Authors: F OHarte V Gault J Parker P Harriott M Mooney C Bailey P Flatt
Publish Date: 2002/07/16
Volume: 45, Issue: 9, Pages: 1281-1291
Abstract
Methods Degradation studies were carried out on GIP NacetylGIP AcGIP and NpyroglutamylGIP pGluGIP in vitro following incubation with either dipeptidylpeptidase IV or human plasma Cyclic adenosine 3′5′ monophosphate cAMP production was assessed in Chinese hamster lung fibroblast cells transfected with the human GIP receptor Insulinreleasing ability was assessed in vitro in BRINBD11 cells and in obese diabetic ob/ob miceResults GIP was rapidly degraded by dipeptidylpeptidase IV and plasma t1/2 23 and 62 h respectively whereas AcGIP and pGluGIP remained intact even after 24 h Both AcGIP and pGluGIP were extremely potent p0001 at stimulating cAMP production EC50 values 19 and 27 nmol/l respectively almost a tenfold increase compared to native GIP 182 nmol/l Both AcGIP and pGluGIP 10–13–10–8 mmol/l were more potent at stimulating insulin release compared to the native GIP p0001 with 13fold and 12fold increases observed at 10–8 mol/l respectively Administration of GIP analogues 25 nmol/kg body weight ip together with glucose 18 mmol/kg in ob/ob mice lowered p0001 individual glucose values at 60 min together with the areas under the curve for glucose compared to native GIP This antihyperglycaemic effect was coupled to a raised p0001 and more prolonged insulin response after administration of AcGIP and pGluGIP AUC 644±54 and 576±51 ng·ml–1·min respectively compared with native GIP AUC 257±29 ng·ml–1·minConclusion/interpretation AcGIP and pGluGIP show resistance to plasma dipeptidylpeptidase IV degradation resulting in enhanced biological activity and improved antidiabetic potential in vivo raising the possibility of their use in therapy of Type II noninsulindependent diabetes mellitus
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