The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are degraded by dipeptidyl peptidase IV (DPP IV), thereby losing insulinotropic activity. DPP IV inhibition reduces exogenous GLP-1 degradation, but the extent of endogenous incretin protection has not been fully assessed, largely because suitable assays which distinguish between intact and degraded peptides have been unavailable. Using newly developed assays for intact GLP-1 and GIP, the effect of DPP IV inhibition on incretin hormone metabolism was examined. Conscious dogs were given NVP-DPP728, a specific DPP IV inhibitor, at a dose that inhibited over 90% of plasma DPP IV for the first 90 min following treatment. Total and intact incretin concentrations increased (P< 0· 0001) following a mixed meal, but on control days (vehicle infusion), intact peptide concentrations were lower (P< 0· 01) than total peptide concentrations (22· 61· 2% intact GIP; 10· 10· 4% intact GLP-1).

Following inhibitor treatment, the proportion of intact peptide increased (92· 54· 3% intact GIP, P< 0· 0001; 99· 022· 6% intact GLP-1, P< 0· 02). Active (intact) incretins increased after NVP-DPP728 (from 4797364 to 10 649106 pMmin for GIP, P< 0· 03; from 646 134 to 2822528 pMmin for GLP-1, P< 0· 05). In contrast, total incretins fell (from 21632654 to 12 0841723 pMmin for GIP, P< 0· 002; from 5145677 to 3060601 pMmin for GLP-1, P< 0· 05). Plasma glucose, insulin and glucagon concentrations were unaltered by the inhibitor. We have concluded that DPP IV inhibition with NVP-DPP728 prevents N-terminal degradation of endogenous incretins in vivo, resulting in increased plasma concentrations of intact, biologically active GIP and GLP-1. Total incretin secretion was reduced by DPP IV inhibition, suggesting the possibility of a feedback mechanism.