Traumatic spinal cord injury (SCI) can cause permanent disabilities that seriously reduce quality of life. We evaluated the effects of chronic hyperglycemia before SCI on inflammatory markers and functional recovery after SCI in human patients and a rat model. In the human study, multivariate logistical regression analysis revealed that hemoglobin A1c (HbA1c) values, reflecting average plasma glucose concentration over a 3 month period, at admission were a significant risk factor for poor functional recovery. Moreover, patients with chronic hyperglycemia (HbA1c ≥ 6.5%) had high concentrations of inflammatory biomarkers (interleukin [IL]-6 and IL-8) of cerebrospinal fluid after SCI. Consistent with patient findings, chronic hyperglycemia before SCI in rats was associated with increased inflammatory responses and oxygen-free radicals in the spinal cord and blood, thus resulting in poor functional recovery and histological outcomes. Tight glucose control before SCI decreased the harmful effects of hyperglycemia after SCI in both human and rat studies. Our findings suggest that chronic hyperglycemia before SCI may be a significant prognostic factor with a negative impact on functional and histological outcomes, highlighting the importance of tight glucose control before SCI.
Get full access to this article
View all access options for this article.
References
1.
AdamsM.M., and HicksA.L. (2005). Spasticity after spinal cord injury. Spinal Cord, 43, 577–586.
2.
BeattieM.S. (2004). Inflammation and apoptosis: linked therapeutic targets in spinal cord injury. Trends Mol. Med. 10, 580–583.
3.
KimK.T., KimM.J., ChoD.C., ParkS.H., HwangJ.H., SungJ.K., ChoH.J., and JeonY. (2014). The neuroprotective effect of treatment with curcumin in acute spinal cord injury: laboratory investigation. Neurol. Med. Chir. (Tokyo). 54, 387–394.
4.
KimK.T., NamT.K., ParkY.S., KimY.B., and ParkS.W. (2011). Neuroprotective effect of anthocyanin on experimental traumatic spinal cord injury. J. Korean Neurosurg. Soc. 49, 205–211.
5.
ChenX., ChenC., HaoJ., QinR., QianB., YangK., ZhangJ., and ZhangF. (2018). AKR1B1 upregulation contributes to neuroinflammation and astrocytes proliferation by regulating the energy metabolism in rat spinal cord injury. Neurochem. Res. 43, 1491–1499.
6.
JoM.J., KumarH., JoshiH.P., ChoiH., KoW.K., KimJ.M., HwangS.S.S., ParkS.Y., SohnS., BelloA.B., KimK.T., LeeS.H., ZengX., and HanI. (2018). Oral administration of alpha-asarone promotes functional recovery in rats with spinal cord injury. Front. Pharmacol. 9, 445.
7.
KoW.K., KimS.J., JoM.J., ChoiH., LeeD., KwonI.K., LeeS.H., HanI.B., and SohnS. (2018). Ursodeoxycholic acid inhibits inflammatory responses and promotes functional recovery after spinal cord injury in rats. Mol. Neurobiol. 56, 267–277.
ChungJ.H., HyunD.K., LeeM.H., ChoiB.H., ParkH.C., and HaY. (2005). Hypoxia-inducible specific gene expression system in rat spinal cord injury model. Korean J. Spine, 2, 110–115
10.
KimK.T., ChoD.C., SungJ.K., KimC.H., KangH., and KimD.H. (2017). Changes in HbA1c levels and body mass index after successful decompression surgery in patients with type 2 diabetes mellitus and lumbar spinal stenosis: results of a 2-year follow-up study. Spine J. 217, 203–210.
11.
ChenS., AndersonM.V., ChengW.K., and WongworawatM.D. (2009). Diabetes associated with increased surgical site infections in spinal arthrodesis. Clin. Orthop. Relat. Res. 467, 1670–1673.
12.
IvyJ.L., ZdericT.W., and FogtD.L. (1999). Prevention and treatment of non-insulin-dependent diabetes mellitus. Exerc. Sport Sci. Rev. 27, 1–35.
13.
KoS.H., KimS.R., KimD.J., OhS.J., LeeH.J., ShimK.H., WooM.H., KimJ.Y., KimN.H., KimJ.T., KimC.H., KimH.J., JeongI.K., HongE.K., ChoJ.H., MokJ.O., and YoonK.H. (2011). 2011 clinical practice guidelines for type 2 diabetes in Korea. Diabetes Metab. J. 35, 431–436.
14.
BeagleyJ., GuariguataL., WeilC., and MotalaA.A. (2014). Global estimates of undiagnosed diabetes in adults. Diabetes Res. Clin. Pract. 103, 150–160.
15.
Diabetes Canada Clinical Practice Guidelines ExpertC., EkoeJ.M., GoldenbergR., and KatzP. (2018). Screening for diabetes in adults. Can. J. Diabetes 42. Suppl. 1, S16–S19.
16.
Felix-MartinezG.J., and Godinez-FernandezJ.R. (2018). Screening models for undiagnosed diabetes in Mexican adults using clinical and self-reported information. Endocrinol. Diabetes Nutr. 65, 603–610.
17.
GilmerT.P., and O'ConnorP.J. (2010). The growing importance of diabetes screening. Diabetes Care, 33, 1695–1697.
18.
RosellaL.C., LebenbaumM., FitzpatrickT., ZukA., and BoothG.L. (2015). Prevalence of prediabetes and undiagnosed diabetes in Canada (2007–2011) according to fasting plasma glucose and HbA1c screening criteria. Diabetes Care, 38, 1299–1305.
19.
SeghieriG., PolicardoL., ProfiliF., FrancesconiP., AnichiniR., and Del PratoS. (2016). Hospital incidental diagnosis of diabetes: a population study. J. Diabetes Complications, 30, 457–461.
20.
SilvermanR.A., SchleicherM.G., ValenteC.J., KimM., RomanenkoY., SchulmanR.C., TiberioA., GreenblattB., RentalaM., Salvador-KellyA.V., KwonN.S., and JornsayD.L. (2016). Prevalence of undiagnosed dysglycemia in an emergency department observation unit. Diabetes Metab. Res. Rev. 32, 82–86.
21.
KobayakawaK., KumamaruH., SaiwaiH., KubotaK., OhkawaY., KishimotoJ., YokotaK., IdetaR., ShibaK., Tozaki-SaitohH., InoueK., IwamotoY., and OkadaS. (2014). Acute hyperglycemia impairs functional improvement after spinal cord injury in mice and humans. Sci. Transl. Med. 6,256ra137.
22.
KobataH., SugieA., SuehiroE., DohiK., KanekoT., FujitaM., OdaY., KurodaY., YamashitaS., and MaekawaT. (2017). Association between blood glucose levels the day after targeted temperature initiation and outcome in traumatic brain injury: a post-hoc analysis of the B-HYPO study. J. Neurotrauma. 34, 987–995.
23.
KoyfmanL., BrotfainE., FrankD., BichovskyY., KovalenkoI., BenjaminY., BorerA., FrigerM., and KleinM. (2018). The clinical significance of hyperglycemia in nondiabetic critically ill multiple trauma patients. Ther. Adv. Endocrinol. Metab. 9, 223–230.
24.
MachinoM., YukawaY., ItoK., InoueT., KobayakawaA., MatsumotoT., OuchidaJ., TomitaK., and KatoF. (2014). Risk factors for poor outcome of cervical laminoplasty for cervical spondylotic myelopathy in patients with diabetes. J Bone Joint Surg. Am. 96, 2049–2055.
25.
ChenZ.R., MaY., GuoH.H., LuZ.D., and JinQ.H. (2018). Therapeutic efficacy of cyclosporin A against spinal cord injury in rats with hyperglycemia. Mol. Med. Rep. 17, 4369–4375.
26.
JouJ.M., LewisS.M., BriggsC., LeeS.H., De La SalleB., McFaddenS., and International Council for Standardization inHaematology (2011). ICSH review of the measurement of the erythocyte sedimentation rate. Int. J. Lab. Hematol. 33, 125–132.
27.
DalkilicT., FallahN., NoonanV.K., Salimi ElizeiS., DongK., BelangerL., RitchieL., TsangA., Bourassa-MoreauE., HeranM.K.S., PaquetteS.J., AilonT., DeaN., StreetJ., Fishe,r C.G., DvorakM.F., and KwonB.K. (2018). Predicting injury severity and neurological recovery after acute cervical spinal cord injury: a comparison of cerebrospinal fluid and magnetic resonance imaging biomarkers. J. Neurotrauma, 35, 435–445.
28.
American Diabetes Association (2018). 6. Glycemic targets: standards of medical care in diabetes-2018. Diabetes Care, 41, S55–S64.
29.
MurphyM.A., WhitmanI., CampfieldA., MoxeyE., HaddadM., and WhitmanG. (2010). Intense implementation of a strict insulin infusion protocol dose not guarantee postoperative glycemic control. J. Am. Coll. Surg. 211, 465–469
30.
BangW.S., KimK.T., ChoD.C., KimH.J., and SungJ.K. (2013). Valproic acid increases expression of neuronal stem/progenitor cell in spinal cord injury. J. Korean Neurosurg. Soc. 54, 8–13.
31.
KimK.T., KimH.J., ChoD.C., BaeJ.S., and ParkS.W. (2015). Substance P stimulates proliferation of spinal neural stem cells in spinal cord injury via the mitogen-activated protein kinase signaling pathway. Spine J. 15, 2055–2065.
32.
BassoD.M., BeattieM.S., and BresnahanJ.C. (2007). Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp. Neurol. 139, 244–256.
33.
CollinsT.J. (2007). ImageJ for microscopy. BioTechniques, 43, 25–30.
34.
SchmittgenT.D., and LivakK.J. (2008). Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 3, 1101–1108.
35.
KwonB.K., StreijgerF., FallahN., NoonanV.K., BelangerL.M., RitchieL., PaquetteS.J., AilonT., BoydM.C., StreetJ., FisherC.G., and DvorakM.F. (2017). Cerebrospinal fluid biomarkers to stratify injury severity and predict outcome in human traumatic spinal cord injury. J. Neurotrauma, 34, 567–580.
36.
KumamaruH., SaiwaiH., OhkawaY., YamadaH., IwamotoY., and OkadaS. (2012). Age-related differences in cellular and molecular profiles of inflammatory responses after spinal cord injury. J. Cell Physiol. 227, 1335–1346.
37.
HadleyM.N., WaltersB.C., GrabbP.A., OyesikuN.M., PrzybylskiG.J., ResnickD.K., RykenT.C., and MielkeD.H. (2002). Guidelines for the management of acute cervical spine and spinal cord injuries. Clin. Neurosurg. 49, 407–498.
38.
BrackenM.B., ShepardM.J., CollinsW.F., HolfordT.R., YoungW., BaskinD.S., EisenbergH.M., FlammE., Leo-SummersL., and MaroonJ., et al. (1990). A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N. Engl. J. Med. 322, 1405–1411.
39.
FailliV., KoppM.A., GerickeC., MartusP., KlingbeilS., BrommerB., LaginhaI., ChenY., DeVivoM.J., DirnaglU., and SchwabJ.M. (2012). Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain, 135, 3238–3250.
40.
FehlingsM.G, VaccaroA., WilsonJ.R., SinghA., W CadotteD., HarropJ.S., AarabiB., ShaffreyC., DvorakM., FisherC., ArnoldP., MassicotteE.M., LewisS., and RampersaudR. (2012). Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PloS One. 7, e32037.
41.
HerrmannJ.E., ImuraT., SongB., QiJ., AoY., NguyenT.K., KorsakR.A., TakedaK., AkiraS., and SofroniewM.V. (2008). STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J. Neurosci. 28, 7231–7243.
42.
SikarisK. (2009). The correlation of hemoglobin A1c to blood glucose. J. Diabetes Sci Technol. 3, 429–438.
43.
American Diabetes Association (2018). Good to know: factors affecting blood glucose. Clin. Diabetes, 36, 202.
44.
KoS.H., KimS.R., KimD.J., OhS.J., LeeH.J., ShimK.H., WooM.H., KimJ.Y., KimN.H., KimJ.T., KimC.H., KimH.J., JeongI.K., HongE.K., ChoJ.H., MokJ.O., YoonK.H., and Committee of Clinical Practice Guidelines Korean DiabetesAssociation (2011). 2011 clinical practice guidelines for type 2 diabetes in Korea. Diabetes Metab. J. 35, 431–436.
45.
Felix-MartinezG.J., and Godinez-FernandezJ.R. (2018). Screening models for undiagnosed diabetes in Mexican adults using clinical and self-reported information. Endocrinol. Diabetes Nutr. 65, 603–610.
46.
YuS.H., ChoD.C., KimK.T., NamK.H., ChoH.J., and SungJ.K. (2012). The neuroprotective effect of treatment of valproic Acid in acute spinal cord injury. J. Korean Neurosurgical Soc. 51, 191–198.
47.
SonnevilleR., den HertogH.M., GuizaF., GunstJ., DereseI., WoutersP.J., BroulandJ.P., PolitoA., GrayF., ChretienF., CharlierP., AnnaneD., SharsharT., Van den BergheG., and VanhorebeekI. (2012). Impact of hyperglycemia on neuropathological alterations during critical illness. J. Clin. Endocrinol. Metab. 97, 2113–2123.
48.
GenoveseT., EspositoE., MazzonE., MuiaC., Di PaolaR., MeliR., BramantiP., and CuzzocreaS. (2008). Evidence for the role of mitogen-activated protein kinase signaling pathways in the development of spinal cord injury. J. Pharmacol. Exp. Ther. 325, 100–114.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
