Advertisement

Improved fatigue properties, bone microstructure and blood glucose in type 2 diabetic rats with verapamil treatment

  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Shaowei Jia
    Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Affiliations
    Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Jingwen Li
    Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.
    Affiliations
    Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
    Search for articles by this author
  • Xiaorong Hu
    Affiliations
    Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
    Search for articles by this author
  • Xiaodan Wu
    Affiliations
    Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
    Search for articles by this author
  • He Gong
    Correspondence
    Corresponding author at: No.37, Xueyuan Road, Haidian District, Beijing, China.
    Affiliations
    Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors.

      Highlights

      • Verapamil presented a significant potential to improve bone quality of diabetic rats.
      • Bone microstructure and fatigue properties were improved in varapamil-treated diabetic rats.
      • High-dose verapamil had a significant effect on bone in diabetic rats.

      Abstract

      Background

      Type 2 diabetes mellitus is a global epidemic disease, which leads to a severe complication named increased bone fracture risk. This study aimed to explore if verapamil treatment could improve bone quality of type 2 diabetes mellitus.

      Methods

      Rat models of control, diabetes and verapamil treatment with 4/12/24/48 mg/kg/d were established, respectively. Blood glucose was monitored during 12-week treatment, and bilateral tibiae were collected. Microstructural images of bilateral metaphyseal cancellous bone and high-resolution images of cortical bone of left tibial shafts were obtained by micro-computed tomography. Fatigue properties of bone were evaluated via cyclic compressive tests of right tibial shafts.

      Findings

      Verapamil treatment had no significant effect on blood glucose, but blood glucose tended to decline with the increase of verapamil-treated time and dose. Compared with controls, osteocyte lacunar and canal porosities in diabetes and verapamil-treated groups were significantly decreased (P < 0.05), trabecular separation and degree of anisotropy were significantly increased (P < 0.05), while trabecular tissue mineral density, trabecular bone volume fraction and trabecular number in verapamil-treated (48 mg/kg/d) group were significantly higher than those in diabetes (P < 0.05). Compared with diabetes, initial compressive elastic moduli in verapamil-treated (12/24/48 mg/kg/d) groups were significantly increased (P < 0.05), while secant modulus degradations in verapamil-treated (24/48 mg/kg/d) groups were significantly decreased (P < 0.05).

      Interpretation

      Verapamil could improve bone microstructure and fatigue properties in type 2 diabetic rats; and high-dose verapamil presented a significant effect on improving bone quality. These findings provided a new possibility for preventing the high bone fracture risk of type 2 diabetes mellitus in clinics.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Biomechanics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Acevedo C.
        • Sylvia M.
        • Schaible E.
        • Graham J.L.
        • Stanhope K.L.
        • Metz L.N.
        • Gludovatz B.
        • Schwartz A.V.
        • Ritchie R.O.
        • Alliston T.N.
        • Havel P.J.
        • Fields A.J.
        Contributions of material properties and structure to increased bone fragility for a given bone mass in the UCD-T2DM rat model of type 2 diabetes.
        J. Bone Miner. Res. 2018; 33: 1066-1075
        • Bajaj D.
        • Geissler J.R.
        • Allen M.R.
        • Burr D.B.
        • Fritton J.C.
        The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate.
        Bone. 2016; 83: 57-64
        • Benoit A.
        • Guérard S.
        • Gillet B.
        • Guillot G.
        • Hild F.
        • Mitton D.
        • Périé J.-N.
        • Roux S.
        3D analysis from micro-MRI during in situ compression on cancellous bone.
        J. Biomech. 2009; 42: 2381-2386
        • Bokam P.
        • Germaneau A.
        • Breque C.
        • Rigoard P.
        • Vendeuvre T.
        • Valle V.
        Fracture behavior of cancellous bone and cancellous bone-PMMA bone cement interface: an experimental study using an integrated methodology (wedge splitting test and Heaviside-based digital image correlation).
        J. Mech. Behav. Biomed. Mater. 2021; 122104663
        • Brouwers J.
        • Ruchelsman M.
        • Rietbergen B.V.
        • Bouxsein M.L.
        Determination of rat vertebral bone compressive fatigue properties in untreated intact rats and zoledronic-acid-treated, ovariectomized rats.
        Osteoporos. Int. 2009; 20: 1377-1384
        • Burghardt A.J.
        • Issever A.S.
        • Schwartz A.V.
        • Davis K.A.
        • Masharani U.
        • Majumdar S.
        • Link T.M.
        High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus.
        J. Clin. Endocrinol. Metab. 2010; 95: 5045-5055
        • Carnovale C.
        • Dassano A.
        • Mosini G.
        • Mazhar F.
        • Clementi E.
        The β-cell effect of verapamil-based treatment in patients with type 2 diabetes: a systematic review.
        Acta Diabetol. 2019; 57: 1-15
        • Compston J.
        Type 2 diabetes mellitus and bone.
        J. Intern. Med. 2018; 283: 140-153
        • Cooper D.
        • Turinsky A.
        • Sensen C.
        • Hallgrimsson B.
        Effect of voxel size on 3D micro-CT analysis of cortical bone porosity.
        Calcif. Tissue Int. 2007; 80: 211-219
        • Dhaliwal R.
        • Cibula D.
        • Ghosh C.
        • Weinstock R.
        • Moses A.
        Bone quality assessment in type 2 diabetes mellitus.
        Osteoporos. Int. 2014; 25: 1969-1973
        • Dong X.N.
        • Guo X.E.
        The dependence of transversely isotropic elasticity of human femoral cortical bone on porosity.
        J. Biomech. 2004; 37: 1281-1287
        • Du J.Y.
        • Flanagan C.D.
        • Bensusan J.S.
        • Knusel K.D.
        • Akkus O.
        • Rimnac C.
        Raman biomarkers are associated with cyclic fatigue life of human allograft cortical bone.
        J. Bone Joint Surg. (Am. Vol.). 2019; 101: e85(1-6)
        • Erdal N.
        • Gurgul S.
        • Kavak S.
        • Yildiz A.
        • Emre M.
        Deterioration of bone quality by streptozotocin (STZ)-induced type 2 diabetes mellitus in rats.
        Biol. Trace Elem. Res. 2011; 140: 342-353
        • Fernando O.
        • Tiffany G.
        • Xu G.
        • Patel A.J.
        • Grayson T.B.
        • Thielen L.A.
        • Peng L.
        • Anath S.
        Verapamil and beta cell function in adults with recent-onset type 1 diabetes.
        Nat. Med. 2018; 24: 1108-1112
        • Gaeta M.
        • Mileto A.
        • Ascenti G.
        • Bernava G.
        • Murabito A.
        • Minutoli F.
        Bone stress injuries of the leg in athletes.
        La Radiol. Medica. 2013; 118: 1034-1044
        • Hamann C.
        • Rauner M.
        • Höhna Y.
        • Bernhardt R.
        • Mettelsiefen J.
        • Goettsch C.
        • Günther K.P.
        • Stolina M.
        • Han C.Y.
        • Asuncion F.J.
        Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus.
        J. Bone Miner. Res. 2013; 28: 627-638
        • Hussein R.M.
        Biochemical relationships between bone turnover markers and blood glucose in patients with type 2 diabetes mellitus.
        Diabetes Metabol. Synd.: Clin. Res. Rev.s. 2017; 11: S369-S372
        • Janghorbani M.
        • Dam R.M.V.
        • Willett W.C.
        • Hu F.B.
        Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture.
        Am. J. Epidemiol. 2007; 166: 495-505
        • Jung H.
        • Kim Hyung
        • Jin Choi
        • Eu Jeong
        • Ku Kyoung
        Trabecular bone score as an indicator for skeletal deterioration in diabetes.
        J. Clin. Endocrinol. Metab. 2015; 100: 475-482
        • Karim L.
        • Bouxsein M.L.
        Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties.
        Bone. 2016; 82: 21-27
        • Kerckhofs G.
        • Durand M.
        • Vangoitsenhoven R.
        • Marin C.
        • Van D.
        • Carmeliet G.
        • Luyten F.P.
        • Geris L.
        • Vandamme K.
        Changes in bone macro- and microstructure in diabetic obese mice revealed by high resolution microfocus X-ray computed tomography.
        Sci. Rep. 2016; 6 (35517(1-13))
        • Khodneva Y.
        • Shalev A.
        • Frank S.J.
        • Carson A.P.
        • Safford M.M.
        Calcium channel blocker use is associated with lower fasting serum glucose among adults with diabetes from the REGARDS study.
        Diabetes Res. Clin. Pract. 2016; 115: 115-121
        • Li J.
        • Gong H.
        Fatigue behavior of cortical bone: a review.
        Acta Mech. Sinica. 2020; 37: 516-526
        • Liu X.
        • Li W.
        • Cai J.
        • Yan Z.
        • Shao X.
        • Xie K.
        • Guo X.E.
        • Luo E.
        • Jing D.
        Spatiotemporal characterization of microdamage accumulation and its targeted remodeling mechanisms in diabetic fatigued bone.
        FASEB J. 2020; 34: 2579-2594
        • Lonsberry B.B.
        • Dubo D.F.
        • Thomas S.M.
        • Docherty J.C.
        • Maddaford T.G.
        • Pierce G.N.
        Effect of high-dose verapamil administration on the Ca2+ channel density in rat cardiac tissue.
        Pharmacology. 1994; 49: 23-32
        • Malayeri A.
        • Zakerkish M.
        • Ramesh F.
        • Galehdari H.
        • Hemmati A.A.
        • Angali K.A.
        The effect of verapamil on TXNIP gene expression, GLP1R mRNA, FBS, HbA1c, and lipid profile in T2DM patients receiving metformin and Sitagliptin.
        Diabetes Therapy. 2021; 12: 2701-2713
        • Merlo K.
        • Aaronson J.
        • Vaidya R.
        • Rezaee T.
        • Chalivendra V.
        • Karim L.
        In vitro-induced high sugar environments deteriorate human cortical bone elastic modulus and fracture toughness.
        J. Orthop. Res. 2020; 38: 972-983
        • Napoli N.
        • Chandran M.
        • Pierroz D.D.
        • Abrahamsen B.
        • Schwartz A.V.
        • Ferrari S.L.
        Mechanisms of diabetes mellitus-induced bone fragility.
        Nat. Rev. Endocrinol. 2017; 13: 208-219
        • Niu H.J.
        • Shao X.N.
        • Wang L.
        • Tian H.M.
        • Fan Y.B.
        Correlation study on bone density, microstructure and acoustic parameters of cancellous bone at different stages of decalcification.
        J. Med. Biomech. 2011; 26: 527-533
        • Palacio-Mancheno P.E.
        • Larriera A.I.
        • Doty S.B.
        • Cardoso L.
        • Fritton S.P.
        3D assessment of cortical bone porosity and tissue mineral density using high-resolution CT: effects of resolution and threshold method.
        J. Bone Miner. Res. 2014; 29: 142-150
        • Qian C.
        • Zhu C.
        • Yu W.
        • Jiang X.
        • Zhang F.
        High-fat diet/low-dose streptozotocin-induced type 2 diabetes in rats impacts osteogenesis and Wnt signaling in bone marrow stromal cells.
        PLoS One. 2015; 10 (e0136390(1-15))
        • Raisz L.G.
        Physiology and pathophysiology of bone remodeling.
        Clin. Chem. 1999; 45: 1353-1358
        • Samelson E.J.
        • Demissie S.
        • Cupples L.A.
        • Zhang X.
        • Xu H.
        • Liu C.
        • Boyd S.K.
        • Mclean R.R.
        • Broe K.E.
        • Kiel D.P.
        Diabetes and deficits in cortical bone density, microarchitecture, and bone size: rramingham HR-pQCT study.
        J. Bone Miner. Res. 2017; 33: 1-9
        • Samnegård E.
        • Sjödén G.
        Verapamil induces increased bone volume and osteopenia in female rats but has the opposite effect in male rats.
        Calcif. Tissue Int. 1992; 50: 524-526
        • Szabó M.
        • Thurner P.J.
        Anisotropy of bovine cortical bone tissue damage properties.
        J. Biomech. 2013; 46: 2-6
        • Wynnyckyj C.
        • Willett T.L.
        • Omelon S.
        • Jian W.
        • Wang Z.
        • Grynpas M.
        Changes in bone fatigue resistance due to collagen degradation.
        J. Orthop. Res. 2011; 29: 197-203
        • Xu G.
        • Chen J.
        • Gu J.
        • Shalev A.
        Preventing β-cell loss and diabetes wth calcium channel blockers.
        Diabetes. 2012; 61: 848-856
        • Yasushi T.
        • Atsunori K.
        • Tsutomu O.
        • Nanami A.
        • Takayuki A.
        • Motoyoshi I.
        • Yoshihumi T.
        • Yukio S.
        Effect of verapamil on cardiac protein kinase C activity in diabetic rats.
        Eur. J. Pharmacol. 1991; 200: 353-356
        • Yerramshetty J.S.
        • Akkus O.
        The associations between mineral crystallinity and the mechanical properties of human cortical bone.
        Bone. 2008; 42: 476-482
        • Zeitoun D.
        • Caliaperoumal G.
        • Bensidhoum M.
        • Constans J.M.
        • Anagnostou F.
        • Bousson V.
        Microcomputed tomography of the femur of diabetic rats: alterations of trabecular and cortical bone microarchitecture and vasculature-a feasibility study.
        Eur. Radiol. Exper. 2019; 3: 1-9
        • Zimmermann E.A.
        • Schaible E.
        • Bale H.
        • Barth H.D.
        • Tang S.Y.
        • Reichert P.
        • Busse B.
        • Alliston T.
        • Ager J.W.
        • Ritchie R.O.
        Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales.
        Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 14416-14421
        • Zimmermann E.A.
        • Gludovatz B.
        • Schaible E.
        • Busse B.
        • Ritchie R.O.
        Fracture resistance of human cortical bone across multiple length-scales at physiological strain rates.
        Biomaterials. 2014; 35: 5472-5481