Improved glycaemic control in obese diabetic ob/ob mice using N-terminallymodified gastric inhibitory polypeptide

Gastric inhibitory polypeptide (GIP) is an important insulin-releasing horm one of the enteroinsular axis which is rapidly inactivated by the exopeptid ase dipeptidyl peptidase (DPP) IV. The present study has examined the abili ty of Tyr(1)-glucitol GIP to be protected from plasma degradation and to en hance insulin-releasing and antihyperglycaemic activity in 20- to 25-week-o ld obese diabetic ob/ob mice. Degradation of GIP by incubation at 37 degree s C with obese mouse plasma was clearly evident after 3 h (35% degraded). A fter 6 h, more than 61% of GIP was converted to GIP(3-42) whereas N-termina lly modified Tyr(1)-glucitol GIP was resistant to degradation in plasma (>9 9% intact after 6 h). The formation of GIP(3-42) was almost completely abol ished by inhibition of plasma DPP IV with diprotin A. Effects of GIP and Ty r(1)-glucitol GIP were examined in overnight-fasted obese mice following i. p. injection of either peptide (20 nmol/kg) together with glucose (18 mmol/ kg) or in association with feeding. Most prominent effects were observed in the former group where plasma glucose values at 60 min together with the a rea under the curve (AUC) for glucose were significantly lower following GI P (AUC, 874 +/- 72 mmol/l.min; P < 0.01) or Tyr(1)-glucitol GIP (770 +/- 13 4 mmol/l.min; P < 0.001) as compared with administration of glucose alone ( 1344 +/- 136 mmol/l.min). This was associated with a significantly greater and more protracted insulin response following Tyr(1)-glucitol GIP than GIP (AUC, 491 +/- 118 vs 180 +/- 33 ng/ml.min; P < 0.05). Administration of Ty r(1)-glucitol GIP also enhanced the glucose-lowering ability of 50 units/kg insulin (218.4 +/- 30.2 vs insulin alone 133.9 +/- 16.2 mmol/l.min; P < 0. 05). These data demonstrate that Tyr(1)-glucitol GIP displays resistance to plasma DPP IV degradation in a commonly used animal model of type 2 diabet es, resulting in enhanced antihyperglycaemic activity and insulin-releasing action in vivo.