The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs

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The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs. / Simonsen, L; Holst, Jens Juul; Madsen, K; Deacon, C F.

In: Regulatory Peptides, Vol. 181, No. 10, 10.02.2013, p. 17-21.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Simonsen, L, Holst, JJ, Madsen, K & Deacon, CF 2013, 'The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs', Regulatory Peptides, vol. 181, no. 10, pp. 17-21. https://doi.org/10.1016/j.regpep.2012.12.012

APA

Simonsen, L., Holst, J. J., Madsen, K., & Deacon, C. F. (2013). The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs. Regulatory Peptides, 181(10), 17-21. https://doi.org/10.1016/j.regpep.2012.12.012

Vancouver

Simonsen L, Holst JJ, Madsen K, Deacon CF. The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs. Regulatory Peptides. 2013 Feb 10;181(10):17-21. https://doi.org/10.1016/j.regpep.2012.12.012

Author

Simonsen, L ; Holst, Jens Juul ; Madsen, K ; Deacon, C F. / The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs. In: Regulatory Peptides. 2013 ; Vol. 181, No. 10. pp. 17-21.

Bibtex

@article{7ce1074cf4b7406599f324c2f2d79684,
title = "The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs",
abstract = "The most striking sequence difference between glucagon-like peptide-1 (GLP-1)(2) and the longer-acting GLP-1 receptor agonist, exendin-4 (Ex-4),(3) is the nine-amino acid COOH-terminal extension of Ex-4. We investigated the contribution of this extension to the survival time of Ex-4. We assessed the overall metabolism of GLP-1, Ex-4, a COOH-terminally extended GLP-1 peptide (GLP-1+Ex(31-39); GLP-Ex),(4) and a COOH-terminally truncated exendin peptide (Ex(1-30)) in anaesthetized, catheterized pigs, with focus on the extraction across the kidneys and a peripheral tissue (a hindleg, representing muscle, adipose- and connective tissue). Peptide analysis was carried out with assays against the mid-region of the peptides, whereby the role of dipeptidyl peptidase-4 (DPP-4)(5) mediated NH(2)-terminal degradation could be disregarded. The half-life of GLP-1 was significantly increased when the COOH-terminal extension of Ex-4 was added (GLP-1 4.8±3.3min; GLP-Ex 19.5±3.3min). In contrast, there was no effect of truncating Ex-4 (Ex-4 32.4±4.1min; Ex(1-30) 28.4±1.7min). Ex-4 and Ex(1-30) were cleared solely by the kidneys at rates corresponding to the glomerular filtration rate (GFR),(6) while GLP-1 and GLP-Ex were cleared by both the kidneys and peripheral tissues. Both extraction rates were, however, significantly reduced with GLP-Ex compared to GLP-1. The renal clearance rate of GLP-1 greatly exceeded GFR, while GLP-Ex was cleared at a rate resembling GFR. In conclusion, the COOH-terminal extension of Ex-4 contributes minimally to the increased survival time of Ex-4, while addition of this sequence to GLP-1 significantly reduces its clearance.",
author = "L Simonsen and Holst, {Jens Juul} and K Madsen and Deacon, {C F}",
note = "Copyright {\circledC} 2013 Elsevier B.V. All rights reserved.",
year = "2013",
month = "2",
day = "10",
doi = "10.1016/j.regpep.2012.12.012",
language = "English",
volume = "181",
pages = "17--21",
journal = "Regulatory Peptides",
issn = "0167-0115",
publisher = "Elsevier",
number = "10",

}

RIS

TY - JOUR

T1 - The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs

AU - Simonsen, L

AU - Holst, Jens Juul

AU - Madsen, K

AU - Deacon, C F

N1 - Copyright © 2013 Elsevier B.V. All rights reserved.

PY - 2013/2/10

Y1 - 2013/2/10

N2 - The most striking sequence difference between glucagon-like peptide-1 (GLP-1)(2) and the longer-acting GLP-1 receptor agonist, exendin-4 (Ex-4),(3) is the nine-amino acid COOH-terminal extension of Ex-4. We investigated the contribution of this extension to the survival time of Ex-4. We assessed the overall metabolism of GLP-1, Ex-4, a COOH-terminally extended GLP-1 peptide (GLP-1+Ex(31-39); GLP-Ex),(4) and a COOH-terminally truncated exendin peptide (Ex(1-30)) in anaesthetized, catheterized pigs, with focus on the extraction across the kidneys and a peripheral tissue (a hindleg, representing muscle, adipose- and connective tissue). Peptide analysis was carried out with assays against the mid-region of the peptides, whereby the role of dipeptidyl peptidase-4 (DPP-4)(5) mediated NH(2)-terminal degradation could be disregarded. The half-life of GLP-1 was significantly increased when the COOH-terminal extension of Ex-4 was added (GLP-1 4.8±3.3min; GLP-Ex 19.5±3.3min). In contrast, there was no effect of truncating Ex-4 (Ex-4 32.4±4.1min; Ex(1-30) 28.4±1.7min). Ex-4 and Ex(1-30) were cleared solely by the kidneys at rates corresponding to the glomerular filtration rate (GFR),(6) while GLP-1 and GLP-Ex were cleared by both the kidneys and peripheral tissues. Both extraction rates were, however, significantly reduced with GLP-Ex compared to GLP-1. The renal clearance rate of GLP-1 greatly exceeded GFR, while GLP-Ex was cleared at a rate resembling GFR. In conclusion, the COOH-terminal extension of Ex-4 contributes minimally to the increased survival time of Ex-4, while addition of this sequence to GLP-1 significantly reduces its clearance.

AB - The most striking sequence difference between glucagon-like peptide-1 (GLP-1)(2) and the longer-acting GLP-1 receptor agonist, exendin-4 (Ex-4),(3) is the nine-amino acid COOH-terminal extension of Ex-4. We investigated the contribution of this extension to the survival time of Ex-4. We assessed the overall metabolism of GLP-1, Ex-4, a COOH-terminally extended GLP-1 peptide (GLP-1+Ex(31-39); GLP-Ex),(4) and a COOH-terminally truncated exendin peptide (Ex(1-30)) in anaesthetized, catheterized pigs, with focus on the extraction across the kidneys and a peripheral tissue (a hindleg, representing muscle, adipose- and connective tissue). Peptide analysis was carried out with assays against the mid-region of the peptides, whereby the role of dipeptidyl peptidase-4 (DPP-4)(5) mediated NH(2)-terminal degradation could be disregarded. The half-life of GLP-1 was significantly increased when the COOH-terminal extension of Ex-4 was added (GLP-1 4.8±3.3min; GLP-Ex 19.5±3.3min). In contrast, there was no effect of truncating Ex-4 (Ex-4 32.4±4.1min; Ex(1-30) 28.4±1.7min). Ex-4 and Ex(1-30) were cleared solely by the kidneys at rates corresponding to the glomerular filtration rate (GFR),(6) while GLP-1 and GLP-Ex were cleared by both the kidneys and peripheral tissues. Both extraction rates were, however, significantly reduced with GLP-Ex compared to GLP-1. The renal clearance rate of GLP-1 greatly exceeded GFR, while GLP-Ex was cleared at a rate resembling GFR. In conclusion, the COOH-terminal extension of Ex-4 contributes minimally to the increased survival time of Ex-4, while addition of this sequence to GLP-1 significantly reduces its clearance.

U2 - 10.1016/j.regpep.2012.12.012

DO - 10.1016/j.regpep.2012.12.012

M3 - Journal article

C2 - 23318502

VL - 181

SP - 17

EP - 21

JO - Regulatory Peptides

JF - Regulatory Peptides

SN - 0167-0115

IS - 10

ER -

ID: 45682339