Dipeptidyl Peptidase IV-Resistant [d-Ala2]Glucose-Dependent Insulinotropic Polypeptide (GIP) Improves Glucose Tolerance in Normal and Obese Diabetic Rats
- Simon A. Hinke1,
- Richard W. Gelling1,
- Raymond A. Pederson1,
- Susanne Manhart2,
- Cuilan Nian1,
- Hans-Ulrich Demuth2 and
- Christopher H.S. McIntosh1
- 1Department of Physiology, University of British Columbia, Vancouver, Canada
- 2Probiodrug Research, Halle (Saale), Germany
The therapeutic potential of glucose-dependent insulinotropic polypeptide (GIP) for improving glycemic control has largely gone unstudied. A series of synthetic GIP peptides modified at the NH2-terminus were screened in vitro for resistance to dipeptidyl peptidase IV (DP IV) degradation and potency to stimulate cyclic AMP and affinity for the transfected rat GIP receptor. In vitro experiments indicated that [d-Ala2]GIP possessed the greatest resistance to enzymatic degradation, combined with minimal effects on efficacy at the receptor. Thus, [d-Ala2]GIP1–42 was selected for further testing in the perfused rat pancreas and bioassay in conscious Wistar and Zucker rats. When injected subcutaneously in normal Wistar, Fa/?, or fa/fa Vancouver Diabetic Fatty (VDF) Zucker rats, both GIP and [d-Ala2]GIP significantly reduced glycemic excursions during a concurrent oral glucose tolerance test via stimulation of insulin release. The latter peptide displayed greater in vivo effectiveness, likely because of resistance to enzymatic degradation. Hence, despite reduced bioactivity in diabetic models at physiological concentrations, GIP and analogs with improved plasma stability still improve glucose tolerance when given in supraphysiological doses, and thus may prove useful in the treatment of diabetic states.
Address correspondence and reprint requests to Christopher McIntosh, Department of Physiology, Faculty of Medicine, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. E-mail:.
Received for publication 12 September 2001 and accepted in revised form 19 November 2001.
DP IV, dipeptidyl peptidase IV; EC50, half-maximal stimulatory concentration; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; GRH, growth hormone-releasing hormone; HBS, HEPES-buffered saline; HPLC, high-performance liquid chromatography; IC50, half-maximal inhibitory concentration; OGTT, oral glucose tolerance test; RIA, radioimmunoassay; RT, retention time; TFA, trifluoroacetic acid.