Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes

Anne-Caroline Jeannin, Joe-Elie Salem, Ziad Massy, Carole Elodie Aubert, Cees Vermeer, Chloé Amouyal, Franck Phan, Marine Halbron, Christian Funck-Brentano, Agnès Hartemann, Olivier Bourron, Anne-Caroline Jeannin, Joe-Elie Salem, Ziad Massy, Carole Elodie Aubert, Cees Vermeer, Chloé Amouyal, Franck Phan, Marine Halbron, Christian Funck-Brentano, Agnès Hartemann, Olivier Bourron

Abstract

Aims/hypothesis: Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated with sensitive diabetic neuropathy in Type 2 Diabetes, and, in particular, dephospho-uncarboxylated MGP (dp-ucMGP), the inactive form of MGP.

Methods: 198 patients with Type 2 Diabetes were included. Presence of sensitive diabetic neuropathy was defined by a neuropathy disability score (NDS) ≥6. Plasma levels of dp-ucMGP were measured by ELISA.

Results: In this cohort, the mean age was 64+/-8.4 years old, and 80% of patients were men. Peripheral neuropathy was present in 15.7% of the patients and was significantly associated (r = 0.51, p<0.0001) with dp-ucMGP levels (β = -0.26, p = 0.045) after integrating effects of height (β = -0.38, p = 0.01), insulin treatment (β = 0.42, p = 0.002), retinopathy treated by laser (β = 0.26, p = 0.02), and total cholesterol levels (β = 0.3, p = 0.03) by multivariable analysis.

Conclusions: The association between diabetic neuropathy and the inactive form of MGP suggests the existence of new pathophysiological pathways to explore. Further studies are needed to determine if dp-ucMGP may be used as a biomarker of sensitive neuropathy. Since dp-ucMGP is a marker of poor vitamin K status, clinical studies are warranted to explore the potential protective effect of high vitamin K intake on diabetic peripheral neuropathy.

Conflict of interest statement

A patent has been filed on a method using circulating Matrix Gla protein measurement for diagnosis and treating peripheral neuropathies by Assistance Publique Hôpitaux de Paris - APHP). Olivier Bourron, Joe-Elie Salem and Agnès Hartemann are the inventors. The application number is 18306503.6 – 1118. Status of application: recorded. The patent specific aspect of manuscript covered in patent application: use of circulating Matrix Gla protein measurement for diagnosis and treating peripheral neuropathies. This study was supported by a fund from Lilly Company. The company was involved neither in the design of the study nor in data collection. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

References

    1. 11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019. January;42(Suppl 1):S124–S38. 10.2337/dc19-S011
    1. Forsblom CM, Sane T, Groop PH, Totterman KJ, Kallio M, Saloranta C, et al. Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia. 1998. November;41(11):1253–62. 10.1007/s001250051062
    1. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation. Basis for prevention. Diabetes Care. 1990. May;13(5):513–21. 10.2337/diacare.13.5.513
    1. Papanas N, Ziegler D. Risk Factors and Comorbidities in Diabetic Neuropathy: An Update 2015. Rev Diabet Stud. 2015 Spring-Summer;12(1–2):48–62.
    1. Alleman CJ, Westerhout KY, Hensen M, Chambers C, Stoker M, Long S, et al. Humanistic and economic burden of painful diabetic peripheral neuropathy in Europe: A review of the literature. Diabetes Res Clin Pract. 2015. August;109(2):215–25. 10.1016/j.diabres.2015.04.031
    1. Feldman EL, Nave KA, Jensen TS, Bennett DLH. New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron. 2017. March 22;93(6):1296–313. 10.1016/j.neuron.2017.02.005
    1. Aubert CE, Michel PL, Gillery P, Jaisson S, Fonfrede M, Morel F, et al. Association of peripheral neuropathy with circulating advanced glycation end products, soluble receptor for advanced glycation end products and other risk factors in patients with type 2 diabetes. Diabetes Metab Res Rev. 2014. November;30(8):679–85. 10.1002/dmrr.2529
    1. Schurgers LJ, Spronk HM, Skepper JN, Hackeng TM, Shanahan CM, Vermeer C, et al. Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost. 2007. December;5(12):2503–11. 10.1111/j.1538-7836.2007.02758.x
    1. Engelke JA, Hale JE, Suttie JW, Price PA. Vitamin K-dependent carboxylase: utilization of decarboxylated bone Gla protein and matrix Gla protein as substrates. Biochim Biophys Acta. 1991. May 30;1078(1):31–4. 10.1016/0167-4838(91)90088-h
    1. Price PA, Rice JS, Williamson MK. Conserved phosphorylation of serines in the Ser-X-Glu/Ser(P) sequences of the vitamin K-dependent matrix Gla protein from shark, lamb, rat, cow, and human. Protein Sci. 1994. May;3(5):822–30. 10.1002/pro.5560030511
    1. Price PA, Urist MR, Otawara Y. Matrix Gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone. Biochem Biophys Res Commun. 1983. December 28;117(3):765–71. 10.1016/0006-291x(83)91663-7
    1. Goritz C, Thiebaut R, Tessier LH, Nieweg K, Moehle C, Buard I, et al. Glia-induced neuronal differentiation by transcriptional regulation. Glia. 2007. August 15;55(11):1108–22. 10.1002/glia.20531
    1. Hur DJ, Raymond GV, Kahler SG, Riegert-Johnson DL, Cohen BA, Boyadjiev SA. A novel MGP mutation in a consanguineous family: review of the clinical and molecular characteristics of Keutel syndrome. Am J Med Genet A. 2005. May 15;135(1):36–40. 10.1002/ajmg.a.30680
    1. Cranenburg EC, KY VANS-Z, Bonafe L, Mittaz Crettol L, Rodiger LA, Dikkers FG, et al. Circulating matrix gamma-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome. J Thromb Haemost. 2011. June;9(6):1225–35. 10.1111/j.1538-7836.2011.04263.x
    1. Mertsch S, Schurgers LJ, Weber K, Paulus W, Senner V. Matrix gla protein (MGP): an overexpressed and migration-promoting mesenchymal component in glioblastoma. BMC Cancer. 2009. August 27;9:302 10.1186/1471-2407-9-302
    1. Santa-Maria I, Avila J, Rabano A. Differential gene expression analysis of human entorhinal cortex support a possible role of some extracellular matrix proteins in the onset of Alzheimer disease. Neurosci Lett. 2010. January 14;468(3):225–8. 10.1016/j.neulet.2009.11.002
    1. Bourron O, Aubert CE, Liabeuf S, Cluzel P, Lajat-Kiss F, Dadon M, et al. Below-knee arterial calcification in type 2 diabetes: association with receptor activator of nuclear factor kappaB ligand, osteoprotegerin, and neuropathy. J Clin Endocrinol Metab. 2014. November;99(11):4250–8. 10.1210/jc.2014-1047
    1. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 1993. February;36(2):150–4. 10.1007/bf00400697
    1. Abbott CA, Carrington AL, Ashe H, Bath S, Every LC, Griffiths J, et al. The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med. 2002. May;19(5):377–84. 10.1046/j.1464-5491.2002.00698.x
    1. Gadia MT, Natori N, Ramos LB, Ayyar DR, Skyler JS, Sosenko JM. Influence of height on quantitative sensory, nerve-conduction, and clinical indices of diabetic peripheral neuropathy. Diabetes Care. 1987. Sep-Oct;10(5):613–6. 10.2337/diacare.10.5.613
    1. Grote CW, Wright DE. A Role for Insulin in Diabetic Neuropathy. Front Neurosci. 2016;10:581 10.3389/fnins.2016.00581
    1. Zebboudj AF, Imura M, Bostrom K. Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2. J Biol Chem. 2002. February 8;277(6):4388–94. 10.1074/jbc.M109683200
    1. Moon JI, Birren SJ. Target-dependent inhibition of sympathetic neuron growth via modulation of a BMP signaling pathway. Dev Biol. 2008. March 15;315(2):404–17. 10.1016/j.ydbio.2007.12.041
    1. Majdazari A, Stubbusch J, Muller CM, Hennchen M, Weber M, Deng CX, et al. Dendrite complexity of sympathetic neurons is controlled during postnatal development by BMP signaling. J Neurosci. 2013. September 18;33(38):15132–44. 10.1523/JNEUROSCI.4748-12.2013
    1. Dore JJ, Crotty KL, Birren SJ. Inhibition of glial maturation by bone morphogenetic protein 2 in a neural crest-derived cell line. Dev Neurosci. 2005. Jan-Feb;27(1):37–48. 10.1159/000084531
    1. Wang YL, Wang DZ, Nie X, Lei DL, Liu YP, Zhang YJ, et al. The role of bone morphogenetic protein-2 in vivo in regeneration of peripheral nerves. Br J Oral Maxillofac Surg. 2007. April;45(3):197–202. 10.1016/j.bjoms.2006.06.003
    1. Gonzalez-Perez F, Udina E, Navarro X. Extracellular matrix components in peripheral nerve regeneration. Int Rev Neurobiol. 2013;108:257–75. 10.1016/B978-0-12-410499-0.00010-1
    1. Nishimoto SK, Nishimoto M. Matrix Gla protein C-terminal region binds to vitronectin. Co-localization suggests binding occurs during tissue development. Matrix Biol. 2005. August;24(5):353–61. 10.1016/j.matbio.2005.05.004
    1. Nishimoto SK, Nishimoto M. Matrix gla protein binds to fibronectin and enhances cell attachment and spreading on fibronectin. Int J Cell Biol. 2014;2014:807013 10.1155/2014/807013
    1. Cranenburg EC, Koos R, Schurgers LJ, Magdeleyns EJ, Schoonbrood TH, Landewe RB, et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost. 2010. October;104(4):811–22. 10.1160/TH09-11-0786
    1. Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, Vermeer C, Verschuren WM, Boer JM, et al. Matrix Gla protein species and risk of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2013. November;36(11):3766–71. 10.2337/dc13-0065
    1. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. 1980. January;68(1):122–40. 10.1016/0002-9343(80)90181-3
    1. Popescu DC, Huang H, Singhal NK, Shriver L, McDonough J, Clements RJ, et al. Vitamin K enhances the production of brain sulfatides during remyelination. PLoS One. 2018;13(8):e0203057 10.1371/journal.pone.0203057
    1. Coetzee T, Fujita N, Dupree J, Shi R, Blight A, Suzuki K, et al. Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability. Cell. 1996. July 26;86(2):209–19. 10.1016/s0092-8674(00)80093-8
    1. Nakajima M, Furukawa S, Hayashi K, Yamada A, Kawashima T, Hayashi Y. Age-dependent survival-promoting activity of vitamin K on cultured CNS neurons. Brain Res Dev Brain Res. 1993. May 21;73(1):17–23. 10.1016/0165-3806(93)90041-8
    1. Druet C, Bourdel-Marchasson I, Weill A, Eschwege E, Penfornis A, Fosse S, et al. [Type 2 diabetes in France: epidemiology, trends of medical care, social and economic burden]. Presse Med. 2013. May;42(5):830–8. 10.1016/j.lpm.2013.02.312
    1. Zhu T, Meng Q, Ji J, Lou X, Zhang L. Toll-like receptor 4 and tumor necrosis factor-alpha as diagnostic biomarkers for diabetic peripheral neuropathy. Neurosci Lett. 2015. January 12;585:28–32. 10.1016/j.neulet.2014.11.020
    1. Li J, Zhang H, Xie M, Yan L, Chen J, Wang H. NSE, a potential biomarker, is closely connected to diabetic peripheral neuropathy. Diabetes Care. 2013. November;36(11):3405–10. 10.2337/dc13-0590
    1. Roumeliotis S, Dounousi E, Eleftheriadis T, Liakopoulos V. Association of the Inactive Circulating Matrix Gla Protein with Vitamin K Intake, Calcification, Mortality, and Cardiovascular Disease: A Review. Int J Mol Sci. 2019. February 1;20(3).
    1. Puzantian H, Akers SR, Oldland G, Javaid K, Miller R, Ge Y, et al. Circulating Dephospho-Uncarboxylated Matrix Gla-Protein Is Associated With Kidney Dysfunction and Arterial Stiffness. Am J Hypertens. 2018. August 3;31(9):988–94. 10.1093/ajh/hpy079
    1. Kurnatowska I, Grzelak P, Masajtis-Zagajewska A, Kaczmarska M, Stefanczyk L, Vermeer C, et al. Plasma Desphospho-Uncarboxylated Matrix Gla Protein as a Marker of Kidney Damage and Cardiovascular Risk in Advanced Stage of Chronic Kidney Disease. Kidney Blood Press Res. 2016;41(3):231–9. 10.1159/000443426
    1. Wei FF, Huang QF, Zhang ZY, Van Keer K, Thijs L, Trenson S, et al. Inactive matrix Gla protein is a novel circulating biomarker predicting retinal arteriolar narrowing in humans. Sci Rep. 2018. October 10;8(1):15088 10.1038/s41598-018-33257-6
    1. Chalk C, Benstead TJ, Moore F. Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev. 2007. October 17(4):CD004572.
    1. Vinik AI, Bril V, Kempler P, Litchy WJ, Tesfaye S, Price KL, et al. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin Ther. 2005. August;27(8):1164–80. 10.1016/j.clinthera.2005.08.001
    1. Thornalley PJ. Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Arch Biochem Biophys. 2003. November 1;419(1):31–40. 10.1016/j.abb.2003.08.013
    1. Papanas N, Ziegler D. Efficacy of alpha-lipoic acid in diabetic neuropathy. Expert Opin Pharmacother. 2014. December;15(18):2721–31. 10.1517/14656566.2014.972935
    1. Inoue T, Fujita T, Kishimoto H, Makino T, Nakamura T, Sato T, et al. Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab. 2009;27(1):66–75. 10.1007/s00774-008-0008-8
    1. Vissers LE, Dalmeijer GW, Boer JM, Monique Verschuren WM, van der Schouw YT, Beulens JW. Intake of dietary phylloquinone and menaquinones and risk of stroke. J Am Heart Assoc. 2013. December 10;2(6):e000455 10.1161/JAHA.113.000455
    1. Dyck PJ. Detection, characterization, and staging of polyneuropathy: assessed in diabetics. Muscle Nerve. 1988. January;11(1):21–32. 10.1002/mus.880110106
    1. Dyck PJ, Bushek W, Spring EM, Karnes JL, Litchy WJ, O'Brien PC, et al. Vibratory and cooling detection thresholds compared with other tests in diagnosing and staging diabetic neuropathy. Diabetes Care. 1987. Jul-Aug;10(4):432–40. 10.2337/diacare.10.4.432
    1. Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ 3rd, O'Brien PC, et al. The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology. 1991. June;41(6):799–807. 10.1212/wnl.41.6.799
    1. Dyck PJ, Karnes JL, O'Brien PC, Litchy WJ, Low PA, Melton LJ, 3rd. The Rochester Diabetic Neuropathy Study: reassessment of tests and criteria for diagnosis and staged severity. Neurology. 1992. June;42(6):1164–70.
    1. Feki I, Lefaucheur JP. Correlation between nerve conduction studies and clinical scores in diabetic neuropathy. Muscle Nerve. 2001. April;24(4):555–8. 10.1002/mus.1040
    1. Roustit M, Loader J, Deusenbery C, Baltzis D, Veves A. Endothelial Dysfunction as a Link Between Cardiovascular Risk Factors and Peripheral Neuropathy in Diabetes. J Clin Endocrinol Metab. 2016. September;101(9):3401–8. 10.1210/jc.2016-2030
    1. Andreassen CS, Jakobsen J, Andersen H. Muscle weakness: a progressive late complication in diabetic distal symmetric polyneuropathy. Diabetes. 2006. March;55(3):806–12. 10.2337/diabetes.55.03.06.db05-1237
    1. Weintrob N, Amitay I, Lilos P, Shalitin S, Lazar L, Josefsberg Z. Bedside neuropathy disability score compared to quantitative sensory testing for measurement of diabetic neuropathy in children, adolescents, and young adults with type 1 diabetes. J Diabetes Complications. 2007. Jan-Feb;21(1):13–9. 10.1016/j.jdiacomp.2005.11.002
    1. Dyck PJ, Sherman WR, Hallcher LM, Service FJ, O'Brien PC, Grina LA, et al. Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry. Ann Neurol. 1980. December;8(6):590–6. 10.1002/ana.410080608
    1. Dyck PJ, Karnes JL, Daube J, O'Brien P, Service FJ. Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain. 1985. December;108 (Pt 4):861–80.
    1. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993. April;43(4):817–24. 10.1212/wnl.43.4.817

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