Truncated GLP-1 (proglucagon 78?107-amide) inhibits gastric and pancreatic functions in man

Wettergren, André; Schjoldager, Birgit; Mortensen, Poul Erik; Myhre, J.; Christiansen, John; Holst, Jens J.

doi:10.1007/bf01316798

Cited by 638 publications

(428 citation statements)

References 37 publications

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“…sensitizes the alpha cell to the suppressive effects of glucose [98]. It may be noted that the magnitude of the decrease in the PG 50 for the AGR arg in response to GLP-1 to is very similar to the increase in this parameter estimated from mean data comparing patients with type 2 diabetes with healthy volunteers (cf. Fig.…”

Section: Acute Effects Of Exogenous and Endogenous Glp-1 On Alpha Celmentioning

confidence: 69%

“…7b) occurs. The PG 50 for prestimulus glucagon averaged 15.5±1.0 mmol/l when saline was infused and 11.0±0.8 mmol/l during GLP-1 infusion (p<0.001). Similarly, the PG 50 for AGR arg was 15.5±0.7 mmol/l during saline and 12.1±0.8 mmol/l during GLP-1 (p<0.001).…”

Section: Acute Effects Of Exogenous and Endogenous Glp-1 On Alpha Celmentioning

confidence: 93%

“…However, GLP-1 is inactive, requiring N-terminal truncation of amino acids 1-6 for activation. The biologically active forms of GLP-1 are GLP-1 and GLP-1 amide, previously known as insulinotropin [48], glucagon-like insulinotropic peptide (GLIP) [49] and truncated GLP-1 [50]. This latter designation is unhelpful, since inactivation of GLP-1 and GLP-1 Adapted from [34] peptidase IV (DPP-4), yielding GLP-1 and GLP-1 amide, which have also been referred to as truncated GLP-1.…”

Section: Glp-1mentioning

confidence: 99%

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Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

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Section: Acute Effects Of Exogenous and Endogenous Glp-1 On Alpha Celmentioning

confidence: 69%

Section: Acute Effects Of Exogenous and Endogenous Glp-1 On Alpha Celmentioning

confidence: 93%

Section: Glp-1mentioning

confidence: 99%

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Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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“…Further important effects of GLP-1 include inhibition of gastrointestinal secretion and motility, notably gastric emptying [96,97]. This effect is also desirable in patients with diabetes, because the slower gastric emptying rate reduces postprandial glucose excursions as is evident from the use of another potent gastric inhibitor, amylin, for diabetes treatment [98]; finally, GLP-1 inhibits appetite and food intake.…”

Section: Incretin Hormones As Therapeutic Agentsmentioning

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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“…Furthermore, GLP-1 not only stimulated glucose-induced insulin secretion, but also all steps of insulin biosynthesis and insulin gene expression [31]. GLP-1 also turned out to have powerful effects on gastrointestinal secretion and motility [32,33], and it was shown that inhibition of gastric emptying had strong effects on postprandial glucose excursions [34] in healthy subjects and patients with type 2 diabetes [35]. In addition, GLP-1 was shown to inhibit appetite and food intake, both in healthy individuals [36], and in patients with type 2 diabetes [37].…”

Section: Glp-1 and Diabetes Treatmentmentioning

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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Truncated GLP-1 (proglucagon 78?107-amide) inhibits gastric and pancreatic functions in man

Cited by 638 publications

References 37 publications

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Alpha cell function in health and disease: influence of glucagon-like peptide-1

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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