ROSE-010

Glucagon-like peptide-1 (GLP-1) secretion from l-cells and postprandial inhibition of gastrointestinal motility.

Investigate whether physiological plasma concentrations of GLP-1 inhibit human postprandial motility and determine mechanism of action of GLP-1 and analog ROSE-010 action.

Single-blind parallel study.

University hospital laboratory.

Healthy volunteers investigated with antroduodenal manometry. Human gastric and intestinal muscle strips.

Motility indices (MIs) obtained before and during GLP-1 or saline infusion. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips investigated for GLP-1- and ROSE-010-induced relaxation employing GLP-1 and GLP-2 and their receptor localization, and blockers exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2',5'-dideoxyadenosine (DDA), and tetrodotoxin (TTX) to reveal target mechanism of GLP-1 action.

Postprandial gastrointestinal relaxation by GLP-1.

In humans, food intake increased MI to 6.4 ± 0.3 (antrum), 5.7 ± 0.4 (duodenum), and 5.9 ± 0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg/min suppressed corresponding MI to 4.6 ± 0.2, 4.7 ± 0.4, and 5.0 ± 0.2, whereas 1.2 pmol/kg/min suppressed MI to 5.4 ± 0.2, 4.4 ± 0.3, and 5.4 ± 0.3 (P < 0.0001 to 0.005). In vitro, GLP-1 and ROSE-010 prevented contractions by bethanechol and electric field stimulation (P < 0.005 to 0.05). These effects were disinhibited by exendin(9-39)amide, L-NMMA, DDA, or TTX. GLP-1 and GLP-2 were localized to epithelial cells, GLP-1 also at myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle.

GLP-1 and ROSE-010 inhibit postprandial gastrointestinal motility through GLP-1R at myenteric neurons, involving nitrergic and cyclic adenosine monophosphate-dependent mechanisms.

The glucagon-like peptide-1 (GLP-1) analog, ROSE-010, plays a critical role in alleviating abdominal pain in patients with irritable bowel syndrome (IBS); however, the underling mechanism is unclear. In the present study, we determined the serum GLP-1 level in patients with constipation-predominant IBS (IBS-C). The relationship between GLP-1 and abdominal pain was investigated. In addition, the expression of the GLP-1 receptor in the colon was determined.

Rectosigmoid biopsies were gathered from 38 patients with IBS-C who met the Rome III criteria, and 22 healthy controls. Abdominal pain was quantified by a validated questionnaire. Serum GLP-1 was measured by ELISA and correlated with abdominal pain scores. The presence of the GLP-1 receptor in the colonic mucosa was assessed by immunohistochemistry.

Serum GLP-1 was substantially decreased in patients with IBS-C. Decreased serum GLP-1 had a negative correlation with the abdominal pain scores. Biopsies from patients with IBS-C revealed a significant down-regulation of the GLP-1 receptor in colonic mucosa compared with control subjects.

Decreased serum GLP-1 correlates with abdominal pain in patients with IBS-C. Decreased expression of GLP-1 and GLP-1 receptor may be the basis for alleviation of abdominal pain in patients with IBS-C by ROSE-010.