| First Author | Hutch CR | Year | 2019 |
| Journal | Diabetologia | Volume | 62 |
| Issue | 10 | Pages | 1928-1937 |
| PubMed ID | 31414143 | Mgi Jnum | J:280275 |
| Mgi Id | MGI:6364576 | Doi | 10.1007/s00125-019-4963-5 |
| Citation | Hutch CR, et al. (2019) The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice. Diabetologia 62(10):1928-1937 |
| abstractText | 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(DeltaNull)) or is expressed exclusively in the intestine (GcgRA(DeltaVilCre)) or pancreas and duodenum (GcgRA(DeltaPDX1Cre)). 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(DeltaNull) mice and control littermates and in GcgRA(DeltaVilCre) and GcgRA(DeltaPDX1Cre) mice. The potent GLP-1 receptor antagonist, exendin-[9-39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRA(DeltaPDX1Cre) mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRA(DeltaNull) or in GcgRA(DeltaVilCre) 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(DeltaNull) 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. |
