incretins and Irritable-Bowel-Syndrome

The incretin effect of the gut peptide hormone glucagon-like peptide-1 (GLP-1) is a combined result of inhibition of gastric emptying and stimulation of insulin secretion via an incretin mechanism. The temporal pattern of these events implicate that gastric emptying is primarily delayed, while later in the digestive process insulin is released for nutrient disposal. Since the inhibitory effect of GLP-1 on gastric motility is very outspoken, we considered it of value to study its effects on gut motility. Animal experimentation in the rat clearly showed that not only gastric emptying, but also small bowel motility with the migrating myoelectric complex was profoundly inhibited by GLP-1 at low doses. Similar effects were seen with analogues of the peptide. Extending the studies to man supported our earliest data indicating that the migrating motor complex of the small intestine was affected, and even more noticeable, the summarized motility index inhibited. Further extension of our studies to patients with irritable bowel syndrome (IBS) displayed similar results. This encouraged us to embark on a clinical pain-relief multi-centre study in IBS patients using a GLP-1 analogue, ROSE-010, with longer half-life than the native peptide. The outcome of the IBS study proved ROSE-010 to be superior to placebo with a pain-relief response rate of 24% for ROSE-010 compared to 12% for placebo. Taken together, the GLP-1 analogue ROSE-010 is believed to cause relaxation of the gut and can thereby relieve an acute pain attack of IBS, even though its precise mechanism is yet to be defined.

Topics: Animals; Gastrointestinal Motility; Glucagon-Like Peptide 1; Humans; Incretins; Irritable Bowel Syndrome

Patients with irritable bowel syndrome (IBS) may experience postprandial symptom exacerbation. Nutrients stimulate intestinal release of glucagon-like peptide 1 (GLP-1), an incretin hormone with known gastrointestinal effects. However, prior to the postprandial rise in GLP-1, levels of the hunger hormone, ghrelin, peak. The aims of this study were to determine if ghrelin sensitizes colonic intrinsic and extrinsic neurons to the stimulatory actions of a GLP-1 receptor agonist, and if this differs in a rat model of IBS.. Calcium imaging of enteric neurons was compared between Sprague Dawley and Wistar Kyoto rats. Colonic contractile activity and vagal nerve recordings were also compared between strains.. Circulating GLP-1 concentrations differ between IBS subtypes. Mechanistically, we have provided evidence that calcium responses evoked by exendin-4, a GLP-1 receptor agonist, are potentiated by a ghrelin receptor (GHSR-1) agonist, in both submucosal and myenteric neurons. Although basal patterns of colonic contractility varied between Sprague Dawley and Wister Kyoto rats, the capacity of exendin-4 to alter smooth muscle function was modified by a GHSR-1 agonist in both strains. Gut-brain signaling via GLP-1-mediated activation of vagal afferents was also potentiated by the GHSR-1 agonist.. These findings support a temporal interaction between ghrelin and GLP-1, where the preprandial peak in ghrelin may temporarily sensitize colonic intrinsic and extrinsic neurons to the neurostimulatory actions of GLP-1. While the sensitizing effects of the GHSR-1 agonist were identified in both rat strains, in the rat model of IBS, underlying contractile activity was aberrant.

Topics: Animals; Colon; Constipation; Diarrhea; Electrophysiological Phenomena; Enteric Nervous System; Exenatide; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Irritable Bowel Syndrome; Muscle Contraction; Muscle, Smooth; Neurons; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Ghrelin; Vagus Nerve