Glucagon-Like Peptide-1 Inhibits Prandial Gastrointestinal Motility Through Myenteric Neuronal Mechanisms in Humans

Halim, Abdul; Degerblad, Marie; Sundbom, Magnus; Karlbom, Urban; Holst, Jens J.; Webb, Dominic-Luc; Hellström, Per M.

doi:10.1210/jc.2017-02006

Cited by 37 publications

(30 citation statements)

References 46 publications

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“…The peak of circulating GLP-1 levels coincides with postprandial symptom manifestation in patients with IBS 12 and in addition to its role as an incretin hormone, GLP-1 also modifies GI function, 13 both in healthy controls 46 and in patients with IBS. The peak of circulating GLP-1 levels coincides with postprandial symptom manifestation in patients with IBS 12 and in addition to its role as an incretin hormone, GLP-1 also modifies GI function, 13 both in healthy controls 46 and in patients with IBS.…”

Section: Discussionmentioning

confidence: 99%

“…GLP-1 can act as a classic hormone, a paracrine molecule, or a neuromodulatory factor. The peak of circulating GLP-1 levels coincides with postprandial symptom manifestation in patients with IBS 12 and in addition to its role as an incretin hormone, GLP-1 also modifies GI function, 13 both in healthy controls 46 and in patients with IBS. [14][15][16] Given our previous work, 10 where we determined that fasting GLP-1 levels are decreased in diarrhea-predominant…”

Section: Discussionmentioning

confidence: 99%

“…31 Wister Kyoto rats exhibited anxious behaviors such as freezing and avoiding the exposed inner zone of the open field arena and, although fecal water content was not significantly increased, they defecated more often than their control comparators. [14][15][16]46 We have previously established the intricate relationship between hormones and immune molecules and demonstrated the efficacy of xIL-6R in reducing stress-induced defecation in WKY rats. 48 Therefore, in our studies Ex-4 was administered 1 hour prior to behavioral assessments.…”

Section: Discussionmentioning

confidence: 99%

“…Decreased excretion of fecal boli in Ex-4 treated WKY rats is consistent with reports in humans that Ex-4 mollified colonic transit. [14][15][16]46 We have previously established the intricate relationship between hormones and immune molecules and demonstrated the efficacy of xIL-6R in reducing stress-induced defecation in WKY rats. 31 However, in this study, no further change in stress-induced defecation was observed in WKY rats co-treated with xIL-6R and Ex-4.…”

Section: Ibs Patients One Could Propose That Supplementing Patients mentioning

confidence: 99%

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The Glucagon‐like peptide‐1 receptor agonist, exendin‐4, ameliorated gastrointestinal dysfunction in the Wistar Kyoto rat model of Irritable Bowel Syndrome

O’Brien

O’Malley

2019

Neurogastroenterology Motil

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Background: Glucagon-like peptide-1 (GLP-1) is beneficial in relieving pain-related symptoms of Irritable bowel syndrome (IBS), a prevalent, multi-factorial functional bowel disorder characterized by diarrhea and/or constipation, abdominal bloating, and pain. Activation of myenteric neurons has been implicated in the inhibitory effects of GLP-1 on gastrointestinal motility; however, the mechanisms of action underlying this are not clear. Methods: A rat model of IBS was used to examine physiological changes evoked by intraperitoneal administration of a GLP-1 receptor agonist, exendin-4. Behavioral and physiological analysis of stress-sensitive Wister Kyoto (WKY) rats was used to determine if administration of exendin-4, in the presence or absence of neutralizing interleukin-6 receptor monoclonal antibodies, modified IBS-like symptoms. Immunofluorescence, calcium imaging, and Western blotting techniques were used to investigate the potential role of enteric neural plexi and tight junction protein expression in this effect. Key Results: Consistent with the expression of GLP-1 and interleukin-6 receptors in both submucosal and myenteric ganglia, exendin-4 and interleukin-6 stimulated calcium responses in these neurons. In vivo administration of exendin-4 normalized stress-induced defecation and visceral pain sensitivity in WKY rats. No additional changes were noted in rats co-treated with exendin-4 and anti-interleukin-6 receptor antibodies. Mucosal expression of occludin, a tight junction protein, was decreased by exendin-4. Centrally regulated anxiety-like behaviors were not modified. Conclusions and Inferences: These data suggest that intraperitoneal injection of exendin-4 improves bowel dysfunction in WKY rats without impacting on centrally regulated anxiety-like behaviors. Modulation of enteric neuronal function and tight junction expression appear to underlie the functional benefits of this intervention. K E Y W O R D S colorectal distension, exendin-4, glucagon-like peptide-1, interleukin-6, open field, stress, Wister Kyoto

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ibs Patients One Could Propose That Supplementing Patients mentioning

confidence: 99%

See 2 more Smart Citations

The Glucagon‐like peptide‐1 receptor agonist, exendin‐4, ameliorated gastrointestinal dysfunction in the Wistar Kyoto rat model of Irritable Bowel Syndrome

O’Brien

O’Malley

2019

Neurogastroenterology Motil

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“…Using vagal neural pathways, GLP-1 has been shown to delay gastric emptying (Imeryüz et al, 1997) and small intestinal secretion (Baldassano, Wang, Mule, & Wood, 2011) and motility (Nauck et al, 2011). GLP-1 also inhibits postprandial motility in the antrum, jejunum and duodenum through direct actions on myenteric neurons (Halim et al, 2018). In contrast to the inhibitory effects in the proximal GI tract, central administration of GLP-1 resulted in increased colonic transit, also through vagal signalling (Nakade, Tsukamoto, Iwa, Pappas, & Takahashi, 2007).…”

Section: Glucagon-like Peptide-1 Modulates Gastrointestinal Functionmentioning

confidence: 99%

Endocrine regulation of gut function – a role for glucagon‐like peptide‐1 in the pathophysiology of irritable bowel syndrome

O’Malley

2018

Experimental Physiology

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New Findings What is the topic of this review?Pathophysiological changes linked to irritable bowel syndrome (IBS) include stress and immune activation, changes in gastrointestinal microbial and bile acid profiles and sensitization of extrinsic and intrinsic gut neurons. This review explores the potential role for L‐cells in these pathophysiological changes. What advances does it highlight?L‐cells, which secrete glucagon‐like peptide‐1 in response to nutrients, microbial factors, bile acids and short‐chain fatty acids, may sense IBS‐related changes in the luminal environment. Glucagon‐like peptide‐1 can act as a hormone, a paracrine factor or a neuromodulatory factor and, through its actions on central or peripheral neurons, may play a role in gastrointestinal dysfunction. Abstract The prevalent and debilitating functional bowel disorder, irritable bowel syndrome (IBS), is characterized by symptoms that include abdominal pain, bloating, diarrhoea and/or constipation. The heterogeneity of IBS underscores a complex multifactorial pathophysiology, which is not completely understood but involves dysfunction of the bi‐directional signalling axis between the brain and the gut. This axis incorporates efferent and afferent branches of the autonomic nervous system, circulating endocrine hormones and immune factors, local paracrine and neurocrine factors and microbial metabolites. L‐cells, which are electrically excitable biosensors embedded in the gastrointestinal epithelium, secrete glucagon‐like peptide‐1 (GLP‐1) in response to nutrients in the small intestine. However, they appear to function in a different manner more distally in the gastrointestinal tract, where they are activated by luminal factors including short‐chain fatty acids, bile acids and microbial metabolic products, all of which are altered in IBS patients. Glucagon‐like peptide‐1 can also interact with the hypothalamic–pituitary–adrenal stress axis and the immune system, both of which are activated in IBS. Given that a GLP‐1 mimetic has been found to alleviate acute pain symptoms in IBS patients, GLP‐1 might be important in the manifestation of IBS symptoms. This review assesses the current knowledge about the role of GLP‐1 in IBS pathophysiology and its potential role as a signal transducer in the microbiome–gut–brain signalling axis.

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Glucagon‐Like Peptide‐1 Receptor Activators

Wagner¹,

Evers²,

Bossart³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Type 2 diabetes (T2D) and obesity have reached pandemic levels and represent a major health burden to modern society. Peptidic GLP‐1 receptor agonists (GLP‐1RAs) have been established as an effective therapy with respect to glycemic control and provide moderate body weight reduction. Marketed first‐generation GLP‐1RAs are suitable for once‐ or twice‐daily subcutaneous dosing. Their substantial benefit on glucose control led to the discovery and development of longer lasting therapeutic options to improve patient convenience and compliance. Recently reported positive cardiovascular outcome studies for some GLP‐1RAs further underscore their therapeutic value. Besides long‐lasting action, alternative delivery formats for injectable GLP‐1RAs have been explored, for example oral formulations. One such oral formulation of a GLP‐1 analog has completed Phase 3 studies and is now approved for the treatment of T2D. In contrast, the discovery of orally available small molecule agonists of the GLP‐1R has been historically challenging, and only recently a few compounds have reached early clinical development. To further improve the efficacy of GLP‐1RAs, so‐called GLP‐1R dual or triple agonists have been developed. These peptides show promising results in early clinical trials but are awaiting confirmation of their therapeutic benefit in late‐stage development.

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Glucagon-Like Peptide-1 Inhibits Prandial Gastrointestinal Motility Through Myenteric Neuronal Mechanisms in Humans

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

Cited by 37 publications

References 46 publications

The Glucagon‐like peptide‐1 receptor agonist, exendin‐4, ameliorated gastrointestinal dysfunction in the Wistar Kyoto rat model of Irritable Bowel Syndrome

The Glucagon‐like peptide‐1 receptor agonist, exendin‐4, ameliorated gastrointestinal dysfunction in the Wistar Kyoto rat model of Irritable Bowel Syndrome

Endocrine regulation of gut function – a role for glucagon‐like peptide‐1 in the pathophysiology of irritable bowel syndrome

Glucagon‐Like Peptide‐1 Receptor Activators

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