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Sitagliptin Alters Bone Composition in High-Fat-Fed Mice

  • Sity Aishah Mansur
  • Aleksandra Mieczkowska
  • Peter R. Flatt
  • Daniel Chappard
  • Nigel Irwin
  • Guillaume MabilleauEmail author
Original Research

Abstract

Type 2 diabetes mellitus is recognized as a significant risk factor for fragility of bone. Among the newer anti-diabetic agents, dipeptidyl peptidase-4 inhibitors (DPP4i) have been reported to decrease the occurrence of bone fractures although the reason is unclear. The main aim of this study was to evaluate the impact of sitagliptin treatment on tissue bone strength and compositional parameters in the high-fat-fed mouse model. Male NIH swiss mice were allowed free access to high-fat diet for 150 days to induce chronic hyperglycemia and insulin resistance. Sitagliptin was administered once daily for 3 weeks. High-fat-fed mice administered with saline were used as controls. Bone strength was assessed at the organ and tissue level by three-point bending and nanoindentation, respectively. Bone microarchitecture was investigated by microcomputed tomography and bone composition was evaluated by Fourier transform infrared imaging and quantitative backscattered electron imaging. Administration of sitagliptin increased non-fasting insulin, improved glucose tolerance and increased insulin sensitivity. This was associated with clear ameliorations in bone strength at the organ and tissue level. No changes in trabecular or cortical microarchitectures were observed. On the other hand, higher values of Camean, Caturn, collagen maturity, mineral/matrix ratio, mineral maturity and crystal size index were evidenced after sitagliptin treatment. Correlation analysis significantly linked the modifications of bone strength to changes in bone compositional parameters. These results bring new light on the mode of action of sitagliptin on bone physiology and demonstrate a benefit of DPP4i.

Keywords

Sitagliptin Bone fragility Bone composition Type 2 diabetes 

Notes

Acknowledgements

The authors are grateful to Nadine Gaborit and Stéphanie Lemière (University of Angers, GEROM-LHEA, Institut de Biologie en Santé, Angers, France) for their help with microCT. This work was supported by Grants from the Irish Endocrine Society as well as University of Ulster Research Challenge Fund and Proof of Principle Funding Programs.

Compliance with Ethical Standards

Conflict of interest

Sity Aishah Mansur, Aleksandra Mieczkowska, Peter R Flatt, Daniel Chappard, Nigel Irwin and Guillaume Mabilleau, declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All procedures were conducted according to UK Home Office Regulations (UK Animals Scientific Procedures Act 1986) and approved by Institutional Animal Care and Use Committee of University of Ulster. Animal study is reported in compliance with the ARRIVE guidelines.

References

  1. 1.
    Janghorbani M, Van Dam RM, Willett WC, Hu FB (2007) Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 166:495–505CrossRefGoogle Scholar
  2. 2.
    Strotmeyer ES, Cauley JA, Schwartz AV, Nevitt MC, Resnick HE, Zmuda JM, Bauer DC, Tylavsky FA, de Rekeneire N, Harris TB, Newman AB, Health ABCS (2004) Diabetes is associated independently of body composition with BMD and bone volume in older white and black men and women: the Health, Aging, and Body Composition Study. J Bone Miner Res 19:1084–1091CrossRefGoogle Scholar
  3. 3.
    Vestergaard P (2007) Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis. Osteoporos Int 18:427–444CrossRefGoogle Scholar
  4. 4.
    Burr DB (2004) Bone quality: understanding what matters. J Musculoskelet Neuronal Interact 4:184–186PubMedGoogle Scholar
  5. 5.
    Burghardt AJ, Issever AS, Schwartz AV, Davis KA, Masharani U, Majumdar S, Link TM (2010) High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 95:5045–5055CrossRefGoogle Scholar
  6. 6.
    Krakauer JC, McKenna MJ, Buderer NF, Rao DS, Whitehouse FW, Parfitt AM (1995) Bone loss and bone turnover in diabetes. Diabetes 44:775–782CrossRefGoogle Scholar
  7. 7.
    Patsch JM, Burghardt AJ, Yap SP, Baum T, Schwartz AV, Joseph GB, Link TM (2013) Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res 28:313–324CrossRefGoogle Scholar
  8. 8.
    Tang SY, Vashishth D (2010) Non-enzymatic glycation alters microdamage formation in human cancellous bone. Bone 46:148–154CrossRefGoogle Scholar
  9. 9.
    Farr JN, Drake MT, Amin S, Melton LJ 3rd, McCready LK, Khosla S (2014) In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res 29:787–795CrossRefGoogle Scholar
  10. 10.
    Dicker D (2011) DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care 34(Suppl 2):S276–S278CrossRefGoogle Scholar
  11. 11.
    Choi HJ, Park C, Lee YK, Ha YC, Jang S, Shin CS (2016) Risk of fractures and diabetes medications: a nationwide cohort study. Osteoporos Int 27:2709–2715CrossRefGoogle Scholar
  12. 12.
    Dombrowski S, Kostev K, Jacob L (2017) Use of dipeptidyl peptidase-4 inhibitors and risk of bone fracture in patients with type 2 diabetes in Germany-A retrospective analysis of real-world data. Osteoporos Int 28:2421–2428CrossRefGoogle Scholar
  13. 13.
    Driessen JH, van den Bergh JP, van Onzenoort HA, Henry RM, Leufkens HG, de Vries F (2017) Long-term use of dipeptidyl peptidase-4 inhibitors and risk of fracture: a retrospective population-based cohort study. Diabetes Obes Metab 19:421–428CrossRefGoogle Scholar
  14. 14.
    Josse RG, Majumdar SR, Zheng Y, Adler A, Bethel MA, Buse JB, Green JB, Kaufman KD, Rodbard HW, Tankova T, Westerhout CM, Peterson ED, Holman RR, Armstrong PW, Group TS (2017) Sitagliptin and risk of fractures in type 2 diabetes: results from the TECOS trial. Diabetes Obes Metab 19:78–86CrossRefGoogle Scholar
  15. 15.
    Mamza J, Marlin C, Wang C, Chokkalingam K, Idris I (2016) DPP-4 inhibitor therapy and bone fractures in people with Type 2 diabetes—a systematic review and meta-analysis. Diabetes Res Clin Pract 116:288–298CrossRefGoogle Scholar
  16. 16.
    Monami M, Dicembrini I, Antenore A, Mannucci E (2011) Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care 34:2474–2476CrossRefGoogle Scholar
  17. 17.
    Mosenzon O, Wei C, Davidson J, Scirica BM, Yanuv I, Rozenberg A, Hirshberg B, Cahn A, Stahre C, Strojek K, Bhatt DL, Raz I (2015) Incidence of fractures in patients with type 2 diabetes in the SAVOR-TIMI 53 Trial. Diabetes Care 38:2142–2150CrossRefGoogle Scholar
  18. 18.
    Yang J, Huang C, Wu S, Xu Y, Cai T, Chai S, Yang Z, Sun F, Zhan S (2017) The effects of dipeptidyl peptidase-4 inhibitors on bone fracture among patients with type 2 diabetes mellitus: a network meta-analysis of randomized controlled trials. PLoS ONE 12:e0187537CrossRefGoogle Scholar
  19. 19.
    Cusick T, Mu J, Pennypacker BL, Li Z, Scott KR, Shen X, Fisher JE, Langdon RB, Kimmel DB, Zhang BB, Glantschnig H (2013) Bone loss in the oestrogen-depleted rat is not exacerbated by sitagliptin, either alone or in combination with a thiazolidinedione. Diabetes Obes Metab 15:954–957CrossRefGoogle Scholar
  20. 20.
    Eom YS, Gwon AR, Kwak KM, Kim JY, Yu SH, Lee S, Kim YS, Park IB, Kim KW, Lee K, Kim BJ (2016) Protective effects of vildagliptin against pioglitazone-induced bone loss in type 2 diabetic rats. PLoS ONE 11:e0168569CrossRefGoogle Scholar
  21. 21.
    Gallagher EJ, Sun H, Kornhauser C, Tobin-Hess A, Epstein S, Yakar S, LeRoith D (2014) The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes. Diabetes Metab Res Rev 30:191–200CrossRefGoogle Scholar
  22. 22.
    Glorie L, Behets GJ, Baerts L, De Meester I, D’Haese PC, Verhulst A (2014) DPP IV inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats. Am J Physiol Endocrinol Metab 307:E447–E455CrossRefGoogle Scholar
  23. 23.
    Kyle KA, Willett TL, Baggio LL, Drucker DJ, Grynpas MD (2011) Differential effects of PPAR-γ activation versus chemical or genetic reduction of DPP-4 activity on bone quality in mice. Endocrinology 152:457–467CrossRefGoogle Scholar
  24. 24.
    Mabilleau G, Mieczkowska A, Irwin N, Flatt PR, Chappard D (2013) Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor. J Endocrinol 219:59–68CrossRefGoogle Scholar
  25. 25.
    Mieczkowska A, Irwin N, Flatt PR, Chappard D, Mabilleau G (2013) Glucose-dependent insulinotropic polypeptide (GIP) receptor deletion leads to reduced bone strength and quality. Bone 56:337–342CrossRefGoogle Scholar
  26. 26.
    Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 25:1468–1486CrossRefGoogle Scholar
  27. 27.
    Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610CrossRefGoogle Scholar
  28. 28.
    Oliver WC, Pharr GM (1992) An improved technique for determining hardness and elastic modulus using load and displacement sensing indentation experiments. J Mater Res 7:1564–1583CrossRefGoogle Scholar
  29. 29.
    Gupta HS, Schratter S, Tesch W, Roschger P, Berzlanovich A, Schoeberl T, Klaushofer K, Fratzl P (2005) Two different correlations between nanoindentation modulus and mineral content in the bone-cartilage interface. J Struct Biol 149:138–148CrossRefGoogle Scholar
  30. 30.
    Paschalis EP (2012) Fourier transform infrared imaging of bone. Methods Mol Biol 816:517–525CrossRefGoogle Scholar
  31. 31.
    Gadaleta SJ, Paschalis EP, Betts F, Mendelsohn R, Boskey AL (1996) Fourier transform infrared spectroscopy of the solution-mediated conversion of amorphous calcium phosphate to hydroxyapatite: new correlations between X-ray diffraction and infrared data. Calcif Tissue Int 58:9–16CrossRefGoogle Scholar
  32. 32.
    Ou-Yang H, Paschalis EP, Mayo WE, Boskey AL, Mendelsohn R (2001) Infrared microscopic imaging of bone: spatial distribution of CO3(2-). J Bone Miner Res 16:893–900CrossRefGoogle Scholar
  33. 33.
    Boyde A, McCorkell FA, Taylor GK, Bomphrey RJ, Doube M (2014) Iodine vapor staining for atomic number contrast in backscattered electron and X-ray imaging. Microsc Res Tech 77:1044–1051CrossRefGoogle Scholar
  34. 34.
    Mabilleau G, Filmon R, Petrov PK, Basle MF, Sabokbar A, Chappard D (2010) Cobalt, chromium and nickel affect hydroxyapatite crystal growth in vitro. Acta Biomater 6:1555–1560CrossRefGoogle Scholar
  35. 35.
    Jepsen KJ, Silva MJ, Vashishth D, Guo XE, van der Meulen MC (2015) Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. J Bone Miner Res 30:951–966CrossRefGoogle Scholar
  36. 36.
    Wang C, Xiao F, Qu X, Zhai Z, Hu G, Chen X, Zhang X (2017) Sitagliptin, an anti-diabetic drug, suppresses estrogen deficiency-induced osteoporosisin vivo and inhibits RANKL-induced osteoclast formation and bone resorption in vitro. Front Pharmacol 8:407CrossRefGoogle Scholar
  37. 37.
    Mansur SA, Mieczkowska A, Bouvard B, Flatt PR, Chappard D, Irwin N, Mabilleau G (2015) Stable incretin mimetics counter rapid deterioration of bone quality in type 1 diabetes mellitus. J Cell Physiol 230:3009–3018CrossRefGoogle Scholar
  38. 38.
    Mieczkowska A, Mansur SA, Irwin N, Flatt PR, Chappard D, Mabilleau G (2015) Alteration of the bone tissue material properties in type 1 diabetes mellitus: a Fourier transform infrared microspectroscopy study. Bone 76:31–39CrossRefGoogle Scholar
  39. 39.
    Rubin MR, Paschalis EP, Poundarik A, Sroga GE, McMahon DJ, Gamsjaeger S, Klaushofer K, Vashishth D (2016) Advanced glycation endproducts and bone material properties in type 1 diabetic mice. PLoS ONE 11:e0154700CrossRefGoogle Scholar
  40. 40.
    Hammond MA, Gallant MA, Burr DB, Wallace JM (2014) Nanoscale changes in collagen are reflected in physical and mechanical properties of bone at the microscale in diabetic rats. Bone 60:26–32CrossRefGoogle Scholar
  41. 41.
    Ambrosi TH, Scialdone A, Graja A, Gohlke S, Jank AM, Bocian C, Woelk L, Fan H, Logan DW, Schurmann A, Saraiva LR, Schulz TJ (2017) Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell 20:771–784 (e776)CrossRefGoogle Scholar
  42. 42.
    Hegazy SK (2015) Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab 33:207–212CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Biomedical SciencesUniversity of UlsterColeraineUK
  2. 2.University Tun Hussein Onn MalaysiaParit RajaMalaysia
  3. 3.GEROM, UPRES EA 4658UNIV Angers, SFR ICATAngersFrance
  4. 4.SCIAMUNIV Angers, SFR ICATAngersFrance
  5. 5.Bone Pathology UnitAngers University HospitalAngers CedexFrance

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