Incretins are intestinal factors that stimulate postprandial insulin secretion in preparation for subsequent rises in plasma levels of ingested nutrients. Glucose-dependent insulinotropic peptide (GIP), a duodenal endocrine peptide, is ideally located for such a function. In contrast, the intestinal proglucagon-derived peptide (PGDP), truncated GLP-1 [GLP-1(7-37) or tGLP-1] is equipotent to GIP in insulinotropic activity, but due to its localization in the distal ileum, appears to be poorly situated to fulfill an incretin role in response to direct nutrient stimulation. Despite its distribution, rapid increments in plasma levels of tGLP-1 have been noted in response to nutrient ingestion. We have recently reported that GIP (but not other nutrient-stimulated duodenal endocrine peptides) can stimulate intestinal PGDP secretion in vitro, and therefore hypothesized that GIP might regulate secretion of the intestinal PGDPs, including tGLP-1, in response to nutrient ingestion in vivo in the rat. Placement of either fat or glucose directly into the ileal lumen was demonstrated to significantly stimulate secretion of the intestinal PGDPs (P < 0.05), whereas fat or glucose in the duodenal lumen significantly increased plasma levels of GIP (P < 0.05). In addition, however, duodenal fat treatment also increased the secretion of intestinal PGDPs into the circulation (P < 0.05), with levels rising to same extent as observed after direct administration of fat into the ileum. The rise in plasma GIP levels in response to duodenal fat treatment occurred slightly before the increments in intestinal PGDP levels, suggesting a relationship between the two peptides. Intravenous infusion of GIP to give concentrations similar to those observed after duodenal fat administration induced a 2-fold increase in plasma levels of intestinal PGDPs that was independent of glycemic levels (P < 0.05). No increment in intestinal PGDPs was found in response to infusion of another duodenal endocrine peptide, cholecystokinin. Thus, these data demonstrate a specific effect of GIP to stimulate secretion of the intestinal PGDPs in vivo in the rat. This enteroendocrine loop between the duodenal peptide GIP and the ileal PGDPs may account for some of the early rises in secretion of tGLP-1 observed in response to nutrient ingestion.