Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs
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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+/-2.1 min, p<0.0001; MCR 1.7+/-0.3 ml min(-1) kg(-1), p<0.01). Differences in arteriovenous concentrations revealed organ extraction of GLP-1 by the kidneys (C-terminal 56.6+/-2.6%; N-terminal 48.3+/-5.9%), liver (N-terminal 41.4+/-3.8%), and peripheral tissues (C-terminal 42.3+/-6.0%; N-terminal 33.0+/-7.8%), whereas organ extraction of exendin-4 was limited to the kidneys (21.3+/-4.9%). While the renal extraction of exendin-4 (6.9+/-2.5 pmol/min) did not differ significantly from the amount undergoing glomerular filtration (8.4+/-2.0 pmol/min), the renal extraction of C-terminal GLP-1 (9.0+/-1.1 pmol/min), exceeded the amount which could be accounted for by glomerular filtration (4.2+/-0.5 pmol/min, p<0.0005).Conclusions/interpretation In addition to an increased resistance to enzymatic degradation, the increased stability of exendin-4 is the result of reduced differential organ extraction compared to GLP-1. The data suggest that in the anaesthetised pig, extraction occurs only in the kidney and can be fully accounted for by glomerular filtration.
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EX is resistant to DPP-4 proteolysis and has prolonged kinetics compared with human GLP-1.
“Human GLP-1 was rapidly degraded by DPP-4, while EX showed prolonged kinetics because of its resistance to proteolysis of DPP-4 (48).”
From GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach (2023) · cites this paper as [48]
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References 34 · Cited by 133
- Authors
- Simonsen, L., Holst, J. J., & Deacon, C. F.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Deacon, C. F.
- Venue
- Diabetologia
- Published
- 2006-01-31
- Volume
- 49
- Issue
- 4
- Pages
- 706-712
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W1967331905
- Cited by
- 133
- References
- 34
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 7 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 4 · 2014: 10 · 2013: 11 · 2012: 16
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Velux Stiftung
- Sundhed og Sygdom, Det Frie Forskningsråd
- Toyota Foundation
- European Foundation for the Study of Diabetes
- Novo Nordisk
- Novo Nordisk Fonden
- Medical Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- exendin-4, glucagon-like peptide-1, renal extraction, glomerular filtration, metabolic clearance rate, drug metabolism, type 2 diabetes, GLP-1 receptor agonists, pigs, pharmacokinetics, enzyme degradation, duration of action
- MeSH terms
- Exenatide, Anesthesia, Animals, Female, Glomerular Mesangium, Metabolic Clearance Rate, Peptides, Swine, Venoms, Glucagon-Like Peptide 1
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