Nutrient‐Stimulated Secretory Response and Mechanisms of the Incretins GLP‐1 and GIP Using Lymph as a Novel Assay Model

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins produced in the intestine that play a central role in glucose metabolism and insulin secretion. Plasma GLP-1 and GIP are low, in the range of 5–20 pM, and difficult to assay accurately in rodents. We have established a novel method of assaying GLP-1 and GIP using the intestinal lymph fistula model. Using this model, we have now determined that GLP-1 and GIP levels are 5–6 times higher in lymph than portal vein plasma, reaching postprandial peaks of 300 and 50 pM respectively. Intraduodenal administration of isocaloric meal of Intralipid, dextrin (a glucose polymer), or Intralipid plus dextrin caused significant increases in peak intestinal lymphatic GLP-1 and GIP secretion both at their peak and over 6 hours (P < 0.001). Incretin secretion was more rapid in response to Intralipid than dextrin. The combination of Intralipid plus dextrin additively stimulated GLP-1 and potentiated GIP secretion. When the surfactant, Pluronic L-81, was given concurrently with nutrients, GLP-1 and GIP secretion was blunted demonstrating the importance of chylomicron formation in incretin secretion. In conclusion, we have demonstrated that intestinal lymph is enriched with GLP-1 and GIP and the potential for lymphatic sampling as a novel and powerful means of studying the secretion and secretory mechanism of gut hormones in vivo.