, probably through augmentation of levels of CLP-I and other incretin h ormones. Therefore, inhibition of dipeptidyl peptidase IV activity is feasi ble to exploit as a treatment for glucose intolerance and type 2 diabetes. (C) 2000 Elsevier Science B.V. All rights reserved.