Molecular heterogeneity of glucagon in normal subjects and in patients with glucagon-producing tumours

Jj, Holst

doi:10.1007/bf00251825

Cited by 63 publications

(59 citation statements)

References 27 publications

(34 reference statements)

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“…The major component of the enteroglucagons present in human plasma is a molecule that is homologous to glicentin, whereas oxyntomodulin constitutes a minor fraction. However, specific measurement of oxyntomodulin, which requires chromatography, has been carried out in only a few studies [7,8], and it is possible that oxyntomodulin, which is a prominent component of the enteroglucagons in extracts of the distal intestine in humans [9], may occasionally be present in plasma in concentrations similar to those obtained in this study. In a recent study using high pressure liquid chromatography for the determination of oxyntomodulin in rat plasma, Kervran et al [19] found that oxyntomodulin was the predominating circulating enteroglucagon and that its concentration increased markedly in response to a meal.…”

Section: Discussionsupporting

confidence: 51%

“…A similar peptide has been identified in human ileal mucosa extracts [4-61 and, by means of gel filtration of concentrated samples collected after carbohydrate meals [7,8], in human plasma. Recent studies from our laboratory have shown that a peptide that corresponds to oxyntomodulin is secreted from the isolated perfused ileum upon stimulation with intraluminal glucose.…”

Section: Introductionmentioning

confidence: 88%

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Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man

Schjoldager

Baldissera²,

Mortensen

et al. 1988

Eur J Clin Investigation

124

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Abstract. Synthetic oxyntomodulin, a predicted product of the glucagon gene, which is produced in the human lower intestinal mucosa, was infused in doses of 100 and 400 ng kg-' h-' into six volunteers to study its pharmacokinetics and effects on pentagastrinstimulated gastric acid secretion (100 ng kg-' h-I). The concentration of oxyntomodulin in plasma measured with a cross-reacting glucagon assay increased from 37+5 to 106+ 17and 301 k40pmol I-', respectively. The metabolic clearance rate was 5.2k0.7 ml kg-' min-' and the half-life in plasma was 12 & 1 min. Oxyntomodulin reduced the pentagastrin-stimulated acid secretion by 20 f 9% during the low-rate infusion ( P < 0.05) and by 76 f 10% during the high-rate infusion (P < 0.05). In accordance with the homology with glucagon, there was a small, significant rise in plasma concentrations of insulin and insulin C-peptide during oxyntomodulin infusion. Oxyntomodulin may therefore be included among the potential incretins and enterogastrones in man.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 88%

Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man

Schjoldager

Baldissera²,

Mortensen

et al. 1988

Eur J Clin Investigation

124

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“…This peptide is insulinotropic [34], and probably explains the insulinotropic activity of some preparations of "gut glucagon", described in earlier publications. However, as a circulating hormone in humans, its concentration is probably too low to influence insulin secretion under physiological circumstances [35]. GLP-1 secretion is stimulated by the presence of nutrients in the lumen of the gut (but additional neural or endocrine mechanisms could also operate) [36], and the secretion of GLP-1 throughout the day is highly correlated to the release of insulin [37].…”

Section: Glucagon-like Peptide-1 (Glp-1)mentioning

confidence: 99%

Incretins, insulin secretion and Type 2 diabetes mellitus

2004

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When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously so as to result in similar glucose concentrations. This effect, which is called the incretin effect and is estimated to be responsible for 50 to 70% of the insulin response to glucose, is caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their contributions have been confirmed in mimicry experiments, in experiments with antagonists of their actions, and in experiments where the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown to be able to near-normalize both fasting and postprandial glycaemic concentrations in the patients, perhaps because the treatment compensates for both the impaired secretion of GLP-1 and the impaired action of GIP. Several GLP-1 analogues are currently in clinical development and the reported results are, so far, encouraging. The incretin effectThe incretin effect seems to play a major role in the regulation of glucose metabolism in healthy subjects. "The incretin effect" implies that ingestion of carbohydrates (glucose) causes the release from the intestinal mucosa of substances that enhance insulin secretion beyond the release caused by the absorbed glucose itself [1]. The effect can be quantified by comparing insulin or C-peptide responses to oral or intravenous glucose loads, adjusted to cause identical increases of plasma glucose concentrations. The much higher responses observed after oral administration

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“…Nevertheless, it was not as potent as glucagon. It was therefore questionable whether this molecule, which circulates in low concentrations [9], would contribute to the incretin effect.…”

Section: Discovery Of Glucagon-like Peptide-1mentioning

confidence: 99%

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

2006

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The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal insulinotropic products of proglucagon gene expression. The incretin effect is markedly impaired or absent in patients with type 2 diabetes because of decreased secretion of GLP-1 and a loss of the insulinotropic effects of GIP. Metabolic control can be restored or greatly improved by administration of exogenous GLP-1, but this peptide is almost immediately degraded by dipeptidyl peptidase IV (DPP-IV), and therefore has little clinical value. DPP-IV-resistant analogues (incretin mimetics) have been identified or developed, and inhibitors of DPP-IV have also proved effective in protecting endogenous GLP-1 (and GIP) from degradation. Both principles have been tested in clinical studies. The incretin mimetics, administered by sc injection, have demonstrated lasting improvement in HbA 1 c in patients insufficiently treated with conventional oral therapy, and their use has been associated with steady weight loss for up to 2 years. The DPP-IV inhibitors, given once or twice daily by mouth, also appear to provide lasting improvement in HbA 1 c, but are weight-neutral. The first incretin mimetic has reached the market in the US, and applications for approval of the first inhibitors are expected to be filed early in 2006.

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Molecular heterogeneity of glucagon in normal subjects and in patients with glucagon-producing tumours

Cited by 63 publications

References 27 publications

Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man

Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man

Incretins, insulin secretion and Type 2 diabetes mellitus

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

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