GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment

Research output: Contribution to journalJournal articlepeer-review

Standard

GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. / Gabe, Maria Buur Nordskov; Skov-Jeppesen, Kirsa; Gasbjerg, Lærke Smidt; Schiellerup, Sine Pasch; Martinussen, Christoffer; Gadgaard, Sarina; Boer, Geke Aline; Oeke, Jannika; Torz, Lola Julia; Veedfald, Simon; Svane, Maria Saur; Bojsen-Møller, Kirstine Nyvold; Madsbad, Sten; Holst, Jens Juul; Hartmann, Bolette; Rosenkilde, Mette Marie.

In: Pharmacological Research, Vol. 176, 106058, 2022.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Gabe, MBN, Skov-Jeppesen, K, Gasbjerg, LS, Schiellerup, SP, Martinussen, C, Gadgaard, S, Boer, GA, Oeke, J, Torz, LJ, Veedfald, S, Svane, MS, Bojsen-Møller, KN, Madsbad, S, Holst, JJ, Hartmann, B & Rosenkilde, MM 2022, 'GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment', Pharmacological Research, vol. 176, 106058. https://doi.org/10.1016/j.phrs.2022.106058

APA

Gabe, M. B. N., Skov-Jeppesen, K., Gasbjerg, L. S., Schiellerup, S. P., Martinussen, C., Gadgaard, S., Boer, G. A., Oeke, J., Torz, L. J., Veedfald, S., Svane, M. S., Bojsen-Møller, K. N., Madsbad, S., Holst, J. J., Hartmann, B., & Rosenkilde, M. M. (2022). GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. Pharmacological Research, 176, [106058]. https://doi.org/10.1016/j.phrs.2022.106058

Vancouver

Gabe MBN, Skov-Jeppesen K, Gasbjerg LS, Schiellerup SP, Martinussen C, Gadgaard S et al. GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. Pharmacological Research. 2022;176. 106058. https://doi.org/10.1016/j.phrs.2022.106058

Author

Gabe, Maria Buur Nordskov ; Skov-Jeppesen, Kirsa ; Gasbjerg, Lærke Smidt ; Schiellerup, Sine Pasch ; Martinussen, Christoffer ; Gadgaard, Sarina ; Boer, Geke Aline ; Oeke, Jannika ; Torz, Lola Julia ; Veedfald, Simon ; Svane, Maria Saur ; Bojsen-Møller, Kirstine Nyvold ; Madsbad, Sten ; Holst, Jens Juul ; Hartmann, Bolette ; Rosenkilde, Mette Marie. / GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. In: Pharmacological Research. 2022 ; Vol. 176.

Bibtex

@article{5874b6b523644574916747f581651529,
title = "GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment",
abstract = "The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.",
author = "Gabe, {Maria Buur Nordskov} and Kirsa Skov-Jeppesen and Gasbjerg, {L{\ae}rke Smidt} and Schiellerup, {Sine Pasch} and Christoffer Martinussen and Sarina Gadgaard and Boer, {Geke Aline} and Jannika Oeke and Torz, {Lola Julia} and Simon Veedfald and Svane, {Maria Saur} and Bojsen-M{\o}ller, {Kirstine Nyvold} and Sten Madsbad and Holst, {Jens Juul} and Bolette Hartmann and Rosenkilde, {Mette Marie}",
note = "Copyright {\textcopyright} 2022 Elsevier Ltd. All rights reserved.",
year = "2022",
doi = "10.1016/j.phrs.2022.106058",
language = "English",
volume = "176",
journal = "Pharmacological Research",
issn = "1043-6618",
publisher = "Academic Press",

}

RIS

TY - JOUR

T1 - GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment

AU - Gabe, Maria Buur Nordskov

AU - Skov-Jeppesen, Kirsa

AU - Gasbjerg, Lærke Smidt

AU - Schiellerup, Sine Pasch

AU - Martinussen, Christoffer

AU - Gadgaard, Sarina

AU - Boer, Geke Aline

AU - Oeke, Jannika

AU - Torz, Lola Julia

AU - Veedfald, Simon

AU - Svane, Maria Saur

AU - Bojsen-Møller, Kirstine Nyvold

AU - Madsbad, Sten

AU - Holst, Jens Juul

AU - Hartmann, Bolette

AU - Rosenkilde, Mette Marie

N1 - Copyright © 2022 Elsevier Ltd. All rights reserved.

PY - 2022

Y1 - 2022

N2 - The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.

AB - The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.

U2 - 10.1016/j.phrs.2022.106058

DO - 10.1016/j.phrs.2022.106058

M3 - Journal article

C2 - 34995796

VL - 176

JO - Pharmacological Research

JF - Pharmacological Research

SN - 1043-6618

M1 - 106058

ER -

ID: 290597438