NH2-terminally modified gastric inhibitory polypeptide exhibits amino-peptidase resistance and enhanced antihyperglycemic activity

Gastric inhibitory polypeptide (GIP) is an important insulin-releasing horm one of the enteroinsular axis that, like glucagon-like peptide 1(7-36) amid e (tGLP-I), has a functional profile of possible therapeutic value for type 2 diabetes, Both incretin hormones are rapidly inactivated in plasma by th e exopeptidase dipeptidyl peptidase (DPP) IV, The present study examined th e ability of NH2-terminal modification of human GIP to protect Born plasma degradation and enhance insulin-releasing and antihyperglycemic activity De gradation of GIP by incubation at 37 degrees C with purified DPP IV was cle arly evident after 4 h (54% intact). After 12 h, >60% of GIP was converted to GIP(3-42), whereas >99% of NH2-terminally modified Tyr(1)-glucitol GIP r emained intact. Tyr(1)-glucitol GIP was similarly resistant to serum degrad ation. The formation of GIP(3-42) was almost completely abolished by inhibi tion of plasma DPP IV with diprotin A, Effects of GIP and Tyr(1)-glucitol G IP were examined in Wistar rats after intraperitoneal injection of either p eptide (10 nmol/kg) together with glucose (18 mmol/kg), Plasma glucose conc entrations were significantly lower and insulin concentrations higher after both peptides compared with glucose alone. More importantly, individual gl ucose values at 15 and 30 min together with the areas under the curve (AUCs ) for glucose were significantly lower after administration of Tyr(1)-gluci tol GIP compared with GIP (AUC 255 +/- 33 vs. 368 +/- 8 mmol.l(-1).min(-1), respectively; P < 0.01), This was associated with a significantly greater and more protracted insulin response after Tyr(1)-glucitol GIP than GIP (AU C 773 +/- 41 vs. 639 +/- 39 ng.ml(-1).min(-1) P < 0.05). These data demonst rate that Tyr(1)-glucitol GIP displays resistance to plasma DPP IV degradat ion and exhibits enhanced antihyperglycemic activity and insulin-releasing action in vivo.