The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis. METHODS: We have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRA(ΔNull)) or is expressed exclusively in the intestine (GcgRA(ΔVilCre)) or pancreas and duodenum (GcgRA(ΔPDX1Cre)). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists. RESULTS: Administration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance in GcgRA(Δnull) mice and control littermates and in GcgRA(ΔVilCre) and GcgRA(ΔPDX1Cre) mice. The potent GLP-1 receptor antagonist, exendin-[9–39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRA(ΔPDX1Cre) mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRA(ΔNull) or in GcgRA(ΔVilCre) mice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked in GcgRA(ΔNull) mice. CONCLUSIONS/INTERPRETATION: Taken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.