Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

Simonsen, Lene; Holst, Jens J.; Deacon, Carolyn F.

doi:10.1007/s00125-005-0128-9

Cited by 115 publications

(86 citation statements)

References 33 publications

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“…Exendin 4 was isolated from the venom of the lizard, Heloderma suspectum, in a systematic search for biologically active peptides (64) and is, as discussed above, a full agonist for the GLP-1 receptor which is equipotent with GLP-1 (284). Unlike GLP-1, it is not degraded by DPP-IV and is cleared in the kidneys only by glomerular filtration (266), whereby the molecule obtains a half-life of ϳ30 min (58). After subcutaneous injection of the maximally tolerated dose, a significant elevation of its plasma concentration may be observed for 5 h (156).…”

Section: Diabetesmentioning

confidence: 99%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,699

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: Diabetesmentioning

confidence: 99%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,699

2,385

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“…Glycosylated GLP-1 may be more rapidly excreted by glomerular filtration compared with GLP-1, due to its higher hydrophilicity as compared with GLP-1. Although exendin-4, which is a GLP-1 analogue isolated from the saliva of the Gila monster Heloderma suspectum, is exclusively filtered in the glomeruli 8 , its use for treatment of type 2 diabetes with once-weekly dosing is available using a long-acting release formulation, microspheres which consists of a poly (lactide-coglycolide) polymeric matrix 32 .…”

Section: Discussionmentioning

confidence: 99%

“…However, the use of GLP-1 as a therapeutic agent is limited by its low in vivo activity. Under physiological conditions, GLP-1 is rapidly eliminated by glomerular filtration 8 and hepatic extraction 5,9 .…”

Section: Introductionmentioning

confidence: 99%

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Effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1

et al. 2011

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Objective Glycosylation is generally applicable as a strategy for increasing the activity of bioactive proteins. In this study, we examined the effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1 (GLP-1) as a bioactive peptide for type 2 diabetes.Methods Noninvasive imaging studies were performed using a gamma camera after the Conclusions This study demonstrated that glycosylation significantly decreased the distribution of radiolabeled GLP-1 into the liver and increased the concentration of 2 radiolabeled GLP-1 in plasma. These results suggested that glycosylation is a useful strategy for decreasing the distribution into the liver of bioactive peptides as desirable pharmaceuticals.

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“…38 Exenatide is eliminated by the kidneys exclusively, by way of glomerular filtration and subsequent tubular catabolism. [39][40][41] In patients with renal dysfunction, exenatide shows reduced clearance and may thereby increase the risk of exposuredependent side effects. 42 The exenatide LAR formulation was later developed, using biodegradable polymeric microspheres that entrap exenatide.…”

mentioning

confidence: 99%

Optimizing glycemic control: clinical utility of exenatide prolonged release injection

Derosa¹,

Maffioli²

2012

RRED

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Abstract:Despite the large variety of antidiabetic drugs currently available, reaching an adequate glycemic control is still difficult. Recently, a new exenatide long acting release (LAR) formulation, which can be administered once a week, has been released. We conducted a review analyzing the clinical utility of this new formulation and its place in antidiabetic therapy, and included the most important studies about exenatide LAR in the latest 10 years. A systematic search strategy was developed to identify randomized controlled trials in both MEDLINE and the Cochrane Register of Controlled Trials. The terms "exenatide," "exenatide long active release," "GLP-1 agonists," "incretins," and "glycemic control" were incorporated into an electronic search strategy that included the Dickersin filter for randomized controlled trials. We concluded that exenatide LAR can be a valid option for the treatment of type 2 diabetes mellitus because it showed to be effective in reducing HbA 1c , and because of its pleiotropic effects, such as the reduction of blood pressure, the improvement of the patient's lipid profile, and the positive effects on body weight and β-cell function. Moreover, exenatide LAR has demonstrated a favorable cost/effectiveness ratio, and its once weekly administration may help to increase patient compliance.

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Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

Cited by 115 publications

References 33 publications

The Physiology of Glucagon-like Peptide 1

The Physiology of Glucagon-like Peptide 1

Effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1

Optimizing glycemic control: clinical utility of exenatide prolonged release injection

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