糖尿病周围神经病变（DPN）是糖尿病最常见的慢性并发症之一，其发病机制暂不完全明确，而发病率高，检查方法又比较局限，需要寻找更为简便准确的方法进行早诊早治。Dickkopf-1（DKK1）是DKK家族的重要成员。有研究表明DKK1与代谢紊乱、糖尿病微血管病变、炎症、自身免疫均有关，这些因素也恰恰参与了DPN的发生发展。所以本文就糖尿病周围神经病变发病机制与DKK1水平关系做一综述。

[1] GUARIGUATA L,WHITING D R,HAMBLETON I,et al.Global Estimates Of Diabetes Prevalence For 2013 And Projections For 2035[J].Diabetes Res Clin Pract.2014,103(2):137-149.
[2] 中华医学会糖尿病学分会慢性并发症调查组.1991~2000年全国住院糖尿病患者慢性并发症及相关大血管病变回顾性分析[J].中国医学科学院学报,2002,24(5):447-451.
[3] 李海莎,李才锐,孙曙光.糖尿病周围神经病变的影响因素[J].世界最新医学信息文摘,2016,16(26):37-38.
[4] WANG X D,HUANG X F,YAN Q R,et al.Aberrant activation of the WNT/β-catenin signaling pathway in lupus nephritis[J].PLoS One,2014,9(1):e84852.
[5] GLINKA A,WU W,DELIUS H,et al.Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction[J].Nature,1998,391(6665):357-362.
[6] MACDONALD B T,ADAMSKA M,MEISLER M H,et al.Hypomorphic expression of DKK1 in doubleridge mouse:dose dependence and compensatory interactions with Lrp6[J].Development,2004,131(11):2543-2552.
[7] MAO B,WU W,DAVIDSON G,et al.Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signaling[J].Nature,2002,417(6889):664-667.
[8] MAURY E,BRICHARD S M.Adipokine dysregulation,adipose tissue inflammation and metabolic syndrome[J].Mol Cell Endocrinol,2010,314(1):1-16.
[9] OUCHI N,HIGUCHI A,OHASHI K,et al.Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity[J].Science,2010,329(5990):454-457.
[10] BREMER A A,DEVARAJ S,AFIFY A,et al.Adipose tissue dysregulation in patients with metabolic syndrome[J].J Clin Endocrinol Metab,2011,96(11):E1782-788.
[11] VANELLA L,SODHI K,KIM D H,et al.Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade[J].Stem Cell Res Ther,2013,4(2):28.
[12] BLUHER M,MANTZOROS C S.From leptin to other adipokines in health and disease:facts and expectations at the beginning of the 21STcentury[J].Metabolism,2015,64(1):131-145.
[13] PARK J R,JUNG J W,LEE Y S,et al.The roles of Wnt antagonists DKK1 and sFRP4 during adipogenesis of human adipose tissue-derived mesenchymal stem cells[J].Cell Prolif,2008,41(6):859-874.
[14] LU H,LI X,MU P,et al.Dickkopf-1 promotes the differentiation and adipocytokines secretion via canonical Wnt singaling pathway in primary cultured human preadipocytes[J].Obes Res Clin Pract,2016,10(4):454-464.
[15] 杨秀颖,张莉,陈熙,等.2型糖尿病周围神经病变机制研究进展[J].中国药理学通报,2016,32(5):598-602.
[16] ZHANG Y,GE C,WANG L,et al.Induction of DKK1 by ox-LDL negatively regulates intracellular lipid accumulation in macrophages[J].FEBS Lett,2015,589(1):52-58.
[17] LI X,SHAN J,CHANG W,et al.Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism[J].Proc Natl Acad Sci USA,2012,109(28):11402-11407.
[18] LATTANZIO S,SANTILLI F,LIANI R,et al.Circulating Dickkopf-1 in diabetes Mellitus:Association with platelet activation and effects of improved metabolic control and low-dose aspirin[J].J Am Heart Assoc,2014,3(4):604-613.
[19] LIN C L,WANG J Y,KO J Y,et al.Dickkopf-1 promotes hyperglycemia-induced accumulation of mesangial matrix and renal dysfunction[J].J Am Soc Nephrol,2010,21(1):124-135.
[20] QIU F,HE J,ZHOU Y,et al.Plasma and vitreous fluid levels of Dickkopf-1 in patients with diabetic retinopathy[J].Eye(Lond),2014,28(4):402-409.
[21] 高新晓,彭晓燕,孟忻,等.增殖性糖尿病视网膜病变患者血清Dickkopf-1水平分析[J].眼科新进展,2015,35(6):536-538.
[22] ZHOU J,JIANG J,WANG S,et al.DKK1 inhibits proliferation and migration in human retinal pigment epithelial cells via the Wnt/β-catenin signaling pathway[J].Exp Ther Med,2016,12(2):859-863.
[23] 贾安奎,刘彦轩.糖尿病视网膜病变患者血小板平均体积与视网膜厚度及尿清蛋白排泄率的关系[J].中国实用内科杂志,2007,27(15):1202-1204.
[24] DINDAR S,CINEMRE H,SENGUL E,et al.Mean platelet volume is associated with glycaemic controland retinopathy in patients with type 2 diabetes mellitus[J].West Indian Med J,2013,62(6):519-523.
[25] JIANG S J,LI W,LI Y J,et al.Dickkopfrelated protein 1 induces angiogenesis by upregulating vascular endothelial growth factor in the synovial fbroblasts of patients with temporomandibular joint disorders[J].Molecular Medicine Reports,2015,12(4):4959-4966.
[26] SMADJA D M,d'AUDIGIER C,WEISWALD L B,et al.The Wnt antagonist Dickkopf-1 increases endothelial progenitor cell angiogenic potential[J].Arterioscler Thromb Vasc Biol,2010,30(12):2544-2552.
[27] UELAND T,OTTERDAL K,LEKVA T,et al.Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis[J].Arterioscler Thromb Vasc Biol,2009,29(8):1228-1234.
[28] BLUHER M,UNGER R,RASSOUL F,et al.Relation between glycaemic control,hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type Ⅱ diabetes[J].Diabetologia,2002,45(2):210-216.
[29] 陈亚军,戴先鹏.2型糖尿病患者血清游离脂肪酸与周围神经病变相关性分析[J].延边医学,2015,10(15):264-265.
[30] 胡仁明,谢颖,鹿斌,等.2型糖尿病患者高发"代谢性炎症综合征"[J].中华内分泌代谢杂志,2016,32(1):27-32.
[31] No authors listed.Calcified atherosclerotic plaques inversely associated with plasma DKK1[J].Bonekey Rep,2013,2:360.
[32] POLYZOS S A,ANASTASILAKIS A D,KOUNTOURAS J,et al.Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease[J].J Bone Miner Metab,2016,34(4):447-456.
[33] GUSTAFSON B,SMITH U.The WNT inhibitor Dickkopf 1 and bone morphogenetic protein 4 rescue adipogenesis in hypertrophic obesity in humans[J].Diabetes,2012,61(5):1217-1224.
[34] Chae W J,Ehrlich A K,Chan P Y,et al.The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation[J].Immunity,2016,44(2):246-258.
[35] PFEIFER M A,SCHUMER M P.Clinical Trials of Diabetic Neuropathy:Past,Present,and Future[J].Diabetes,1995,44(12):1355-1361.
[36] 李妮,周微雅.糖尿病周围神经病变患者免疫状态的观察[J].中华临床医药杂志,2001,(7):1-4.
[37] KOLLA V K,MADHAVI G,PULLA REDDY B,et al.Association of tumor necrosis factor alpha,interferon gamma and interleukin 10 gene polymorphisms with peripheral neuropathy in South Indian patients with type 2 diabetes[J].Cytokine,2009,47(3):173-177.
[38] MATSUDA K,KONDOH H.Dkk1-dependent inhibition of Wnt signaling activates Hesx1 expression through its 5' enhancer anddirects forebrain precursor development[J].Genes Cells,2014,19(5):374-385.
[39] RIBEIRO D,ELLWANGER K,GLAGOW D,et al.Dkk1 regulates ventral midbrain dopaminergic differentiation and morphogenesis[J].PLoS One,2011,6(2):e15786.
[40] BUSCETI C L,BIAGIONI F,ARONICA E,et al.Induction of the Wnt inhibitor,Dickkopf-1,is associated with neurodegeneration related to temporal lobeepilepsy[J].Epilepsia,2007,48(4):694-705.
[41] CARICASOLE A,COPANI A,CARACI F,et al.Induction of Dickkopf-1,a negative modulator of the Wnt pathway,is associated with neuronaldegeneration in Alzheimer's brain[J].J Neurosci,2004,24(26):6021-6027.
[42] MASTROIACOVO F,BUSCETI C L,BIAGIONI F,et al.Induction of the Wnt antagonist,Dickkopf-1,contributes to the development of neuronal death in modelsof brain focal ischemia[J].J Cereb Blood Flow Metab,2009,29(2):264-276.
[43] ROSI M C,LUCCARINI I,GROSSI C,et al.Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease[J].J Neurochem,2010,112(6):1539-1551.
[44] SEIB D R,CORSINI N S,ELLWANGER K,et al.Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline[J].Cell Stem Cell,2013,12(2):204-214.