Nitrergic contribution to gastric relaxation induced by glucagon-like peptide-1 (GLP-1) in healthy adults

Andrews, Christopher N.; Bharucha, Adil E.; Camilleri, Michael; Low, Phillip A.; Seide, Barbara M.; Burton, Duane D.; Baxter, Kari; Zinsmeister, Alan R.

doi:10.1152/ajpgi.00403.2006

Cited by 24 publications

(24 citation statements)

References 54 publications

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“…Although the magnitude of the slowing of gastric emptying that we observed during euglycemia on GLP-1 is consistent with previous studies using acute administration of GLP-1 (13,28,29), this was dramatically potentiated during hyperglycemia, such that mean gastric emptying was only ;15% at 4 h. The mechanisms underlying the inhibitory effect of GLP-1 are incompletely understood; however, a number of studies indicate a putative role of vagal cholinergic pathways (28,35), and nitric oxide has been implicated as an important efferent neurotransmitter in GLP-1-induced gastric relaxation (36). Accordingly, there appears to be substantial overlap between the mechanisms governing slower gastric emptying during GLP-1 stimulation and hyperglycemia, which we speculate may account for the summative interaction observed in our study.…”

Section: Discussionsupporting

confidence: 88%

Hyperglycemia Potentiates the Slowing of Gastric Emptying Induced by Exogenous GLP-1

et al. 2015

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OBJECTIVEAcute hyperglycemia markedly slows gastric emptying. Exogenous GLP-1 also slows gastric emptying, leading to diminished glycemic excursions. The primary objective was to determine whether hyperglycemia potentiates the slowing of gastric emptying induced by GLP-1 administration. RESEARCH DESIGN AND METHODSTen healthy participants were studied on 4 separate days. Blood glucose was clamped at hyperglycemia using an intravenous infusion of 25% dextrose (∼12 mmol/L; hyper) on 2 days, or maintained at euglycemia (∼6 mmol/L; eu) on 2 days, between t = 215 and 240 min. During hyperglycemic and euglycemic days, participants received intravenous GLP-1 (1.2 pmol/kg/min) and placebo in a randomized double-blind fashion. At t = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq technetium-99m-sulfur colloid and 3 g 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from t = 0 to 240 min and serum 3-OMG taken at regular intervals from t = 15 to 240 min. The areas under the curve for gastric emptying and 3-OMG were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests. RESULTSHyperglycemia slowed gastric emptying (eu/placebo vs. hyper/placebo; P < 0.001) as did GLP-1 (eu/placebo vs. eu/GLP-1; P < 0.001). There was an additive effect of GLP-1 and hyperglycemia, such that gastric emptying was markedly slower compared with GLP-1 administration during euglycemia (eu/GLP-1 vs. hyper/GLP-1; P < 0.01). CONCLUSIONSAcute administration of exogenous GLP-1 profoundly slows gastric emptying during hyperglycemia in excess of the slowing induced by GLP-1 during euglycemia. Studies are required to determine the effects of hyperglycemia on gastric emptying with the subcutaneously administered commercially available GLP-1 agonists in patients with type 2 diabetes.Gastric emptying is a major determinant of postprandial glycemia in health, as well as in type 1 and type 2 diabetes (1,2), and accounts for ;35% of the variance in the initial glycemic response to oral carbohydrate (1). Accordingly, dietary and pharmacological strategies that slow gastric emptying, including short-acting GLP-1 agonists, are useful interventions to attenuate postprandial glycemic excursions and overall glycemia in type 2 diabetes (3).

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Section: Discussionsupporting

confidence: 88%

Hyperglycemia Potentiates the Slowing of Gastric Emptying Induced by Exogenous GLP-1

et al. 2015

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“…Tonini et al [22] elucidated that NO and VIP have different roles in the human gastric fundus relaxations: NO being accountable for relaxation evoked by low frequency electrical stimulation and VIP for high frequency stimulation-induced relaxation. In addition, a few in vivo experiments on healthy adults have shown that NOS inhibitor, N G -monomethyl-L-arginine (L-NMMA), blunts postprandial gastric accommodation by demonstrating a decrease in change of gastric volume after meal ingestion using either 99mTc-single-photon-emission computed tomography imaging [23] or gastric barostat [24,25]. In the same context, we investigated the inhibitory influences of NO in the early relaxation of the proximal human stomach in this study.…”

Section: Discussionmentioning

confidence: 99%

Nitrergic Pathway Is the Main Contributing Mechanism in the Human Gastric Fundus Relaxation: An In Vitro Study

Hong

et al. 2016

PLoS ONE

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BackgroundHuman gastric fundus relaxation is mediated by intrinsic inhibitory pathway. We investigated the roles of nitrergic and purinergic pathways, two known inhibitory factors in gastric motility, on spontaneous and nerve-evoked contractions in human gastric fundus muscles.MethodsGastric fundus muscle strips (12 circular and 13 longitudinal) were obtained from patients without previous gastrointestinal motility disorder who underwent gastrectomy for stomach cancer. Using these specimens, we examined basal tone, peak, amplitude, and frequency of spontaneous contractions, and peak and nadir values under electrical field stimulation (EFS, 150 V, 0.3 ms, 10 Hz, 20 s). To examine responses to purinergic and nitrergic inhibition without cholinergic innervation, atropine (muscarinic antagonist, 1 μM), MRS2500 (a purinergic P2Y1 receptor antagonist, 1 μM), and N-nitro-L-arginine (L-NNA, a nitric oxide synthase inhibitor, 100 μM) were added sequentially for spontaneous and electrically-stimulated contractions. Tetrodotoxin was used to confirm any neuronal involvement.ResultsIn spontaneous contraction, L-NNA increased basal tone and peak in both muscle layers, while amplitude and frequency were unaffected. EFS (up to 10 Hz) uniformly induced initial contraction and subsequent relaxation in a frequency-dependent manner. Atropine abolished initial on-contraction and induced only relaxation during EFS. While MRS2500 showed no additional influence, L-NNA reversed relaxation (p = 0.012 in circular muscle, and p = 0.006 in longitudinal muscle). Tetrodotoxin abolished any EFS-induced motor response.ConclusionsThe relaxation of human gastric fundus muscle is reduced by nitrergic inhibition. Hence, nitrergic pathway appears to be the main mechanism for the human gastric fundus relaxation.

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“…Furthermore, the inhibitory effect of GLP1 was also abolished in the presence of L-NNA, a blocker of NO synthesis, suggesting that it is mediated by NO production. Indeed, the involvement of nitrergic neural pathways has been reported in the effects induced by exogenous GLP1 on gastrointestinal motor function in different animal species, including humans (Tolessa et al 1998b, Andrews et al 2007, Amato et al 2010, Rotondo et al 2011.…”

Section: Discussionmentioning

confidence: 99%

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

Amato¹,

Baldassano²,

Liotta

et al. 2014

Journal of Endocrinology

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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.

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Nitrergic contribution to gastric relaxation induced by glucagon-like peptide-1 (GLP-1) in healthy adults

Cited by 24 publications

References 54 publications

Hyperglycemia Potentiates the Slowing of Gastric Emptying Induced by Exogenous GLP-1

Hyperglycemia Potentiates the Slowing of Gastric Emptying Induced by Exogenous GLP-1

Nitrergic Pathway Is the Main Contributing Mechanism in the Human Gastric Fundus Relaxation: An In Vitro Study

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

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