硫氧还蛋白相互作用蛋白在2型糖尿病患者血清中的变化及临床意义
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摘要
目的本研究拟分析血清硫氧还蛋白相互作用蛋白(thioredoxin interacting protein,TXNIP)在2型糖尿病(T2DM)患者血清中的变化规律。方法收集2013年11月至2014年7月在解放军总医院内分泌科住院、明确诊断为2型糖尿病患者(270例)与同时期健康体检者(73例)血清,分别检测血清TXNIP(ELISA法)、血清葡萄糖(Glu)、糖化血红蛋白(HbA1c)等指标。结果①2型糖尿病慢性并发症患病率为视网膜病变20.5%、糖尿病肾病20.1%、神经病变34.3%、高血压50.4%、冠心病12.6%。②血清TXNIP水平在年龄与并发症分组中差异具有统计学意义(P <0. 05)。在年龄分组中,年龄<45岁组血清TXNIP水平显著高于年龄45～60岁组(P=0.026),年龄> 60岁组血清TXNIP水平显著高于年龄45～60岁组(P=0. 021),其余无统计学差异。在并发症分组中,D组TXNIP水平显著高于A组(P=0. 025),C组TXNIP水平显著高于E组(P=0.025),D组TXNIP水平显著高于E组(P=0.002),D组TXNIP水平显著高于F组(P=0.045),G组TXNIP水平显著高于E组(P=0. 028)。③血清TXNIP水平随Glu与HbA1c分层变化趋势呈波动状态。④相关性分析显示,血清TXNIP与身体质量指数(BMI)呈正相关(r=0.160,P=0.009),与血小板(PLT)呈负相关(r=-0.125,P=0.041)。结论血清TXNIP水平改变与2型糖尿病慢性并发症密切相关,在2型糖尿病及其血管并发症中起着重要的作用。控制血清TXNIP水平可能有助于控制2型糖尿病患者血管并发症的发生与发展。
Objective To analyze the changes of serum thioredoxin interacting protein(TXNIP)in patients with type 2 diabetes mellitus(T2DM). Methods We collected the serum of type 2 diabetic patients(270 cases) and health examiner(73 cases)from November,2013 to July 2014,and detected serum TXNIP,Glu and HbA1 c in all of the cases. Results ①Prevalence of chronic complications of type 2 diabetes in the study cohort were:Diabetic Rretinopathy 20.5%,Diabetic Nephropathy 20.1%,Neuropathy 34. 3%, Hypertension 50.4%,and Coronary Disease 12.6%. ②Among the age stratification groups,the level of serum TXNIP in age <45 years group and age >60 years group were significantly higher than those in age 45-60 years group(P =0.026,P =0. 021). Among the complications groups,the level of TXNIP in group D was significantly higher than that in group A(P =0.025),group E(P =0. 002),and group F(P =0. 045); the level of TXNIP in group C and group G were significantly higher than that in group E(P =0.025,P =0.028). ③The level of serum TXNIP(ng/mL) fluctuated with the stratification of Glu and HbAlc. ④Correlation analysis showed that serum TXNIP was positively correlated with BMI( r =0. 160,P=0.009),while negatively correlated with PLT(r =-0. 125,P=0. 041). Conclusion The changes of serum TXNIP level is associated with diabetic complications, and plays an important role in type 2 diabetes and its vascular complications. Controlling serum TXNIP level might help to control the occurrence and development of vascular complications in type 2 diabetes mellitus.
Objective To analyze the changes of serum thioredoxin interacting protein(TXNIP)in patients with type 2 diabetes mellitus(T2DM). Methods We collected the serum of type 2 diabetic patients(270 cases) and health examiner(73 cases)from November,2013 to July 2014,and detected serum TXNIP,Glu and HbA1 c in all of the cases. Results ①Prevalence of chronic complications of type 2 diabetes in the study cohort were:Diabetic Rretinopathy 20.5%,Diabetic Nephropathy 20.1%,Neuropathy 34. 3%, Hypertension 50.4%,and Coronary Disease 12.6%. ②Among the age stratification groups,the level of serum TXNIP in age <45 years group and age >60 years group were significantly higher than those in age 45-60 years group(P =0.026,P =0. 021). Among the complications groups,the level of TXNIP in group D was significantly higher than that in group A(P =0.025),group E(P =0. 002),and group F(P =0. 045); the level of TXNIP in group C and group G were significantly higher than that in group E(P =0.025,P =0.028). ③The level of serum TXNIP(ng/mL) fluctuated with the stratification of Glu and HbAlc. ④Correlation analysis showed that serum TXNIP was positively correlated with BMI( r =0. 160,P=0.009),while negatively correlated with PLT(r =-0. 125,P=0. 041). Conclusion The changes of serum TXNIP level is associated with diabetic complications, and plays an important role in type 2 diabetes and its vascular complications. Controlling serum TXNIP level might help to control the occurrence and development of vascular complications in type 2 diabetes mellitus.
引文
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[7]韩学尧.2型糖尿病易感基因对中国人2型糖尿病遗传易感性影响的系统评价[J].中国糖尿病杂志,2011,19(3):161-162.
[8]祝方,纪立农,罗斌.硬骨鱼紧张肽Ⅱ基因多态性与中国人2型糖尿病遗传易感性的关系[J].中华医学杂志,2002,82(21):1473-1475.
[9]PRAVEEN E P, SAHOO J, KHURANA M L, et al. Insulin sensitivity andβ-cell function in normoglycemic offspring of individuals with type 2 diabetes mellitus:Impact of line of inheritance[J]. Indian J Endocrinol Metab, 2012,16(1):105-111.
[10]MA X J,JIA W P,HU C,et al. Genetic characteristics of familial type 2 diabetes pedigrees:a preliminary analysis of 4468 persons from 715 pedigrees[J]. Zhonghua Yi Xue Za Zhi,2008,88(36):2541-2543.
[11]中华医学会糖尿病学分会.中国2型糖尿病防治指南(2013年版)[J].中华糖尿病杂志,2014,22(8):2-42.
[12]SINGH L P. Thioredoxin interacting protein(TXNIP)and pathogenesis of diabetic retinopathy[J]. J Clin Exp Ophthalmol,2013,4. doi:10.4172/2155-9570.100287.
[13]PERRONE L,DEVI T S,HOSOYA K I,et al. Inhibition of TXNIP expression in vivo blocks early pathologies of diabetic retinopathy[J].Cell Death Dis,2010,1;e65.
[14]SHAH A, XIA L, GOLDBERG H, et al. Thioredoxin-interacting protein mediates high glucose-induced reactive oxygen species generation by mitochondria and the NADPH oxidase, Nox4, in mesangial cells[J]. J Biol Chem,2013,288(10):6835-6848.
[15]TAN C Y, WEIER Q, ZHANG Y, et al. Thioredoxin-interacting protein:a potential therapeutic target for treatment of progressive fibrosis in diabetic nephropathy[J]. Nephron, 2015, 129(2):109-127.
[16]HUANG C, LIN M Z, CHENG D, et al. Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux[J]. Lab Invest,2014,94(3):309-320.
[17]NG M K,WU J, CHANG E, et al. A central role for nicotinic cholinergic regulation of growth factor-induced endothelial cell migration[J]. Arterioscler Thromb Vasc Biol, 2007, 27(1):106-112.
[18]SPINDEL 0 N,BURKE R M,YAN C,et al. Thioredoxin-interacting protein is a biomechanical regulator of Src activity:key role in endothelial cell stress fiber formation[J]. Circulat Res, 2014,114(7):1125-1132.
[19]RIAHI Y,KAISER N, COHEN G, et al. Foam cell-derived 4-hydroxynonenal induces endothelial cell senescence in a TXNIPdependent manner[J]. J Cell Mol Med,2015,19(8):1887-1899.
[20]WONGEAKIN N,BHATTARAKOSOL P,PATUMRAJ S. Molecular mechanisms of curcumin on diabetes-induced endothelial dysfunctions:Txnip, ICAM-1, and NOX2 expressions[J]. BiomedRes Int,2014,2014:161346.
[21]McCARTER R J,HEMPE J M,CHALEW S A. Mean blood glucose and biological variation have greater influence on HbAlc levels than glucose instability:an analysis of data from the Diabetes Control and Complications Trial[J]. Diabetes Care,2006,29(2):352-355.
[22]VERONESE N,TREVISAN C, De RUI M, et al. Association of osteoarthritis with increase risk of cardiovascular diseases in the elderly:findings from the progetto veneto anziano study cohort[J].Arthritis Rheumatol,2016,68(5):1136-1144.
[23]SHALEV A, PISE-MASISON CA, RADONOVICH M, et al.Oligonucleotide microarray analysis of intact human pancreatic islets:identification of glucose-responsive genes and a highlyregulated TGFbeta signaling pathway[J]. Endocrinology, 2002,143(9):3695-3698.
[24]KIM H J,KIM Y G, PARK J S, et al. Association between blood glucose level derived using the oral glucose tolerance test and glycated hemoglobin level[J]. Korean J Intern Med,2016,31(3):535-542.
[25]XING Y,JI Q,LI X,et al. Asiaticoside protects cochlear hair cells from high glucose-induced oxidative stress via suppressing AGEs/RAGE/NF-κB pathway[J]. Biomed Pharmacother, 2017, 86:531-536.
[2]LIU H,CAO M M,WANG Y,et al. Endoplasmic reticulum stress is involved in the connection between inflammation and autophagy in type 2 diabetes[J]. Gen Comp Endocrinol,2015,210:124-129.
[3]ZHOU R,TARDIVEL A, THORENS B,et al. Thioredoxin-interacting protein links oxidative stress to inflammasome activation[J]. Nat Immunol,2010,11(2):136-140.
[4]DUNN L L,SIMPSON P J L,PROSSER H C,et al. A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis[J]. Diabetes,2014,63(2):675-687.
[5]American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus[J]. Diabetes Care,1997,20(7):1183-1197.
[6]姜维平,沈洪兵.2型糖尿病核心家系的遗传易感性研究[J].中国慢性病预防与控制,1999,7(6):245-246.
[7]韩学尧.2型糖尿病易感基因对中国人2型糖尿病遗传易感性影响的系统评价[J].中国糖尿病杂志,2011,19(3):161-162.
[8]祝方,纪立农,罗斌.硬骨鱼紧张肽Ⅱ基因多态性与中国人2型糖尿病遗传易感性的关系[J].中华医学杂志,2002,82(21):1473-1475.
[9]PRAVEEN E P, SAHOO J, KHURANA M L, et al. Insulin sensitivity andβ-cell function in normoglycemic offspring of individuals with type 2 diabetes mellitus:Impact of line of inheritance[J]. Indian J Endocrinol Metab, 2012,16(1):105-111.
[10]MA X J,JIA W P,HU C,et al. Genetic characteristics of familial type 2 diabetes pedigrees:a preliminary analysis of 4468 persons from 715 pedigrees[J]. Zhonghua Yi Xue Za Zhi,2008,88(36):2541-2543.
[11]中华医学会糖尿病学分会.中国2型糖尿病防治指南(2013年版)[J].中华糖尿病杂志,2014,22(8):2-42.
[12]SINGH L P. Thioredoxin interacting protein(TXNIP)and pathogenesis of diabetic retinopathy[J]. J Clin Exp Ophthalmol,2013,4. doi:10.4172/2155-9570.100287.
[13]PERRONE L,DEVI T S,HOSOYA K I,et al. Inhibition of TXNIP expression in vivo blocks early pathologies of diabetic retinopathy[J].Cell Death Dis,2010,1;e65.
[14]SHAH A, XIA L, GOLDBERG H, et al. Thioredoxin-interacting protein mediates high glucose-induced reactive oxygen species generation by mitochondria and the NADPH oxidase, Nox4, in mesangial cells[J]. J Biol Chem,2013,288(10):6835-6848.
[15]TAN C Y, WEIER Q, ZHANG Y, et al. Thioredoxin-interacting protein:a potential therapeutic target for treatment of progressive fibrosis in diabetic nephropathy[J]. Nephron, 2015, 129(2):109-127.
[16]HUANG C, LIN M Z, CHENG D, et al. Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux[J]. Lab Invest,2014,94(3):309-320.
[17]NG M K,WU J, CHANG E, et al. A central role for nicotinic cholinergic regulation of growth factor-induced endothelial cell migration[J]. Arterioscler Thromb Vasc Biol, 2007, 27(1):106-112.
[18]SPINDEL 0 N,BURKE R M,YAN C,et al. Thioredoxin-interacting protein is a biomechanical regulator of Src activity:key role in endothelial cell stress fiber formation[J]. Circulat Res, 2014,114(7):1125-1132.
[19]RIAHI Y,KAISER N, COHEN G, et al. Foam cell-derived 4-hydroxynonenal induces endothelial cell senescence in a TXNIPdependent manner[J]. J Cell Mol Med,2015,19(8):1887-1899.
[20]WONGEAKIN N,BHATTARAKOSOL P,PATUMRAJ S. Molecular mechanisms of curcumin on diabetes-induced endothelial dysfunctions:Txnip, ICAM-1, and NOX2 expressions[J]. BiomedRes Int,2014,2014:161346.
[21]McCARTER R J,HEMPE J M,CHALEW S A. Mean blood glucose and biological variation have greater influence on HbAlc levels than glucose instability:an analysis of data from the Diabetes Control and Complications Trial[J]. Diabetes Care,2006,29(2):352-355.
[22]VERONESE N,TREVISAN C, De RUI M, et al. Association of osteoarthritis with increase risk of cardiovascular diseases in the elderly:findings from the progetto veneto anziano study cohort[J].Arthritis Rheumatol,2016,68(5):1136-1144.
[23]SHALEV A, PISE-MASISON CA, RADONOVICH M, et al.Oligonucleotide microarray analysis of intact human pancreatic islets:identification of glucose-responsive genes and a highlyregulated TGFbeta signaling pathway[J]. Endocrinology, 2002,143(9):3695-3698.
[24]KIM H J,KIM Y G, PARK J S, et al. Association between blood glucose level derived using the oral glucose tolerance test and glycated hemoglobin level[J]. Korean J Intern Med,2016,31(3):535-542.
[25]XING Y,JI Q,LI X,et al. Asiaticoside protects cochlear hair cells from high glucose-induced oxidative stress via suppressing AGEs/RAGE/NF-κB pathway[J]. Biomed Pharmacother, 2017, 86:531-536.