Metabolism of glucagon by dipeptidyl peptidase IV (CD26)

Glucagon is a 29-amino acid polypeptide released from pancreatic islet alph a-cells that acts to maintain euglycemia by stimulating hepatic glycogenoly sis and gluconeogenesis. Despite its importance, there remains controversy about the mechanisms responsible for glucagon clearance in the body. In the current study, enzymatic metabolism of glucagon was assessed using sensiti ve mass spectrometric techniques to identify the molecular products. Incuba tion of glucagon with purified porcine dipeptidyl peptidase IV (DP IV) yiel ded sequential production of glucagon(3-29) and glucagon(5-29). In human se rum, degradation to glucagon(3-29) was rapidly followed by N-terminal cycli zation of glucagon, preventing further DP IV-mediated hydrolysis. Bioassay of glucagon, following incubation with purified DP IV or normal rat serum d emonstrated a significant loss of hyperglycemic activity, while a similar i ncubation in DP IV-deficient rat serum did not show any loss of glucagon bi oactivity. Degradation, monitored by mass spectrometry and bioassay, was bl ocked by the specific DP IV inhibitor, isoleucyl thiazolidine. These result s identify DP IV as a primary enzyme involved in the degradation and inacti vation of glucagon. These findings have important implications for the dete rmination of glucagon levels in human plasma. (C) 2001 Elsevier Science B.V . All rights reserved.