Glucose-dependent insulinotropic polypeptide (GIP) is an important incretin hormone, which potentiates glucose-induced insulin secretion. Antihyperglycaemic actions of GIP provide significant potential in Type II diabetes therapy. However, inactivation of GIP by the enzyme dipeptidyl peptidase IV (DPP IV) and its consequent short circulating half-life limit its therapeutic use. Therefore two novel Tyr1-modified analogues of GIP, N-Fmoc-GIP (where Fmoc is 9-fluorenylmethoxycarbonyl) and N-palmitate-GIP, were synthesized and tested for metabolic stability and biological activity. Both GIP analogues were resistant to degradation by DPP IV and human plasma. In Chinese hamster lung (CHL) cells expressing the cloned human GIP receptor, both analogues exhibited a 2-fold increase in cAMP-generating potency compared with native GIP (EC50 values of 9.4, 10.0 and 18.2nM respectively). Using clonal BRIN-BD11 cells, both analogues demonstrated strong insulinotropic activity compared with native GIP (P<0.01 to P<0.001). In obese diabetic (ob/ob) mice, administration of N-Fmoc-GIP or N-palmitate-GIP (25nmol/kg) together with glucose (18mmol/kg) significantly reduced the peak 15min glucose excursion (1.4- and 1.5-fold respectively; P<0.05 to P<0.01) compared with glucose alone. The area under the curve (AUC) for glucose was significantly lower after administration of either analogue compared with glucose administered alone or in combination with native GIP (1.5-fold; P<0.05). This was associated with a significantly greater AUC for insulin (2.1-fold; P<0.001) for both analogues compared with native GIP. A similar pattern of in vivo responsiveness was evident in lean control mice. These data indicate that novel N-terminal Tyr1 modification of GIP with an Fmoc or palmitate group confers resistance to degradation by DPP IV in plasma, which is reflected by increased in vitro potency and greater insulinotropic and antihyperglycaemic activities in an animal model of Type II diabetes mellitus.
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Research Article|
November 01 2002
Enhanced cAMP generation and insulin-releasing potency of two novel Tyr1-modified enzyme-resistant forms of glucose-dependent insulinotropic polypeptide is associated with significant antihyperglycaemic activity in spontaneous obesity-diabetes
Victor A. GAULT;
Victor A. GAULT
∗School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, U.K.
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Peter R. FLATT;
Peter R. FLATT
∗School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, U.K.
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Clifford J. BAILEY;
Clifford J. BAILEY
†School of Pharmaceutical and Biological Sciences, Aston University, Birmingham B4 7ET, U.K.,
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Patrick HARRIOTT;
Patrick HARRIOTT
‡Centre for Peptide and Protein Engineering, School of Biology and Biochemistry, The Queen's University of Belfast, Medical Biology Centre, Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
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Brett GREER;
Brett GREER
‡Centre for Peptide and Protein Engineering, School of Biology and Biochemistry, The Queen's University of Belfast, Medical Biology Centre, Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
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Mark H. MOONEY;
Mark H. MOONEY
∗School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, U.K.
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Finbarr P.M. O'HARTE
Finbarr P.M. O'HARTE
1
∗School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, U.K.
1To whom correspondence should be addressed (e-mail fpm.oharte@ulster.ac.uk).
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Biochem J (2002) 367 (3): 913–920.
Article history
Received:
February 25 2002
Revision Received:
July 04 2002
Accepted:
August 01 2002
Accepted Manuscript online:
August 01 2002
Citation
Victor A. GAULT, Peter R. FLATT, Clifford J. BAILEY, Patrick HARRIOTT, Brett GREER, Mark H. MOONEY, Finbarr P.M. O'HARTE; Enhanced cAMP generation and insulin-releasing potency of two novel Tyr1-modified enzyme-resistant forms of glucose-dependent insulinotropic polypeptide is associated with significant antihyperglycaemic activity in spontaneous obesity-diabetes. Biochem J 1 November 2002; 367 (3): 913–920. doi: https://doi.org/10.1042/bj20020319
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