Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Plamboeck, Astrid; Holst, Jens J.; Carr, Richard D.; Deacon, Carolyn F.

doi:10.1007/s00125-005-1847-7

Cited by 151 publications

(136 citation statements)

References 45 publications

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“…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]. In addition to the substantial enzymatic degradation, several studies have pointed to the kidney as an important mediator in the final elimination of GLP-1 and its metabolites.…”

Section: Introductionmentioning

confidence: 88%

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: Introductionmentioning

confidence: 88%

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

2006

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“…20,21,51 As a result, current GLP-1-receptor agonist therapies require repeated injections to maintain therapeutic plasma concentrations. As an alternative means of raising plasma GLP-1 levels, DPP-IV inhibitors have recently been developed and are now in clinical use for treatment of type-2 diabetes.…”

Section: Aav-mediated Expression Of Glp-1 In Beta-cells Mj Riedel Et Almentioning

confidence: 99%

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

et al. 2009

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone that performs a wide array of well-characterized antidiabetic actions, including stimulation of glucose-dependent insulin secretion, upregulation of insulin gene expression and improvements in beta-cell survival. GLP-1-receptor agonists have been developed for treatment of diabetes; however, the short biological half-lives of these peptide-based therapeutics requires that frequent injections be administered to maintain sufficient circulating levels. Thus, novel methods of delivering GLP-1 remain an important avenue of active research. It has recently been demonstrated that self-complimentary, double-stranded, adeno-associated virus serotype-8 (DsAAV8) can efficiently transduce pancreatic beta-cells in vivo, resulting in long-term transgene expression. In this study, we engineered a DsAAV8 vector containing a GLP-1 transgene driven by the mouse insulin-II promoter (MIP). Biological activity of the GLP-1 produced from this transgene was assessed using a luciferase-based bioassay. DsAAV8-MIP-GLP-1 was delivered via intraperitoneal injection and beta-cell damage induced by multiple low dose streptozotocin (STZ) administration. Glucose tolerance was assessed following intraperitoneal glucose injections and beta-cell proliferation measured by PCNA expression. Expression of GLP-1 in Min6 beta-cells resulted in glucose-dependent secretion of biologically active GLP-1. Intraperitoneal delivery of DsAAV8-MIP-GLP-1 to mice led to localized GLP-1 expression in beta-cells and protection against development of diabetes induced by multiple low-dose STZ administration. This protection was associated with significant increase in beta-cell proliferation. Results from this study indicate that expression and secretion of GLP-1 from beta-cells in vivo via DsAAV8 represents a novel therapeutic strategy for treatment of diabetes.

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“…However, its short circulating half-life means that high doses must be administered frequently, which limits its clinical application. The short half-live of GLP-1 is due to its rapid inactivation and clearance under physiological conditions by proteolytic enzymes such as dipeptidyl peptidase-IV (DPP-IV) [4] and neutral endopeptidase (NEP) 24.11 [5].…”

Section: Introductionmentioning

confidence: 99%

PEGylated glucagon-like peptide-1 displays preserved effects on insulin release in isolated pancreatic islets and improved biological activity in db/db mice

et al. 2006

Diabetologia

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Aims/hypothesis: The rapid degradation and clearance of glucagon-like peptide-1 (GLP-1) by the enzymes dipeptidyl peptidase-IV and neutral endopeptidase 24.11 are the main impediments to the development of GLP-1 as a potential glucose-lowering agent. In this study, new enzyme-resistant polyethylene glycol (PEG)-conjugated GLP-1 analogues were designed and examined for metabolic stability and biological potency. Materials and methods: Two mono-PEGylated GLP-1 analogues, N-terminally modified N-PEG/GLP-1 and Lys-modified Lys-PEG/GLP-1, were prepared. Stability was tested in plasma and tissue extracts. In vitro insulin release studies were performed using isolated rat pancreatic islets, while in vivo glycaemic responses were measured in db/db mice. Results: The half-life of Lys-PEG/GLP-1 was 40-, 10-and 28-fold longer than that of GLP-1 in plasma, liver and kidney homogenates, respectively. Lys-PEG/GLP-1 stimulated insulin secretion in the islets in a dose-and glucose-dependent manner, and was as potent as GLP-1. In contrast, N-PEG/GLP-1 showed extended metabolic stability but had significantly lower biological activity. The administration of Lys-PEG/GLP-1 (9 nmol/kg i.p.) to non-fasted db/db mice stabilised glycaemia (p<0.001), whereas GLP-1 (9 nmol/kg) only caused small changes in glucose level. During OGTT in fasted db/db mice, Lys-PEG/GLP-1 administered at 1, 3 and 9 nmol/kg (i.p.) reduced the glucose AUC 0-3h by 48.7±9.4, 55.0±2.9 and 63.4±2.5%, respectively, compared with placebo (p<0.01), whereas GLP-1 (9 nmol/kg) lowered the glucose level by 39.5±12.9% (p<0.01). Conclusions/interpretation: This study demonstrates that site-specific PEGylated GLP-1 analogues are resistant to degradation. The enhanced biological potencies of these analogues highlight their potential as new, GLP-1-like glucose-lowering agents.

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Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Cited by 151 publications

References 45 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

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

PEGylated glucagon-like peptide-1 displays preserved effects on insulin release in isolated pancreatic islets and improved biological activity in db/db mice

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