Skip to main content

Advertisement

Log in

Diabetes mellitus as a risk factor for intervertebral disc degeneration: a critical review

  • Review Article
  • Published:
European Spine Journal Aims and scope Submit manuscript

Abstract

Purpose

To examine to what extent diabetes mellitus (DM) is implicated as a distinct mechanism in intervertebral disc degeneration (IVDD).

Methods

The published clinical and laboratory data relevant to this matter are critically reviewed. A total of 12 clinical studies evaluate the association between DM and degenerative changes such as IVDD, spinal stenosis (SS) and IVD herniation. A total of 34 laboratory research papers evaluate the association between DM and IVDD.

Results

There are 7 studies that correlate DM with IVDD, 4 of them showing that DM is a significant risk factor for degeneration, and 3 of them failing to establish any association. Three studies demonstrate significant association between DM and SS. However, 2 of these studies also include patients with IVD herniation that failed to demonstrate any correlation with DM. Two other studies indicate a significant association between DM and lumbar disc herniation. Multiple different mechanisms, acting independently or interactively, cause tissue damage leading to IVDD including: microangiopathy of the subchondral vertebral endplate, cellular senescence, cell death (through apoptosis or autophagy), hyperglycaemia, advance glycation end products, adipokines, and cytokines (through oxidative, osmotic, and inflammatory mechanisms).

Conclusion

The clinical evidence is not consistent, but weakly supports the relationship between DM and IVDD. However, the laboratory studies consistently suggest that DM interferes with multipronged aberrant molecular and biochemical pathways that provoke IVDD. Taken as a whole, the strong laboratory evidence and the weak clinical studies implicate DM as a distinct contributing factor for IVDD.

Graphic abstract

These slides can be retrieved under Electronic Supplementary Material.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Silberberg R (1986) The skeleton in diabetes mellitus: a review of the literature. Diabetes Res 3(7):329–338

    CAS  PubMed  Google Scholar 

  2. Robinson D, Mirovsky Y, Halperin N, Evron Z, Nevo Z (1998) Changes in proteoglycans of intervertebral disc in diabetic patients. A possible cause of increased back pain. Spine (Phila Pa 1976) 23(8):849–855

    Article  CAS  Google Scholar 

  3. King KB, Rosenthal AK (2015) The adverse effects of diabetes on osteoarthritis: update on clinical evidence and molecular mechanisms. Osteoarthr Cartil 23(6):841–850. https://doi.org/10.1016/j.joca.2015.03.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hadjipavlou AG, Tzermiadianos MN, Bogduk N, Zindrick MR (2008) The pathophysiology of disc degeneration: a critical review. J Bone Joint Surg Br 90(10):1261–1270. https://doi.org/10.1302/0301-620X.90B10.20910

    Article  CAS  PubMed  Google Scholar 

  5. Agius R, Galea R, Fava S (2016) Bone mineral density and intervertebral disc height in type 2 diabetes. J Diabetes Complicat 30(4):644–650. https://doi.org/10.1016/j.jdiacomp.2016.01.021

    Article  PubMed  Google Scholar 

  6. Jakoi AM, Pannu G, D’Oro A et al (2017) The clinical correlations between diabetes, cigarette smoking and obesity on intervertebral degenerative disc disease of the lumbar spine. Asian Spine J 11(3):337–347. https://doi.org/10.4184/asj.2017.11.3.337

    Article  PubMed  PubMed Central  Google Scholar 

  7. Liu X, Pan F, Ba Z, Wang S, Wu D (2018) The potential effect of type 2 diabetes mellitus on lumbar disc degeneration: a retrospective single-center study. J Orthop Surg Res 13(1):52. https://doi.org/10.1186/s13018-018-0755-8

    Article  PubMed  PubMed Central  Google Scholar 

  8. Steelman T, Lewandowski L, Helgeson M, Wilson K, Olsen C, Gwinn D (2018) Population-based risk factors for the development of degenerative disk disease. Clin Spine Surg. 31(8):E409–E412. https://doi.org/10.1097/BSD.0000000000000682

    Article  PubMed  Google Scholar 

  9. Hangai M, Kaneoka K, Kuno S et al (2008) Factors associated with lumbar intervertebral disc degeneration in the elderly. Spine J 8(5):732–740

    Article  PubMed  Google Scholar 

  10. Fabiane SM, Ward KJ, Iatridis JC, Williams FM (2016) Does type 2 diabetes mellitus promote intervertebral disc degeneration? Eur Spine J 25(9):2716–2720. https://doi.org/10.1016/j.spinee.2007.07.392

    Article  PubMed  PubMed Central  Google Scholar 

  11. Videman T, Battié MC, Gibbons LE et al (2000) Disc degeneration and bone density in monozygotic twins discordant for insulin-dependent diabetes mellitus. J Orthop Res 18(5):768–772. https://doi.org/10.1002/jor.1100180514

    Article  CAS  PubMed  Google Scholar 

  12. Asadian L, Haddadi K, Aarabi M, Zare A (2016) Diabetes mellitus, a new risk factor for lumbar spinal stenosis: a case-control study. Clin Med Insights: Endocrinol Diabetes 9:1–5. https://doi.org/10.4137/CMED.S39035

    Article  Google Scholar 

  13. Anekstein Y, Smorgick Y, Lotan R et al (2010) Diabetes mellitus as a risk factor for the development of lumbar spinal stenosis. Isr Med Assoc J 12(1):16–20

    PubMed  Google Scholar 

  14. Maeda T, Hashizume H, Yoshimura N et al (2018) Factors associated with lumbar spinal stenosis in a large-scale, population-based cohort: the Wakayama Spine Study. PLoS ONE 13(7):e0200208. https://doi.org/10.1371/journal.pone.0200208

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jhawar BS, Fuchs CS, Colditz GA, Stampfer MJ (2006) Cardiovascular risk factors for physician-diagnosed lumbar disc herniation. Spine J 6(6):684–691. https://doi.org/10.1016/j.spinee.2006.04.016

    Article  PubMed  Google Scholar 

  16. Sakellaridis N (2006) The influence of diabetes mellitus on lumbar intervertebral disk herniation. Surg Neurol 66(2):152–154. https://doi.org/10.1016/j.surneu.2006.01.019

    Article  PubMed  Google Scholar 

  17. Tofthagen C (2012) Threats to validity in retrospective studies. J Adv Pract Oncol. 3(3):181–183

    PubMed  PubMed Central  Google Scholar 

  18. Shemesh S, Sidon E, Kaisler E et al (2018) Diabetes mellitus is associated with increased elastin fiber loss in ligamentum flavum of patients with lumbar spinal canal stenosis: results of a pilot histological study. Eur Spine J 27(7):1614–1622. https://doi.org/10.1007/s00586-017-5315-0

    Article  PubMed  Google Scholar 

  19. Carragee EJ, Alamin TF, Miller JL, Carragee JM (2005) Discographic, MRI and psychosocial determinants of low back pain disability and remission: a prospective study in subjects with benign persistent back pain. Spine J 5(1):24–35. https://doi.org/10.1016/j.spinee.2004.05.250

    Article  PubMed  Google Scholar 

  20. Peng B, Wu W, Hou S, Li P, Zhang C, Yang Y (2005) The pathogenesis of discogenic low back pain. J Bone Joint Surg Br 87(1):62–67

    Article  CAS  PubMed  Google Scholar 

  21. Vergroesen PP, Kingma I, Emanuel KS et al (2015) Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthr Cartil 23(7):1057–1070. https://doi.org/10.1016/j.joca.2015.03.028

    Article  PubMed  Google Scholar 

  22. Antoniou J, Steffen T, Nelson F et al (1996) The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Investig 98(4):996–1003. https://doi.org/10.1172/JCI118884

    Article  CAS  PubMed  Google Scholar 

  23. Erwin WM, De Souza L, Funabashi M et al (2015) The biological basis of degenerative disc disease: proteomic and biomechanical analysis of the canine intervertebral disc. Arthr Res Ther 17:240. https://doi.org/10.1186/s13075-015-0733-z

    Article  CAS  Google Scholar 

  24. Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54(6):1615–1625

    Article  CAS  PubMed  Google Scholar 

  25. Chen S, Liao M, Li J, Peng H, Xiong M (2013) The correlation between microvessel pathological changes of the endplate and degeneration of the intervertebral disc in diabetic rats. Exp Ther Med 5(3):711–717. https://doi.org/10.3892/etm.2012.868

    Article  PubMed  Google Scholar 

  26. Stephan S, Johnson WE, Roberts S (2011) The influence of nutrient supply and cell density on the growth and survival of intervertebral disc cells in 3D culture. Eur Cell Mater 5(22):97–108

    Article  Google Scholar 

  27. Won HY, Park JB, Park EY, Riew KD (2009) Effect of hyperglycemia on apoptosis of notochordal cells and intervertebral disc degeneration in diabetic rats. J Neurosurg Spine 11(6):741–748. https://doi.org/10.3171/2009.6.SPINE09198

    Article  PubMed  Google Scholar 

  28. Kong JG, Park JB, Lee D, Park EY (2015) Effect of high glucose on stress-induced senescence of nucleus pulposus cells of adult rats. Asian Spine J 9(2):155–161. https://doi.org/10.4184/asj.2015.9.2.155

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jiang L, Zhang X, Zheng X et al (2013) Apoptosis, senescence, and autophagy in rat nucleus pulposus cells: implications for diabetic intervertebral disc degeneration. J Orthop Res 31(5):692–702. https://doi.org/10.1002/jor.22289

    Article  CAS  PubMed  Google Scholar 

  30. Park JS, Park JB, Park IJ, Park EY (2014) Accelerated premature stress-induced senescence of young annulus fibrosus cells of rats by high glucose-induced oxidative stress. Int Orthop 38(6):1311–1320. https://doi.org/10.1007/s00264-014-2296-z

    Article  PubMed  PubMed Central  Google Scholar 

  31. Park JB, Byun CH, Park EY (2015) Rat notochordal cells undergo premature stress-induced senescence by high glucose. Asian Spine J 9(4):495–502. https://doi.org/10.4184/asj.2015.9.4.495

    Article  PubMed  PubMed Central  Google Scholar 

  32. Park EY, Park JB (2013) Dose- and time-dependent effect of high glucose concentration on viability of notochordal cells and expression of matrix degrading and fibrotic enzymes. Int Orthop 37(6):1179–1186. https://doi.org/10.1007/s00264-013-1836-2

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kong CG, Park JB, Kim MS, Park EY (2014) High glucose accelerates autophagy in adult rat intervertebral disc cells. Asian Spine J 8(5):543–548. https://doi.org/10.4184/asj.2014.8.5.543

    Article  PubMed  PubMed Central  Google Scholar 

  34. Park EY, Park JB (2013) High glucose-induced oxidative stress promotes autophagy through mitochondrial damage in rat notochordal cells. Int Orthop 37(12):2507–2514. https://doi.org/10.1007/s00264-013-2037-8

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chen D, Xia D, Pan Z et al (2016) Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death Dis 7(10):e2441. https://doi.org/10.1038/cddis.2016.334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tsai TT, Ho NY, Lin YT et al (2014) Advanced glycation end products in degenerative nucleus pulposus with diabetes. J Orthop Res 32(2):238–244. https://doi.org/10.1002/jor.22508

    Article  CAS  PubMed  Google Scholar 

  37. Yokosuka K, Park JS, Jimbo K et al (2006) Advanced glycation end-products downregulating intervertebral disc cell production of proteoglycans in vitro. J Neurosurg Spine 5(4):324–329. https://doi.org/10.3171/spi.2006.5.4.324

    Article  PubMed  Google Scholar 

  38. Fields AJ, Berg-Johansen B, Metz LN et al (2015) Alterations in intervertebral disc composition, matrix homeostasis and biomechanical behavior in the UCD-T2DM rat model of type 2 diabetes. J Orthop Res 33(5):738–746. https://doi.org/10.1002/jor.22807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tsuru M, Nagata K, Jimi A et al (2002) Effect of AGEs on human disc herniation: intervertebral disc hernia is also effected by AGEs. Kurume Med J 49(1–2):7–13

    Article  CAS  PubMed  Google Scholar 

  40. Illien-Jünger S, Lu Y, Qureshi SA et al (2015) Chronic ingestion of advanced glycation end products induces degenerative spinal changes and hypertrophy in aging pre-diabetic mice. PLoS ONE 10:e0116625. https://doi.org/10.1371/journal.pone.0116625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Illien-Junger S, Grosjean F, Laudier DM, Vlassara H, Striker GE, Iatridis JC (2013) Combined anti-inflammatory and anti-AGE drug treatments have a protective effect on intervertebral discs in mice with diabetes. PLoS ONE 8:e64302. https://doi.org/10.1371/journal.pone.0064302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Song Y, Wang Y, Zhang Y et al (2017) Advanced glycation end products regulate anabolic and catabolic activities via NLRP3-inflammasome activation in human nucleus pulposus cells. J Cell Mol Med 21(7):1373–1387. https://doi.org/10.1111/jcmm.13067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Krishnamoorthy D, Hoy RC, Natelson DM (2018) Dietary advanced glycation end-product consumption leads to mechanical stiffening of murine intervertebral discs. Dis Model Mech 11(12):dmm036012. https://doi.org/10.1242/dmm.036012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cheng X, Ni B, Zhang Z et al (2013) Polyol pathway mediates enhanced degradation of extracellular matrix via p38 MAPK activation in intervertebral disc of diabetic rats. Connect Tissue Res 54(2):118–122. https://doi.org/10.3109/03008207.2012.754886

    Article  CAS  PubMed  Google Scholar 

  45. Segar A, Urban J, Fairbank JCT (2016) Adipokines and the intervertebral disc: a biochemical link exists between obesity, intervertebral disc degeneration and low back pain. Spine J 16:S225. https://doi.org/10.1016/j.spinee.2016.07.135

    Article  Google Scholar 

  46. Ziv I, Moskowitz RW, Kraise I, Adler JH, Maroudas A (1992) Physicochemical properties of the aging and diabetic sand rat intervertebral disc. J Orthop Res 10(2):205–210

    Article  CAS  PubMed  Google Scholar 

  47. Silberberg R (1988) The vertebral column of diabetic sand rats (Psammomys obesus). Exp Cell Biol 56(4):217–220

    CAS  PubMed  Google Scholar 

  48. Aufdermaur M, Fehr K, Lesker P, Silberberg R (1980) Quantitative histochemical changes in intervertebral discs in diabetes. Exp Cell Biol 48(2):89–94

    CAS  PubMed  Google Scholar 

  49. Jeong SW, Lee JS, Kim KW (2014) In vitro lifespan and senescence mechanisms of human nucleus pulposus chondrocytes. Spine J 14(3):499–504. https://doi.org/10.1016/j.spinee.2013.06.099

    Article  PubMed  Google Scholar 

  50. Miao D, Zhang L (2015) Leptin modulates the expression of catabolic genes in rat nucleus pulposus cells through the mitogen-activated protein kinase and Janus kinase 2/signal transducer and activator of transcription 3 pathways. Mol Med Rep 12(2):1761–1768. https://doi.org/10.3892/mmr.2015.3646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu C, Yang H, Gao F et al (2016) Resistin promotes intervertebral disc degeneration by upregulation of ADAMTS-5 through p38 MAPK signaling pathway. Spine (Phila Pa 1976) 41(18):1414–1420. https://doi.org/10.1097/brs.0000000000001556

    Article  Google Scholar 

  52. Kaplan M, Arici L, Ozturk S, Simsek BC, Hergunsel OB, Erol FS (2018) A comparison of the type IX collagen levels of the intervertebral disc materials in diabetic and non-diabetic patients who treated with lumbar microdiscectomy. Eur Spine J 27(1):214–221. https://doi.org/10.1007/s00586-017-5361-7

    Article  PubMed  Google Scholar 

  53. Jiang Z, Lu W, Zeng Q, Li D, Ding L, Wu J (2018) High glucose-induced excessive reactive oxygen species promote apoptosis through mitochondrial damage in rat cartilage endplate cells. J Orthop Res 36(9):2476–2483. https://doi.org/10.1002/jor.24016

    Article  CAS  PubMed  Google Scholar 

  54. Wang W, Li P, Xu J (2018) Resveratrol attenuates high glucose-induced nucleus pulposus cell apoptosis and senescence through activating the ROS-mediated PI3 K/Akt pathway. Biosci Rep 38(2):BSR20171454. https://doi.org/10.1042/bsr20171454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Qi L, Wang R, Shi Q, Yuan M, Jin M, Li D (2018) Umbilical cord mesenchymal stem cell conditioned medium restored the expression of collagen II and aggrecan in nucleus pulposus mesenchymal stem cells exposed to high glucose. J Bone Miner Metab. https://doi.org/10.1007/s00774-018-0953-9

    Article  PubMed  Google Scholar 

  56. An JL, Zhang W, Zhang J, Lian LC, Shen Y, Ding WY (2017) Vitamin D improves the content of TGF-b and IGF-1 in intervertebral disc of diabetic rats. Exp Biol Med 242(12):1254–1261. https://doi.org/10.1177/1535370217707744

    Article  CAS  Google Scholar 

  57. Urban JP, Smith S, Fairbank JC (2004) Nutrition of the intervertebral disc. Spine (Phila Pa 1976) 29(23):2700–2709

    Article  Google Scholar 

  58. Wang F, Cai F, Shi R, Wang XH, Wu XT (2016) Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration. Osteoarthr Cartil 24(3):398–408. https://doi.org/10.1016/j.joca.2015.09.019

    Article  CAS  PubMed  Google Scholar 

  59. Zhang F, Zhao X, Shen H, Zhang C (2016) Molecular mechanisms of cell death in intervertebral disc degeneration. Int J Mol Med 37(6):1439–1448. https://doi.org/10.3892/ijmm.2016.2573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ding F, Shao ZW, Xiong LM (2013) Cell death in intervertebral disc degeneration. Apoptosis 18(7):777–785. https://doi.org/10.1007/s10495-013-0839-1

    Article  PubMed  Google Scholar 

  61. Zhao CQ, Jiang LS, Dai LY (2006) Programmed cell death in intervertebral disc degeneration. Apoptosis 11(12):2079–2088. https://doi.org/10.1007/s10495-006-0290-7

    Article  PubMed  Google Scholar 

  62. Ye W, Xu K, Huang D, Liang A, Peng Y, Zhu W, Li C (2011) Age-related increases of macroautophagy and chaperone-mediated autophagy in rat nucleus pulposus. Connect Tissue Res 52(6):472–478. https://doi.org/10.3109/03008207.2011.564336

    Article  CAS  PubMed  Google Scholar 

  63. Caramés B, Hasegawa A, Taniguchi N, Miyaki S, Blanco FJ, Lotz M (2012) Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis 71(4):575–581. https://doi.org/10.1136/annrheumdis-2011-200557

    Article  CAS  PubMed  Google Scholar 

  64. Feng C, Liu H, Yang M, Zhang Y, Huang B, Zhou Y (2016) Disc cell senescence in intervertebral disc degeneration: causes and molecular pathways. Cell Cycle 15(13):1674–1684. https://doi.org/10.1080/15384101.2016.1152433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Brownlee M, Cerami A, Vlassara H (1988) Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318(20):1315–1321. https://doi.org/10.1056/NEJM198805193182007

    Article  CAS  PubMed  Google Scholar 

  66. Johnson ZI, Shapiro IM, Risbud MV (2014) Extracellular osmolarity regulates matrix homeostasis in the intervertebral disc and articular cartilage: evolving role of TonEBP. Matrix Biol 40:10–16. https://doi.org/10.1016/j.matbio.2014.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Al-Hamodi Z, Al-Habori M, Al-Meeri A, Saif-Ali R (2014) Association of adipokines, leptin/adiponectin ratio and C-reactive protein with obesity and type 2 diabetes mellitus. Diabetol Metab Syndr 6(1):99. https://doi.org/10.1186/1758-5996-6-99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Brocker C, Thompson DC, Vasiliou V (2012) The role of hyperosmotic stress in inflammation and disease. Biomol Concepts 3(4):345–364. https://doi.org/10.1515/bmc-2012-0001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Burg MB, Ferraris JD, Dmitrieva NI (2007) Cellular response to hyperosmotic stresses. Physiol Rev 87(4):1441–1474. https://doi.org/10.1152/physrev.00056.2006

    Article  CAS  PubMed  Google Scholar 

  70. Ishihara H, Warensjo K, Roberts S, Urban JP (1997) Proteoglycan synthesis in the intervertebral disk nucleus: the role of extracellular osmolality. Am J Physiol 272(5 Pt 1):C1499–C1506. https://doi.org/10.1152/ajpcell.1997.272.5.C1499

    Article  CAS  PubMed  Google Scholar 

  71. Chung SS, Ho EC, Lam KS, Chung SK (2003) Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol 14(8 Suppl 3):S233–S236

    Article  CAS  PubMed  Google Scholar 

  72. Aldhahi W, Hamdy O (2003) Adipokines, inflammation, and the endothelium in diabetes. Curr Diab Rep 3(4):293–298. https://doi.org/10.1007/s11892-003-0020-2

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alexander Hadjipavlou.

Ethics declarations

Conflict of interest

The authors state no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 410 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alpantaki, K., Kampouroglou, A., Koutserimpas, C. et al. Diabetes mellitus as a risk factor for intervertebral disc degeneration: a critical review. Eur Spine J 28, 2129–2144 (2019). https://doi.org/10.1007/s00586-019-06029-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-019-06029-7

Keywords

Navigation