Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle

Abstract

Glucagon-like peptide 1 (GLP1) is a naturally occurring peptide secreted by intestinal L-cells. Though its primary function is to serve as an incretin, GLP1 reduces gastrointestinal motility. However, only a handful of animal studies have specifically evaluated the influence of GLP1 on colonic motility. Consequently, the aims of this study were to investigate the effects induced by exogenous GLP1, to analyze the mechanism of action, and to verify the presence of GLP1 receptors (GLP1Rs) in human colon circular muscular strips. Organ bath technique, RT-PCR, western blotting, and immunofluorescence were used. In human colon, exogenous GLP1 reduced, in a concentration-dependent manner, the amplitude of the spontaneous contractions without affecting the frequency and the resting basal tone. This inhibitory effect was significantly reduced by exendin (9-39), a GLP1R antagonist, which per se significantly increased the spontaneous mechanical activity. Moreover, it was abolished by tetrodotoxin, a neural blocker, or N u -nitro-L-arginine -a blocker of neuronal nitric oxide synthase (nNOS). The biomolecular analysis revealed a genic and protein expression of the GLP1R in the human colon. The double-labeling experiments with anti-neurofilament or anti-nNOS showed, for the first time, that immunoreactivity for the GLP1R was expressed in nitrergic neurons of the myenteric plexus. In conclusion, the results of this study suggest that GLP1R is expressed in the human colon and, once activated by exogenous GLP1, mediates an inhibitory effect on large intestine motility through NO neural release.

Nitric oxide regulation of migrating motor complex: randomized trial of NG‐monomethyl‐l‐arginine effects in relation to muscarinic and serotonergic receptor blockade

“…In line with this, nNOS was distinctively present in the neurones of the gut, whereas no NOS immunoreactivity for any isoform was found in smooth muscle. Our findings are in accordance with Amato et al (2014), who found nNOS immunoreactivity in myenteric neurones. This is consistent with the concept that nNOS inhibition increases basal myogenic tone as well as bethanechol-stimulated contractions.…”

GLP-1 based therapies: clinical implications for gastroenterologists

“…The colonic effects of GLP-1 are less clear 32. GLP-1 seems to inhibit colonic motility, as was shown by reduced circular contractions in full thickness muscular colon strips 79 80. Notably, a reduction in glycaemia tends to increase intestinal motility, thus the direct inhibitory effect of GLP-1 and GLP-1RAs are likely to be underestimated in these studies 81.…”

“…Notably, a reduction in glycaemia tends to increase intestinal motility, thus the direct inhibitory effect of GLP-1 and GLP-1RAs are likely to be underestimated in these studies 81. Similar to the gastric responses, the intestinal effects appear to be indirect and are probably mediated through neuronal involvement 40 79 82 83…”

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“…Recent in vitro studies identified the presence of GLP-1R in muscle cells of the human colon with exposure to GLP-1 reducing the amplitude of spontaneous contractions due to the neural production of NO but without altering the frequency and basal tone of contractions at rest. This action could contribute to delaying enteric propulsion, increasing the absorption of water and electrolytes and may cause constipation [116] .…”