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

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Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. / Simonsen, L; Holst, Jens Juul; Deacon, C F.

In: Diabetologia, Vol. 49, No. 4, 04.2006, p. 706-12.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Simonsen, L, Holst, JJ & Deacon, CF 2006, 'Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs', Diabetologia, vol. 49, no. 4, pp. 706-12. https://doi.org/10.1007/s00125-005-0128-9

APA

Simonsen, L., Holst, J. J., & Deacon, C. F. (2006). Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. Diabetologia, 49(4), 706-12. https://doi.org/10.1007/s00125-005-0128-9

Vancouver

Simonsen L, Holst JJ, Deacon CF. Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. Diabetologia. 2006 Apr;49(4):706-12. https://doi.org/10.1007/s00125-005-0128-9

Author

Simonsen, L ; Holst, Jens Juul ; Deacon, C F. / Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. In: Diabetologia. 2006 ; Vol. 49, No. 4. pp. 706-12.

Bibtex

@article{d5aa0935826b4a9bb6542c806ec0a8fd,
title = "Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs",
abstract = "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.",
keywords = "Anesthesia, Animals, Female, Glomerular Mesangium, Glucagon-Like Peptide 1, Metabolic Clearance Rate, Peptides, Swine, Venoms",
author = "L Simonsen and Holst, {Jens Juul} and Deacon, {C F}",
year = "2006",
month = apr,
doi = "10.1007/s00125-005-0128-9",
language = "English",
volume = "49",
pages = "706--12",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer",
number = "4",

}

RIS

TY - JOUR

T1 - Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

AU - Simonsen, L

AU - Holst, Jens Juul

AU - Deacon, C F

PY - 2006/4

Y1 - 2006/4

N2 - 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.

AB - 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.

KW - Anesthesia

KW - Animals

KW - Female

KW - Glomerular Mesangium

KW - Glucagon-Like Peptide 1

KW - Metabolic Clearance Rate

KW - Peptides

KW - Swine

KW - Venoms

U2 - 10.1007/s00125-005-0128-9

DO - 10.1007/s00125-005-0128-9

M3 - Journal article

C2 - 16447056

VL - 49

SP - 706

EP - 712

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 4

ER -

ID: 132052947