Oxyntomodulin (glucagon‐37) and its C‐terminal octapeptide inhibit gastric acid secretion

Jarrousse, C.; Audousset-Puech, M. P.; Dubrasquet, M; Niel, Huguette; Martinez, Jean; Bataille, D.

doi:10.1016/0014-5793(85)80879-6

Cited by 46 publications

(21 citation statements)

References 7 publications

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“…OXM potently inhibits gastric acid secretion and pancreatic enzyme secretion when infused iv (19,20). The C-terminal fragment of OXM, SP-1, has been described as the minimal active structure of OXM (21), as it has been found to mimic the actions of OXM in gastric mucosa, albeit less potently (19,22,23).…”

Section: P Reproglucagon Is Cleaved In a Tissue-specificmentioning

confidence: 99%

Oxyntomodulin Inhibits Food Intake in the Rat

et al. 2001

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Oxyntomodulin is derived from proglucagon processing in the intestine and the central nervous system. To date, no role in the central nervous system has been demonstrated. We report here that oxyntomodulin inhibits refeeding when injected intracerebroventricularly and into the hypothalamic paraventricular nucleus of 24-h fasted rats [intracerebroventricularly and into the paraventricular nucleus, 1 h, oxyntomodulin (1 nmol), 3.1 ؎ 0.5 g; saline, 6.2 ؎ 0.4 g; P < 0.005]. In addition, oxyntomodulin inhibits food intake in nonfasted rats injected at the onset of the dark phase (intracerebroventricularly, 1 h: oxyntomodulin, 3 nmol, 1.1 ؎ 0.19 g vs. saline, 2.3 ؎ 0.2 g; P < 0.05). This effect of oxyntomodulin on feeding is of a similar time course and magnitude as that of an equimolar dose of glucagon-like peptide-1. Other proglucagonderived products investigated [glucagon, glicentin (intracerebroventricularly, 3 nmol; into the paraventricular nucleus, 1 nmol), and spacer peptide-1 (intracerebroventricularly and into the paraventricular nucleus, 3 nmol)] had no effect on feeding at any time point examined. The anorectic effect of oxyntomodulin (intracerebroventricularly, 3 nmol; into the paraventricular nucleus, 1 nmol) was blocked when it was coadministered with the glucagon-like peptide-1 receptor antagonist, exendin-(9 -39) (intracerebroventricularly, 100 nmol; into the paraventricular nucleus, 10 nmol). However, oxyntomodulin has a lower affinity for the glucagon-like peptide-1 receptor compared with glucagon-like peptide-1 (IC 50 : oxyntomodulin, 8.2 nM; glucagon-like peptide-1, 0.16 nM). One explanation for this is that there might be an oxyntomodulin receptor to which exendin-(9 -39) can also bind and act as an antagonist. (Endocrinology 142: 4244 -4250, 2001)

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Section: P Reproglucagon Is Cleaved In a Tissue-specificmentioning

confidence: 99%

Oxyntomodulin Inhibits Food Intake in the Rat

et al. 2001

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“…The GLP-1R is a family B peptide hormone G protein-coupled receptor primarily expressed in pancreatic ␤-cells that responds to at least four distinct endogenous GLP-1 variants: two full-length GLP-1 peptides [GLP-1(1-36)NH 2 and GLP-1(1-37)] and two truncated and more prominent circulating forms [GLP-1(7-36)NH 2 and GLP-1(7-37)] (Baggio and Drucker, 2007). In addition, the related endogenous peptide oxyntomodulin and exogenous mimetic peptide exendin-4 act at the GLP-1R to increase the biosynthesis and secretion of insulin, decrease ␤-cell apoptosis and decrease gastric emptying in a similar manner to the endogenous GLP-1 peptides (Jarrousse et al, 1984;Jarrousse et al, 1985;Göke et al, 1993). Although levels of GLP-1 are reduced in patients with type II diabetes mellitus, the retention of its insulinotropic properties at the GLP-1R make it one of the most promising ligand-receptor systems to target in the development of treatments for type II diabetes (Nauck et al, 1993;Toft-Nielsen et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation

Koole¹,

Wootten²,

Simms³

et al. 2011

Mol Pharmacol

117

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The glucagon-like peptide-1 receptor (GLP-1R) is a key physiological regulator of insulin secretion and a major therapeutic target for the treatment of type II diabetes. However, regulation of GLP-1R function is complex with multiple endogenous peptides that interact with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can exist in an amidated form (GLP-1(1-36)NH 2 and GLP-1(7-36)NH 2 ) and the related peptide oxyntomodulin. In addition, the GLP-1R possesses exogenous agonists, including exendin-4, and the allosteric modulator, compound 2 (6,7-dichloro-2-methylsulfonyl-3-tert-butylaminoquinoxaline). The complexity of this ligand-receptor system is further increased by the presence of several single nucleotide polymorphisms (SNPs) that are distributed across the receptor. We have investigated 10 GLP-1R SNPs, which were characterized in three physiologically relevant signaling pathways (cAMP accumulation, extracellular signal-regulated kinase 1/2 phosphorylation, and intracellular Ca 2ϩ mobilization); ligand binding and cell surface receptor expression were also determined. We demonstrate both ligandand pathway-specific effects for multiple SNPs, with the most dramatic effect observed for the Met 149 receptor variant. At the Met 149 variant, there was selective loss of peptide-induced responses across all pathways examined, but preservation of response to the small molecule compound 2. In contrast, at the Cys 333 variant, peptide responses were preserved but there was attenuated response to compound 2. Strikingly, the loss of peptide function at the Met 149 receptor variant could be allosterically rescued by compound 2, providing proof-of-principle evidence that allosteric drugs could be used to treat patients with this loss of function variant.

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“…OXM was first characterized in 1982 (7) and is so named after its ability to inhibit gastric acid secretion in gastric oxyntic glands (6,24,31,32). Belonging to a family of hormones known as proglucagon-derived peptides (PGDPs), OXM originates from the proglucagon gene, which is expressed in the L cells of the small intestine, the pancreas, and the central nervous system (CNS) (47).…”

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confidence: 99%

Oxyntomodulin increases intrinsic heart rate in mice independent of the glucagon-like peptide-1 receptor

Sowden

Drucker²,

Weinshenker³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Oxyntomodulin (OXM), a postprandially released intestinal hormone, inhibits food intake via the glucagon-like peptide-1 receptor (GLP-1R). Although OXM may have clinical value in treating obesity, the cardiovascular effects of OXM are not well understood. Using telemetry to measure heart rate (HR), body temperature (Tb), and activity in conscious and freely moving mice, we tested 1) whether OXM affects HR and 2) whether this effect is mediated by the GLP-1R. We found that peripherally administered OXM significantly increased HR in wild-type mice, raising HR by >200 beats/min to a maximum of 728 +/- 11 beats/min. To determine the extent to which the sympathetic nervous system mediates the tachycardia of OXM, we delivered this hormone to mice deficient in dopamine-beta-hydroxylase [Dbh(-/-) mice], littermate controls [Dbh(+/-) mice], and autonomically blocked C57Bl mice. OXM increased HR equally in all groups (192 +/- 13, 197 +/- 21, and 216 +/- 11 beats/min, respectively), indicating that OXM elevated intrinsic HR. Intrinsic HR was also vigorously elevated by OXM in Glp-1R(-/-) mice (200 +/- 28 beats/min). In addition, peripherally administered OXM inhibited food intake and activity levels in wild-type mice and lowered Tb in autonomically blocked mice. None of these effects were observed in Glp-1R(-/-) mice. These data suggest multiple modes of action of OXM: 1) it directly elevates murine intrinsic HR through a GLP-1R-independent mechanism, perhaps via the glucagon receptor or an unidentified OXM receptor, and 2) it lowers food intake, activity, and Tb in a GLP-1R-dependent fashion.

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Oxyntomodulin (glucagon‐37) and its C‐terminal octapeptide inhibit gastric acid secretion

Cited by 46 publications

References 7 publications

Oxyntomodulin Inhibits Food Intake in the Rat

Oxyntomodulin Inhibits Food Intake in the Rat

Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation

Oxyntomodulin increases intrinsic heart rate in mice independent of the glucagon-like peptide-1 receptor

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