The Antiresorptive Effect of GIP, But Not GLP-2, Is Preserved in Patients With Hypoparathyroidism—A Randomized Crossover Study

Abstract

Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐2 (GLP‐2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP‐ and GLP‐2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed‐meal test (n = 7) followed by a peptide injection test (n = 4) using a randomized crossover design. We observed that the meal‐ and GIP‐ but not the GLP‐2‐induced changes in bone turnover markers were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP‐2 receptor (GLP‐2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP‐2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP‐2R were expressed in parathyroid tissue. Our findings suggest that the GIP‐induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP‐2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP‐2R in the parathyroid gland. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Development of a first-in-class unimolecular dual GIP/GLP-2 analogue, GL-0001, for the treatment of bone fragility

“…Indeed, administration of GL-0001 to cultured human osteoclast precursor elicited a significant reduction in osteoclast-mediated bone resorption and osteoclast precursor differentiation. This is also in agreement with the recent observation that GIPr and GLP-2r are expressed by human osteoclasts (24) . However, in our study, despite significant reduction in CTX-I levels with GL-0007 treatment, no effects of this molecule were observed in modulating bone ECM material properties and enhancing bone mechanical resistance in vivo.…”

“…Furthermore, subcutaneous administration of GIP or GLP-2, or co-administration of GIP and GLP-2 in healthy individuals resulted in a marked decreased in CTX-I levels and were mirrored with an acute suppression of PTH secretion (25,54) . Both receptors appear to be expressed with the same magnitude in parathyroid gland tissues, but only GLP-2, and not GIP, exert antiresorptive actions through reduced secretion of PTH (24) . Currently, function of the GIPr on parathyroid gland remains to be fully elucidated.…”

[Gly²]-GLP-2, But Not Glucagon or [D-Ala²]-GLP-1, Controls Collagen Crosslinking in Murine Osteoblast Cultures

“…Previously, effects of GLP-2 action on bone resorption have been hypothesized through a parathyroid hormone-dependent mechanism (31,32). More recent literature is in agreement with such effects (35). However, in the present study, we also evidenced that the action of [Gly²]-GLP-2 on bone physiology is due to a direct stimulation of cAMP in osteoblasts.…”

“…Previously, expression of the GLP-2r had been detected in human osteosarcoma-derived MG-63 and TE-85 cell lines (19). However, more recent human data, acquired in human bone marrow mesenchymal stem cell differentiated towards osteoblasts, suggest the absence of the known GLP-2r (35). Our data gathered in the MC3T3-E1 cells are in agreement with such observation, but it is worth noting that we cannot exclude a low level of expression of this GLP-2r in murine osteoblasts or alternative splicing that could hamper its detection with our primer pair as already evidenced by others recently in the testis (36).…”

Loss of Function Glucose-Dependent Insulinotropic Polypeptide Receptor Variants Are Associated With Alterations in BMI, Bone Strength and Cardiovascular Outcomes

“…The GIPR is not only expressed in pancreatic islet cells and adipocytes but has a wide expression profile including, but possibly not limited to, the heart, spleen, lung, central nervous system, and thyroid cells ( Baggio and Drucker, 2007 ). Additionally, the GIP system is important for bone metabolism through GIPR expression on osteoblasts and osteoclasts ( Bollag et al, 2000 ; Zhong et al, 2007 ; Skov-Jeppesen et al, 2021 ) through which GIP inhibits bone resorption as well as promotes bone formation ( Tsukiyama et al, 2006 ; Zhong et al, 2007 ; Berlier et al, 2015 ; Skov-Jeppesen et al, 2019 ). Even though it is now getting recognized that GIP/GIPR is involved in bone metabolism, it is largely unknown how genetic alterations, influencing GIPR signaling, affect bone growth and resorption.…”