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

Gabe, M; Skov‐Jeppesen, Kirsa; Gasbjerg, Lærke S.; Schiellerup, Sine; Martinussen, Christoffer; Gadgaard, Sarina; Boer, Geke Aline; Oeke, Jannika; Torz, Lola; Veedfald, Simon; Svane, Maria S.; Bojsen‐Møller, Kirstine N.; Madsbad, Sten; Holst, Jens J.; Hartmann, Bolette

doi:10.1016/j.phrs.2022.106058

Cited by 23 publications

(28 citation statements)

References 70 publications

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“…Previously, a similar effect was encountered with single GIP analogues (50)(51)(52) or single GLP-2 analogues (17,53) . Furthermore, subcutaneous administration of GIP or GLP-2, or coadministration 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) .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, others have reported the development of another unimolecular dual GIP/GLP‐2 analogue, peptide 11, that shows ~79% similarity with GL‐0001. ( 56 ) However, and in opposition to GL‐0001, peptide 11 demonstrated a species‐dependency bias toward either GIPr or the GLP‐2r in human and rodent systems, respectively. This behavior was not found with GL‐0001 as a similar enhancement of collagen maturity was observed in human and rodent cultures.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, others have reported the development of another unimolecular dual GIP/GLP-2 analogue, named peptide 11 that shows ~79% similarity with GL-0001 (54) . However, and in opposition to GL-0001, peptide 11 demonstrated a specie-dependency bias towards either the GIPr or the GLP-2r in human and rodent systems, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Development of a First-in-Class Unimolecular Dual GIP/GLP-2 Analogue, GL-0001, for the Treatment of Bone Fragility

Gobron

Couchot

Irwin

et al. 2020

Journal of Bone and Mineral Research

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Due to ageing of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone ECM material properties, i.e. the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual GIP/GLP-2 analogues, GL-0001, that activate simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagonlike peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cAMP-LOX pathway to enhance collagen maturity. Furthermore, in mice with ovariectomy-induced bone fragility, GL-0001 prevented excess trabecular bone degradation at the appendicular skeleton and also enhanced bone ECM material properties through reduction of the degree of mineralization and augmentation in enzymatic collagen crosslinking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering of bone fragility.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Development of a First-in-Class Unimolecular Dual GIP/GLP-2 Analogue, GL-0001, for the Treatment of Bone Fragility

Gobron

Couchot

Irwin

et al. 2020

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…Previously, a similar effect was encountered with single GIP analogues (50-52) or single GLP-2 analogues (17,53) . 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) .…”

Section: Discussionmentioning

confidence: 99%

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

Gobron

Couchot

Irwin

et al. 2022

Preprint

View full text Add to dashboard Cite

Due to ageing of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone ECM material properties, i.e. the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual GIP/GLP-2 analogues, GL-0001, that activate simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cAMP-LOX pathway to enhance collagen maturity. Furthermore, in mice with ovariectomy-induced bone fragility, GL-0001 prevented excess trabecular bone degradation at the appendicular skeleton and also enhanced bone ECM material properties through reduction of the degree of mineralization and augmentation in enzymatic collagen crosslinking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering of bone fragility.

show abstract

“…Recently, the regulation properties of bone turnover of GLP-2 have been reported in various human studies [ 17 , 18 , 19 , 20 ]. However, the effect of GLP-2 on senile osteoporosis, another type of primary osteoporosis with distinct etiology and pathophysiological characteristics, has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Glucagon-Like Peptide-2 Ameliorates Age-Associated Bone Loss and Gut Barrier Dysfunction in Senescence-Accelerated Mouse Prone 6 Mice

Huang

Kuai

et al. 2022

Gerontology

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Introduction: Senile osteoporosis is one of the most common age-related diseases worldwide. Glucagon like peptide-2 (GLP-2), a naturally occurring gastrointestinal peptide, possesses therapeutic effects on bone loss in postmenopausal women and ovariectomized rats. However, the role of GLP-2 in senile osteoporosis and underlying mechanisms has not been explored. Methods: GLP-2 was subcutaneously injected into the 6-month-old male senile osteoporosis model of senescence-accelerated mouse prone 6 (SAMP6) mice for 6 weeks. SAMP6 subjected to normal saline and senescence-accelerated mouse resistant 1 served as control groups. Micro-computed tomography was performed to evaluate the bone mass and microarchitecture of the mice. Osteoblastic and osteoclastic activities were determined by biochemical, quantitative real-time PCR, histological, and histomorphometric analyses combined with hematoxylin-eosin, toluidine blue, and tartrate-resistant acid phosphatase staining. We also examined the proteins and structure of intestinal tight junction using immunohistochemical assay as well as a transmission electron microscope. Serum inflammation marker levels were measured using ELISA. Additionally, anti-oxidative enzymes GPX-4 and SOD-2 and receptors of GLP-2 and vitamin D expression in the ileum and colon were detected under immunofluorescence staining. Results: Six-week GLP-2 treatment attenuated bone loss in SAMP6 mice, as evidenced by increased bone mineral density, improved microarchitecture in femora, and enhanced osteogenic activities. In contrast, the activity of osteoclastic activity was not obviously inhibited. Moreover, GLP-2 ameliorated tight junction structure and protein expression in the intestinal barrier, which was accompanied by the reduction of TNF-α level. The expression of receptors of intestinal GLP-2 and vitamin D in the ileum was elevated. Furthermore, the oxidative stress in the intestines was improved by increasing the GPX-4 and SOD-2 signaling. Conclusion: Our findings suggest that GLP-2 could ameliorate age-associated bone loss, tight junction structure, and improved antioxidant enzyme activity in the gut in SAMP6 mice. Amelioration of gut barrier dysfunction may potentially contribute to improving bone formation and provide evidence for targeting the entero-bone axis in the treatment of senile osteoporosis.

show abstract

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

Cited by 23 publications

References 70 publications

Development of a First-in-Class Unimolecular Dual GIP/GLP-2 Analogue, GL-0001, for the Treatment of Bone Fragility

Development of a First-in-Class Unimolecular Dual GIP/GLP-2 Analogue, GL-0001, for the Treatment of Bone Fragility

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

Glucagon-Like Peptide-2 Ameliorates Age-Associated Bone Loss and Gut Barrier Dysfunction in Senescence-Accelerated Mouse Prone 6 Mice

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