Effects of glucagonlike peptide I-(7-36) on release of insulin, glucagon, and somatostatin by rat pancreatic islet cell monolayer cultures

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Abstract
Glucagonlike peptide I (GLP-I-(7–36)) is cleaved from proglucagon in ileal epithelial cells and increases in human plasma after nutrient ingestion. This peptide has been shown to stimulate insulin secretion in vitro and in vivo and thus potentially acts as an incretin. To characterize its action on islet cells, the release of insulin, glucagon, and somatostatin by rat pancreatic islet monolayer cultures at varying concentrations of GLP-I-(7–36) was measured. The interaction of GLP-I-(7–36) with nutrient substrates was assessed by adding amino acids and differing glucose concentrations to the cultures. Islet cell cultures ( n = 5) were incubated for 1 h in medium containing 1.67 or 16.7 mM glucose or 1.67 mM glucose supplemented with amino acids and GLP-I-(7–36) at 10−13−10−7 M. Hormone release was compared with control cultures containing no GLP-I-(7–36); 1.67−16.7 mM glucose with and without GLP-I-(7–36) at 10−11 M; and 1.67, 3.3, 8.3, or 11.1 mM glucose alone or supplemented with amino acids, GLP-I-(7–36) 10−11 M, or both amino acids and GLP-I-(7–36). In medium with 1.67 or 16.7 mM glucose or 1.67 mM glucose and amino acids, GLP-I-(7–36) increased insulin secretion two- to threefold over control at concentrations of 10−9, 10−11, and 10−12 M, respectively. In medium with increasing concentrations of glucose, GLP-I-(7–36) at 10−11 M significantly increased insulin secretion at glucose concentrations ≥3.34 mM. Amino acids and GLP-I-(7–36) combined caused insulin secretion by the monolayer cultures at low glucose concentrations, whereas neither GLP-I-(7–36) nor amino acids alone were stimulatory. At higher glucose concentrations, amino acids and GLP-I-(7–36) together evoked greater insulin release than amino acids or GLP-I-(7–36) alone. With 16.7 mM glucose and GLP-I-(7–36) at 10−9 M, somatostatin release was increased by 40%. Glucagon release was not affected by any concentration of GLP-I-(7–36). Thus, the effect of GLP-I-(7–36) is enhanced in the presence of amino acids and glucose and, at putative physiological levels, is specific for pancreatic β-cells. We conclude that GLP-I-(7–36) is a potent insulinotropin that may be a physiological humoral modulator of nutrient-stimulated insulin secretion.