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

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). 22GLP-1: glucagon-like peptide-1. and the longer-acting GLP-1 receptor agonist, exendin-4 (Ex-4),. 33Ex-4: exendin-4. 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),44GLP-Ex: GLP-1+Ex(31-39). 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)55DPP-4: dipeptidyl peptidase-4. mediated NH2-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 ± 3.3. min; GLP-Ex 19.5 ± 3.3. min). In contrast, there was no effect of truncating Ex-4 (Ex-4 32.4 ± 4.1. min; Ex(1-30) 28.4 ± 1.7. min). Ex-4 and Ex(1-30) were cleared solely by the kidneys at rates corresponding to the glomerular filtration rate (GFR),. 66GFR: glomerular filtration rate. 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). 22GLP-1: glucagon-like peptide-1. and the longer-acting GLP-1 receptor agonist, exendin-4 (Ex-4),. 33Ex-4: exendin-4. 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),44GLP-Ex: GLP-1+Ex(31-39). 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)55DPP-4: dipeptidyl peptidase-4. mediated NH2-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 ± 3.3. min; GLP-Ex 19.5 ± 3.3. min). In contrast, there was no effect of truncating Ex-4 (Ex-4 32.4 ± 4.1. min; Ex(1-30) 28.4 ± 1.7. min). Ex-4 and Ex(1-30) were cleared solely by the kidneys at rates corresponding to the glomerular filtration rate (GFR),. 66GFR: glomerular filtration rate. 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

SN - 0167-0115

VL - 181

SP - 17

EP - 21

JO - Regulatory Peptides

JF - Regulatory Peptides

IS - 10

ER -