Aims/hypothesis. This study examined the biological effects of the GIP receptor antagonist, (Pro3)GIP and the GLP-1 receptor antagonist, exendin(9–39)amide.
Methods. Cyclic AMP production was assessed in Chinese hamster lung fibroblasts transfected with human GIP or GLP-1 receptors, respectively. In vitro insulin release studies were assessed in BRIN-BD11 cells while in vivo insulinotropic and glycaemic responses were measured in obese diabetic (ob/ob) mice.
Results. In GIP receptor-transfected fibroblasts, (Pro3)GIP or exendin(9–39)amide inhibited GIP-stimulated cyclic AMP production with maximal inhibition of 70.0±3.5% and 73.5±3.2% at 10−6 mol/l, respectively. In GLP-1 receptor-transfected fibroblasts, exendin(9–39)amide inhibited GLP-1-stimulated cyclic AMP production with maximal inhibition of 60±0.7% at 10−6 mol/l, whereas (Pro3)GIP had no effect. (Pro3)GIP specifically inhibited GIP-stimulated insulin release (86%; p<0.001) from clonal BRIN-BD11 cells, but had no effect on GLP-1-stimulated insulin release. In contrast, exendin(9–39)amide inhibited both GIP and GLP-1-stimulated insulin release (57% and 44%, respectively; p<0.001). Administration of (Pro3)GIP, exendin(9–39)amide or a combination of both peptides (25 nmol/kg body weight, i.p.) to fasted (ob/ob) mice decreased the plasma insulin responses by 42%, 54% and 49%, respectively (p<0.01 to p<0.001). The hyperinsulinaemia of non-fasted (ob/ob) mice was decreased by 19%, 27% and 18% (p<0.05 to p<0.01) by injection of (Pro3)GIP, exendin(9–39)amide or combined peptides but accompanying changes of plasma glucose were small.
Conclusions/interpretation. These data show that (Pro3)GIP is a specific GIP receptor antagonist. Furthermore, feeding studies in one commonly used animal model of obesity and diabetes, (ob/ob) mice, suggest that GIP is the major physiological component of the enteroinsular axis, contributing approximately 80% to incretin-induced insulin release.