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GIP analogues augment bone strength by modulating bone composition in diet-induced obesity in mice

Abstract : Receptors to glucose-dependent insulinotropic polypeptide (GIP), have been identified on bone and GIP receptor (GIPr) knockout mice exhibit reduced bone strength and quality. Despite this, little is known on the potential beneficial bone effects of exogenous GIP on bone physiology. The aim of the present study was to assess whether stable GIP analogues were capable of ameliorating bone strength in mice with diet-induced obesity. The stable GIP analogue (D-Ala²)-GIP, and (D-Ala²)-GIP-Tag, a specific GIP analogue homing exclusively to bone, were employed. In vitro studies were used to assess effects of (D-Ala²)-GIP and (D-Ala²)-GIP-Tag on bone miner-alization, lysyl oxidase activity, collagen maturity as well as osteoclast formation and activity. Subsequent in vivo studies employed obese-prediabetic Swiss NIH mice subjected to a 42-day period of daily administration of saline, (D-Ala²)-GIP or (D-Ala²)-GIP-Tag. In vitro studies confirmed that (D-Ala²)-GIP and (D-Ala²)-GIP-Tag had similar beneficial biological effects on bone cells. Administration of (D-Ala²)-GIP and (D-Ala²)-GIP-Tag resulted in lower blood glucose levels without any effects on body weight. Both GIP analogues augmented bone strength to a similar extent. Trabecular or cortical bone microarchitecture were not changed over the time course of the study. However, (D-Ala²)-GIP and (D-Ala²)-GIP-Tag augmented enzymatic collagen crosslinking as well as the heterogeneity of enzymatic collagen crosslinking, mineral-to-matrix ratio and significantly reduced the het-erogeneity in mineral bone crystallite size. This study demonstrates that activation of skeletal GIPr by stable GIP analogues enhance bone strength in prediabetes and suggest that these analogues may be beneficial in the treatment of bone disease.
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https://hal.univ-angers.fr/hal-02431326
Contributeur : Guillaume Mabilleau <>
Soumis le : mercredi 8 janvier 2020 - 11:23:20
Dernière modification le : jeudi 9 janvier 2020 - 01:22:00

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Sagar Vyavahare, Aleksandra Mieczkowska, Peter Flatt, Daniel Chappard, Nigel Irwin, et al.. GIP analogues augment bone strength by modulating bone composition in diet-induced obesity in mice. Peptides, Elsevier, 2019, pp.170207. ⟨10.1016/j.peptides.2019.170207⟩. ⟨hal-02431326⟩

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