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

Maria Buur Nordskov Gabe, Kirsa Skov-Jeppesen, Lærke Smidt Gasbjerg, Sine Pasch Schiellerup, Christoffer Martinussen, Sarina Gadgaard, Geke Aline Boer, Jannika Oeke, Lola Julia Torz, Simon Veedfald, Maria Saur Svane, Kirstine Nyvold Bojsen-Møller, Sten Madsbad, Jens Juul Holst, Bolette Hartmann, Mette Marie Rosenkilde

16 Citations (Scopus)

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.

Original languageEnglish
Article number106058
JournalPharmacological Research
Volume176
ISSN1043-6618
DOIs
Publication statusPublished - Feb 2022

Keywords

  • Bone turnover
  • Co-agonist
  • Dual-agonist
  • Glucagon-like peptide-2 (GLP-2)
  • Glucose-dependent insulinotropic polypeptide (GIP)
  • Osteoporosis

Fingerprint

Dive into the research topics of 'GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment'. Together they form a unique fingerprint.

Cite this