Sitagliptin Alters Bone Composition in High-Fat-Fed Mice
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.
KeywordsSitagliptin Bone fragility Bone composition Type 2 diabetes
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.
- 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 19:1084–1091CrossRefPubMedGoogle Scholar
- 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 95:5045–5055CrossRefPubMedGoogle Scholar
- 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 19:78–86CrossRefPubMedGoogle Scholar
- 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 15:954–957CrossRefPubMedGoogle Scholar
- 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 58:9–16CrossRefPubMedGoogle Scholar
- 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)CrossRefPubMedGoogle Scholar