Evidence has accumulated that the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1(7-36) amide) are degraded and rendered biologically inactive in plasma by the enzyme dipeptidyl peptidase IV (DPIV). A strain of Fischer rats lacking the DPIV enzyme were used in the current investigation as a model for examining the enteroinsular axis under conditions in which normal inactivation of GIP and GLP-1(7-36) does not occur. This was assessed by comparing GIP and GLP-1(7-36) responses following oral glucose in normal versus DPIV-deficient Fischer rats, and by comparing the insulinotropic potency of both peptides in the perfused pancreas of both groups. The insulin response to an oral glucose challenge was decreased slightly in DPIV-negative rats compared with control animals. Of the two incretins, the GIP response to oral glucose was reduced by 50% compared with controls, whereas GLP-1(7-36) release in response to glucose was unchanged. A decrease of 30% in the sensitivity of the perfused pancreas of DPIV-negative rats to GIP was observed, whereas the insulin response to GLP(7-36) was identical in both groups. Incubation of both peptides in plasma from DPIV-positive and -negative rats was performed to determine the effect of the presence or absence of DPIV on the insulinotropic activity of GLP-1(7-36) and GIP in the isolated perfused rat pancreas. Incubation in plasma from DPIV-positive rats resulted in a 65% decrease in insulinotropic activity of both incretins compared with incubation in plasma from DPIV-deficient rats. It was hypothesized that the reduced GIP response and decreased sensitivity of the pancreas to GIP are compensatory mechanisms that maintain insulin and glucose levels within a normal range despite abnormal degradation of GIP. An explanation of the lack of effect of the absence of DPIV on the GLP-1(7-36) response to oral glucose and insulinotropic action of this peptide must await further study.