Gastric inhibitory polypeptide (GIP) is an important insulin-releasing hormone of the enteroinsular axis which is rapidly inactivated by the exopeptidase dipeptidyl peptidase (DPP) IV. The present study has examined the ability of Tyr(1)-glucitol GIP to be protected from plasma degradation and to enhance insulin-releasing and antihyperglycaemic activity in 20- to 25-week-old obese diabetic ob/ob mice. Degradation of GIP by incubation at 37 degrees C with obese mouse plasma was clearly evident after 3 h (35% degraded). After 6 h, more than 61% of GIP was converted to GIP(3-42) whereas N-terminally modified Tyr(1)-glucitol GIP was resistant to degradation in plasma (>99% intact after 6 h). The formation of GIP(3-42) was almost completely abolished by inhibition of plasma DPP IV with diprotin A. Effects of GIP and Tyr(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 area under the curve (AUC) for glucose were significantly lower following GIP (AUC, 874+/-72 mmol/l.min; P<0.01) or Tyr(1)-glucitol GIP (770+/-134 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 Tyr(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 diabetes, resulting in enhanced antihyperglycaemic activity and insulin-releasing action in vivo.