The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7-36 amide on gastric acid secretion in humans depends on an intact vagal innervation.

Wettergren, André; Wøjdemann, Morten; Meisner, Søren; Stadil, F.; Holst, Jens J.

doi:10.1136/gut.40.5.597

Cited by 140 publications

(83 citation statements)

References 31 publications

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“…7). Further studies documented that GLP-1 could completely abolish acid secretion resulting from pure vagal stimulation in humans (as elicited by modified sham feeding: the "chewand-spit technique") (325) and that the inhibitory effect was lost in people that had had a truncal vagotomy for duodenal ulcer disease (329). This would indicate that all of the actions of GLP-1 on gastric functions are mediated via vagal pathways (see below).…”

Section: E Effects On the Gastrointestinal Tractmentioning

confidence: 99%

“…Thus GLP-1 has no effect on vagally stimulated antral motility in isolated perfused preparations of the pig stomach (328) and no effect on vagally stimulated exocrine secretion from isolated perfused porcine pancreas (127). Furthermore, as mentioned, the acid inhibitory activity in humans exclusively depends on vagal mechanisms (325,329). Finally, the inhibitory effect on gastric emptying in rats is lost after vagal deafferentation (139).…”

Section: F Central Targets For Peripherallymentioning

confidence: 99%

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The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,709

2,385

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Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

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Section: E Effects On the Gastrointestinal Tractmentioning

confidence: 99%

Section: F Central Targets For Peripherallymentioning

confidence: 99%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,709

2,385

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“…45 These studies indicate a possible effect of autonomic neuropathy on the incretin effect in type 2 diabetes, through modulation of GIP secretion and hepatic insulin extraction, as suggested in other studies. 4,46,47 It appears that GIP is more affected by autonomic neuropathy than GLP-1. Hence autonomic neuropathy could be an important factor affecting the response rate to gliptins.…”

Section: Autonomic Function and Incretin Responsementioning

confidence: 99%

Predicting response to incretin-based therapy

Kalra¹,

Kalra²,

Sahay³

et al. 2011

RRED

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There are two important incretin hormones, glucose-dependent insulin tropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The biological activities of GLP-1 include stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. GLP-1 appears to have a number of additional effects in the gastrointestinal tract and central nervous system. Incretin based therapy includes GLP-1 receptor agonists like human GLP-1 analogs (liraglutide) and exendin-4 based molecules (exenatide), as well as DPP-4 inhibitors like sitagliptin, vildagliptin and saxagliptin. Most of the published studies showed a significant reduction in HbA 1c using these drugs. A critical analysis of reported data shows that the response rate in terms of target achievers of these drugs is average. One of the first actions identified for GLP-1 was the glucose-dependent stimulation of insulin secretion from islet cell lines. Following the detection of GLP-1 receptors on islet beta cells, a large body of evidence has accumulated illustrating that GLP-1 exerts multiple actions on various signaling pathways and gene products in the β cell. GLP-1 controls glucose homeostasis through well-defined actions on the islet β cell via stimulation of insulin secretion and preservation and expansion of β cell mass. In summary, there are several factors determining the response rate to incretin therapy. Currently minimal clinical data is available to make a conclusion. Key factors appear to be duration of diabetes, obesity, presence of autonomic neuropathy, resting energy expenditure, plasma glucagon levels and plasma free fatty acid levels. More clinical evidence is required to identify the factors affecting response rate to incretin therapy.

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“…1 -3 In humans and rats it has been shown that GLP-1 inhibits gastric acid secretion as well as gastric motility. 4,5 Furthermore, it has recently been reported that peripheral GLP-1 affects appetite. Continuous infusion of GLP-1 in both normal and obese humans coinciding with the presentation of food inhibits energy intake and induces satiety and fullness as assessed using VAS (visual analogue scale) scores.…”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide containing pathways in the regulation of feeding behaviour

2001

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The pre-proglucagon derived peptides, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are both involved in a wide variety of peripheral functions, such as glucose homeostasis, gastric emptying, intestinal growth, insulin secretion as well as the regulation of food intake. Pre-proglucagon is also found in the brainstem in a small population of nerve cells in the nucleus of the solitary tract (NTS) that process the pre-propeptide as in the gut to yield GLP-1 and GLP-2. GLP-1 containing nerve fibres and the GLP-1 receptor are found predominantly in hypothalamic midline nuclei. GLP-1 given centrally to naive rats results in a marked induction of c-Fos protein in the supraoptic nucleus, paraventricular nucleus of the hypothalamus (PVN) and central nucleus of the amygdala, but only a moderate increase in the arcuate nucleus. The pattern of c-Fos activation is compatible with the appetite suppressing effects of GLP-1. This anorectic effect of GLP-1 appears to be mediated by the PVN, as direct injections of GLP-1 into this nucleus cause anorexia without concomitant taste aversion, suggesting a specific action upon neuronal circuits involved in the regulation of feeding. Recent experiments have also shown that GLP-1 is implicated in mediating signals from the gastrointestinal tract pertaining to discomfort and malaise. The distribution of the co-localised peptide, GLP-2, displays a perfect overlap with GLP-1 in the CNS with the highest concentration in the diffuse ventral part of the dorsomedial nucleus (DMHv). In contrast to the widely distributed GLP-1 receptor mRNA, GLP-2 receptor mRNA is exclusively expressed in the compact part of the DMH (DMHc). Interestingly, the DMHc is also the only nucleus responding to central administration of GLP-2 with a significant increase in the number of c-Fos positive cells. When injected into the lateral ventricle, GLP-2 has a marked inhibitory effect on feeding. The effect of GLP-2 on feeding is both behaviourally and pharmacologically specific. Future experiments will elucidate whether or not GLP-1 and GLP-2 are involved in the long-term or short-term regulation of feeding behaviour and hence have an impact on bodyweight.

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The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7-36 amide on gastric acid secretion in humans depends on an intact vagal innervation.

Cited by 140 publications

References 31 publications

The Physiology of Glucagon-like Peptide 1

The Physiology of Glucagon-like Peptide 1

Predicting response to incretin-based therapy

Glucagon-like peptide containing pathways in the regulation of feeding behaviour

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