Improved biological activity of Gly²- and Ser²-substituted analogues of glucose-dependent insulinotrophic polypeptide

The therapeutic potential of glucagon-like peptide-1 (GLP-1) in improving glycaemic control in diabetes has been widely studied, but the potential beneficial effects of glucose-dependent insulinotropic polypeptide (GIP) have until recently been almost overlooked. One of the major problems, however, in exploiting either GIP or GLP-1 as potential therapeutic agents is their short duration of action, due to enzymatic degradation in vivo by dipeptidylpeptidase IV (DPP IV). Therefore, this study examined the plasma stability, biological activity and antidiabetic potential of two novel NH₂-terminal Ala²-substituted analogues of GIP, containing glycine (Gly) or serine (Ser). Following incubation in plasma, (Ser²)GIP had a reduced hydrolysis rate compared with native GIP, while (Gly²)GIP was completely stable. In Chinese hamster lung fibroblasts stably transfected with the human GIP receptor, GIP, (Gly²)GIP and (Ser²) GIP stimulated cAMP production with EC₅₀ values of 18.2, 14.9 and 15.0 nM respectively. In the pancreatic BRIN-BD11 β-cell line, (Gly²)GIP and (Ser²)GIP (10^-8 M) evoked significant increases (1.2- and 1.5-fold respectively; P<0.01 to P<0.001) in insulinotropic activity compared with GIP. In obese diabetic ob/ob mice, both analogues significantly lowered (P<0.001) the glycaemic excursion in response to i.p. glucose. This enhanced glucose-lowering ability was coupled to a significantly raised (P<0.01) and more protracted insulin response compared with GIP. These data indicate that substitution of the penultimate Ala² in GIP by Gly or Ser confers resistance to plasma DPP IV degradation, resulting in enhanced biological activity, therefore raising the possibility of their use in the treatment of type 2 diabetes.