Role of Macronutrients in the Regulation and Secretory Mechanisms of Gastrointestinal Hormones, Glucagon-like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP), in Lymph

Abstract

When glucose is taken orally, insulin secretion is stimulated much more than when glucose is infused intravenously. This effect, termed the incretin effect, is caused mainly by the two intestinal hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These proteins, which are now classified as incretins, are central to the regulation of glucose metabolism. Their effect in type 2 diabetes patients is either greatly impaired or absent.

Studies of GLP-1 and GIP have relied primarily on measurement in the systemic blood. Plasma concentrations of these incretins are relatively low and difficult to assay in rodent models. We have established a novel lymph fistula model to investigate the secretion of GLP-1 and GIP. Using this model, we were able to detect higher levels of incretin in lymph than in hepatic portal plasma. The higher concentration of incretins in lymph results from less dilution and from lower degradation by the metabolizing dipeptidyl peptidase IV enzyme compared to blood. We studied the secretory behavior of GLP-1 and GIP in response to lipid, glucose, or the combination of these nutrients utilizing this model. The findings revealed GLP-1 release was more rapid following Liposyn than dextrin ingestion, while GIP release was greater in response to dextrin than Liposyn. Combination of the two nutrients in an isocaloric and isovolumetric manner induced GLP-1 secretion additively and potentiated the release of GIP.

While numerous studies have been done on the mechanism of glucose-stimulated incretin secretion, the mechanism of lipid-stimulated incretin secretion is not well-understood. We further investigated the role of chylomicron formation in incretin release following lipid ingestion using Pluronic L-81 (L-81), an inhibitor of chylomicron formation and secretion. The presence of L-81 reduced GLP-1 secretion in the early phase and abolished GIP secretion over a six-hour study suggesting chylomicron formation is critical in lipid-stimulated incretin secretion. In summary, the findings demonstrated that GLP-1 and GIP have independent pathways of secretion and that the lymph fistula model is an excellent model for in vivo studies of gastrointestinal hormones as the detected levels may be more reflective of the concentrations to which the enteric cells are exposed.