Improved stability, insulin-releasing activity and antidiabetic potential of two novel N-terminal analogues of gastric inhibitory polypeptide: N-acetyl-GIP and pGlu-GIP

F. P. M O'Harte, V. A. Gault, J. C. Parker, P Harriott, M. H. Mooney, C. J. Bailey, P. R. Flatt

Research output: Contribution to journalArticlepeer-review

Abstract

Aims/hypothesis. This study examined the plasma stability, biological activity and antidiabetic potential of two novel N-terminally modified analogues of gastric inhibitory polypeptide (GIP). Methods. Degradation studies were carried out on GIP, N-acetyl-GIP (Ac-GIP) and N-pyroglutamyl-GIP (pGlu-GIP) 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. Insulin-releasing ability was assessed in vitro in BRIN-BD11 cells and in obese diabetic (ob/ob) mice. Results. GIP was rapidly degraded by dipeptidylpeptidase IV and plasma (t1/2 2.3 and 6.2 h, respectively) whereas Ac-GIP and pGlu-GIP remained intact even after 24 h. Both Ac-GIP and pGlu-GIP were extremely potent (p<0.001) at stimulating cAMP production (EC50 values 1.9 and 2.7 nmol/l, respectively), almost a tenfold increase compared to native GIP (18.2 nmol/l). Both Ac-GIP and pGlu-GIP (10-13-10-8 mmol/l) were more potent at stimulating insulin release compared to the native GIP (p<0.001), with 1.3-fold and 1.2-fold increases observed at 10-8 mol/l, respectively. Administration of GIP analogues (25 nmol/kg body weight, i.p.) together with glucose (18 mmol/kg) in (ob/ob) mice lowered (p<0.001) 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 (p<0.001) and more prolonged insulin response after administration of Ac-GIP and pGlu-GIP (AUC, 644±54 and 576±51 ng·ml-1·min, respectively) compared with native GIP (AUC, 257±29 ng·ml-1·min). Conclusion/interpretation. Ac-GIP and pGlu-GIP, 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 (non-insulin-dependent) diabetes mellitus.

Original languageEnglish
Pages (from-to)1281-1291
Number of pages11
JournalDiabetologia
Volume45
Issue number9
DOIs
Publication statusPublished - 10 Oct 2002

Keywords

  • antihyperglycaemic effects
  • BRIN-BD11 cells
  • DPP IV stability
  • GIP analogues
  • insulin secretion
  • obese hyperglycaemic (ob/ob) mice

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