Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1(7–36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides

Hupe-Sodmann, K.; McGregor, G.P.; Bridenbaugh, Robert; Göke, Rüdiger; Göke, Burkhard; Thole, Hubert; Zimmermann, Bodo; Voigt, Karlheinz

doi:10.1016/0167-0115(95)00063-h

Cited by 214 publications

(202 citation statements)

References 20 publications

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“…As a result of the presence of a penultimate Nterminal glycine in exendin-4, compared with an alanine in GLP-1, exendin-4 is not degraded significantly by DPPIV [15]. Exendin-4 is also a poor substrate in vitro for NEP, whereas GLP-1 is rapidly degraded [8]. Furthermore, it is noteworthy that other peptides, which are structurally similar to GLP-1, show differential susceptibility to DPPIV in vitro (GLP-1≈GIP>GLP-2) [5,23], which does not correlate with their N-terminal half-lives in vivo (GLP-1<GIP≈GLP-2) [2,24].…”

Section: Discussionmentioning

confidence: 98%

“…Part of the difference in metabolic stability between these two peptides, which share 53% sequence homology, is the result of their different susceptibility to enzymatic degradation. Thus, GLP-1 is degraded initially by DPPIV and subsequently by other enzymes, including NEP [8,15]. Exendin-4, however, is reported to be more resistant to enzymatic degradation, and indeed, when incubated in the presence of kidney brush border membranes, which are especially rich in a variety of ectopeptidase activities [22], exendin-4 is remarkably stable, with a rate of proteolysis which is several orders of magnitude less than that of GLP-1 [15].…”

Section: Discussionmentioning

confidence: 99%

“…However, DPPIV may not be the only enzyme involved in the degradation of GLP-1. In vitro studies have demonstrated that neutral endopeptidase 24.11 (NEP) can cleave GLP-1 at multiple sites in both the central and more C-terminal parts of the peptide [8], suggesting a potential role for NEP in the in vivo metabolism of GLP-1. In support of this, a study from this laboratory recently found that NEP inhibition increases the metabolic stability of exogenously administered GLP-1 in anaesthetised pigs [9].…”

Section: Introductionmentioning

confidence: 99%

“…In vitro studies have shown that exendin-4 is apparently more resistant to enzymatic degradation than GLP-1 [15]. It is hardly degraded by DPPIV and is a poor substrate for other enzymes, including NEP [8]. Although the in vivo metabolism of exendin-4 has not been studied in detail, it appears that the kidneys may play an important role in its elimination [14].…”

Section: Introductionmentioning

confidence: 99%

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

2006

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Aims/hypothesis: The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is rapidly degraded in vivo as a result of the combination of extensive enzymatic degradation and renal extraction. The GLP-1 receptor agonist, exendin-4, has a longer duration of action, and has recently been approved as a new agent for the treatment of type 2 diabetes mellitus. Exendin-4 is less prone to enzymatic degradation, but it is still unclear what other factors contribute to the increased metabolic stability. Materials and methods:The overall metabolism of GLP-1 and exendin-4 was directly compared in anaesthetised pigs (n=9). Results: Metabolism of GLP-1 (C-terminal RIA; t 1/2 2.0±0.2 min, metabolic clearance rate [MCR] 23.2±2.8 ml min −1 kg −1 ; N-terminal RIA; t 1/2 1.5±0.2 min, MCR 88.1±10.6 ml min −1 kg −1 ) was significantly faster than the metabolism of exendin-4 (t 1/2 22.0±2

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2006

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“…The GLP-1/Fc fusion protein is expected to have reduced susceptibility to degradation since such degrading enzymes have a preference for smaller peptides. 49 We have not directly measured the binding affinity of GLP-1/IgG1-Fc for the GLP-1 receptor. However, conjugation with an Fc segment and dimerization has increased the avidity of other molecules for their ligand or receptor considerably.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

et al. 2006

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Glucagon-like peptide (GLP-1), a major physiological incretin, plays numerous important roles in modulating blood glucose homeostasis and has been proposed for the treatment of type 2 diabetes. The major obstacles for using native GLP-1 as a therapeutic agent are that it must be delivered by a parenteral route and has a short half-life. In an attempt to develop a strategy to prolong the physiological t 1/2 and enhance the potency of GLP-1, a fusion protein consisting of active human GLP-1 and mouse IgG 1 heavy chain constant regions (GLP-1/Fc) was generated. A plasmid encoding an IgK leader peptide-driven secretable fusion protein of the active GLP-1 and IgG 1 -Fc was constructed for mammalian expression. This plasmid allows for expression of bivalent GLP-1 peptide ligands as a result of IgG-Fc homodimerization. In vitro studies employing purified GLP-1/ Fc indicate that the fusion protein is functional and elevates cAMP levels in insulin-secreting INS-1 cells. In addition, it stimulates insulin secretion in a glucose concentrationdependent manner. Intramuscular gene transfer of the plasmid in db/db mice demonstrated that expression of the GLP-1/Fc peptide normalizes glucose tolerance by enhancing insulin secretion and suppressing glucagon release. This strategy of using a bivalent GLP-1/Fc fusion protein as a therapeutic agent is a novel approach for the treatment of diabetes.

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Bioactive Signaling in Next-Generation Pharmacotherapies for Heart Failure

et al. 2018

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Key PointsQuestionHas the time arrived for new heart failure therapeutic pathways over and above receptor antagonism to be considered?FindingsThis review identified that regulating angiotensin II receptor activation as well as activation of specific receptor pathways can provide favorable cardiovascular effects in the context of heart failure, which cannot be achieved by receptor inhibition alone.MeaningThe positive results of the PARADIGM-HF trial using a drug with both neutral endopeptidase and angiotensin II receptor inhibition properties heralds a shift in conventional concepts from solely using receptor inhibition in heart failure towards simultaneously potentiating novel signaling pathways.

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Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1(7–36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides

Cited by 214 publications

References 20 publications

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

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

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

Bioactive Signaling in Next-Generation Pharmacotherapies for Heart Failure

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