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.
Similar content being viewed by others
References
Silberberg R (1986) The skeleton in diabetes mellitus: a review of the literature. Diabetes Res 3(7):329–338
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Tofthagen C (2012) Threats to validity in retrospective studies. J Adv Pract Oncol. 3(3):181–183
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
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
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
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
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
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
Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54(6):1615–1625
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Silberberg R (1988) The vertebral column of diabetic sand rats (Psammomys obesus). Exp Cell Biol 56(4):217–220
Aufdermaur M, Fehr K, Lesker P, Silberberg R (1980) Quantitative histochemical changes in intervertebral discs in diabetes. Exp Cell Biol 48(2):89–94
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
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
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
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
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
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
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
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
Urban JP, Smith S, Fairbank JC (2004) Nutrition of the intervertebral disc. Spine (Phila Pa 1976) 29(23):2700–2709
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Author information
Authors and Affiliations
Corresponding author
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.
Rights and permissions
About this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00586-019-06029-7