NLRP3炎性小体在2型糖尿病前期的表达及临床意义的研究
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摘要
目的探讨NOD样受体蛋白3(NLRP3)炎性小体在T2DM前期的表达及临床价值。方法选取36名正常糖耐量组(NC)、141例糖尿病前期组(PD)、30例T2DM组(T2DM)共207例研究对象。ELISA检测各组血浆NLRP3、半胱氨酸天冬氨酸蛋白酶1(CASPASE-1)、白介素1β(IL-1β)水平;Pearson相关分析血浆NLRP3、CASPASE-1、IL-1β与临床各指标的相关性;绘制受试者工作特征曲线(ROC)分析敏感性和特异性。结果 NC组、PD组和T2DM组血浆NLRP3、CASPASE-1、IL-1β逐渐升高[(315. 00±84. 22)vs(449. 60±54. 61)vs(608. 56±72. 20)pg/ml,(48. 29±10. 17)vs(59. 98±7. 21)vs(80. 60±8. 72)pg/ml,(31. 52±8. 14)vs(43. 73±5. 79)vs(61. 65±9. 14)pg/ml,P<0. 05];Pearson相关分析显示,PD组NLRP3水平与LDL-C、2 h PG、CASPASE-1、IL-1β呈正相关,CASPASE-1与TG、LDL-C、2 hPG、NLRP3、IL-1β呈正相关,IL-1β与LDL-C、2 h PG、NLRP3、CASPASE-1呈正相关。T2DM组NLRP3水平与FIns、CASPASE-1、IL-1β呈正相关,CASPASE-1与FPG、TG、LDL-C、2 h PG、FIns、HOMA-β、NLRP3、IL-1β呈正相关,IL-1β与FPG、LDL-C、NLRP3、CASPASE-1呈正相关。PD组NLRP3在最佳切点(371. 5)上的敏感性和特异性分别为95. 0%和75. 0%,CASPASE-1在最佳切点(55. 3)上的敏感性和特异性分别为78. 4%和77. 8%,IL-1β在最佳切点(39. 74)上的敏感性和特异性分别为77. 8%和88. 9%。结论糖尿病患者NLRP3、CASPASE-1、IL-1β表达增高,其高表达与糖脂代谢指标密切相关,具有诊断早期糖尿病的潜力。
Objective To evaluate the expression and clinical value of NLRP3 inflammatory bodies in pre-type 2 diabetes mellitus.Methods A total of 207 subjects were enrolled in this study and divided into three groups:normal glucose tolerance groups(NC group,n=36),pre-diabetes patients(PD group,n=141)and type 2 diabetes patients(DM group,n=30). The levels of NLRP3,CASPASE-1 and IL-1β in plasma were detected by ELISA. The correlation between plasma NLRP3,CASPASE-1,IL-1β and clinical indicators was evaluated by Pearson correlation analysis. ROC curve was generated to analyze the sensitivity and specificity of plasma NLRP3,CASPASE-1,IL-1β in diagnosis of pre-diabetes.Results The concentration of plasma NLRP3,CASPASE-1 and IL-1β were gradually increased in NC,PD and T2 DM group[(315. 00±84. 22)vs(449. 60±54. 61)vs(608. 56±72. 20)pg/ml,(48. 29±10. 17)vs(59. 98±7. 21)vs(80. 60±8. 72)pg/ml,(31. 52±8. 14)vs(43. 73±5. 79)vs(61. 65±9. 14)pg/ml,P<0. 05].Pearson correlation analysis showed that in PD group,the level of NLRP3 was positively correlated with LDL-C,2 hPG;CASPASE-1 and IL-1β,CASPASE-1 was positively correlated with TG,LDL-C,2 h PG,NLRP3 and IL-1β;and IL-1β was positively correlated with LDL-C,2 h PG,NLRP3 and CASPASE-1. In T2 DM group,the level of NLRP3 was positively correlated with FIns,CASPASE-1 and IL-1β;CASPASE-1 was positively correlated with FPG,TG,LDL-C,2 hPG,FIns,HOMA-β,NLRP3 and IL-1β;and IL-1β was positively correlated with FPG,LDL-C,NLRP3 and CASPASE-1. In PD group,the sensitivity and specificity of NLRP3 at the optimal cut point(371. 5)were 95% and 75%,respectively;the sensitivity and specificity of CASPASE-1 at the optimal cut point(55. 3)were78. 4% and 77. 8%;the sensitivity and specificity of IL-1β at the optimal cut point(39. 74)were 77. 8% and 88. 9%.Conclusion The expression of NLRP3,CASPASE-1 and IL-1β were increased in diabetic patients. Its high expression was closely related to glucose and lipid metabolism in diabetic patients,and has the potential to diagnose diabetes early.
Objective To evaluate the expression and clinical value of NLRP3 inflammatory bodies in pre-type 2 diabetes mellitus.Methods A total of 207 subjects were enrolled in this study and divided into three groups:normal glucose tolerance groups(NC group,n=36),pre-diabetes patients(PD group,n=141)and type 2 diabetes patients(DM group,n=30). The levels of NLRP3,CASPASE-1 and IL-1β in plasma were detected by ELISA. The correlation between plasma NLRP3,CASPASE-1,IL-1β and clinical indicators was evaluated by Pearson correlation analysis. ROC curve was generated to analyze the sensitivity and specificity of plasma NLRP3,CASPASE-1,IL-1β in diagnosis of pre-diabetes.Results The concentration of plasma NLRP3,CASPASE-1 and IL-1β were gradually increased in NC,PD and T2 DM group[(315. 00±84. 22)vs(449. 60±54. 61)vs(608. 56±72. 20)pg/ml,(48. 29±10. 17)vs(59. 98±7. 21)vs(80. 60±8. 72)pg/ml,(31. 52±8. 14)vs(43. 73±5. 79)vs(61. 65±9. 14)pg/ml,P<0. 05].Pearson correlation analysis showed that in PD group,the level of NLRP3 was positively correlated with LDL-C,2 hPG;CASPASE-1 and IL-1β,CASPASE-1 was positively correlated with TG,LDL-C,2 h PG,NLRP3 and IL-1β;and IL-1β was positively correlated with LDL-C,2 h PG,NLRP3 and CASPASE-1. In T2 DM group,the level of NLRP3 was positively correlated with FIns,CASPASE-1 and IL-1β;CASPASE-1 was positively correlated with FPG,TG,LDL-C,2 hPG,FIns,HOMA-β,NLRP3 and IL-1β;and IL-1β was positively correlated with FPG,LDL-C,NLRP3 and CASPASE-1. In PD group,the sensitivity and specificity of NLRP3 at the optimal cut point(371. 5)were 95% and 75%,respectively;the sensitivity and specificity of CASPASE-1 at the optimal cut point(55. 3)were78. 4% and 77. 8%;the sensitivity and specificity of IL-1β at the optimal cut point(39. 74)were 77. 8% and 88. 9%.Conclusion The expression of NLRP3,CASPASE-1 and IL-1β were increased in diabetic patients. Its high expression was closely related to glucose and lipid metabolism in diabetic patients,and has the potential to diagnose diabetes early.
引文
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[9]Wu D,Yan ZB,Cheng YG,et al.Deactivation of the NLRP3inflammasome in infiltrating macrophages by duodenal-jejunal bypass surgery mediates improvement of beta cell function in type2 diabetes.Metab Clin Exp,2018,81:1-12.
[10]Park YJ,Warnock GL,Ao Z,et al.Dual role of IL-1βin islet amyloid formation and itsβ-cell toxicity:Implications in type 2diabetes and islet transplantation.Diabetes Obes Metab,2017,19:682-694.
[11]Zhao G,Dharmadhikari G,Maedler K,et al.Possible role of interleukin-1βin type 2 diabetes onset and implications for antiinflammatory therapy strategies.PloS Comput Biol,2014,10:e1003798.
[12]Stanley TL,Zanni MV,Johnsen S,et al.TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome.J Clin Endocrinol Metab,2011,96:146-150.
[13]Wada J,Makino H.Inflammation and the pathogenesis of diabetic nephropathy.Clin Sci,2013,124:139-152.
[14]Jourdan T,Godlewski G,Cinar R,et al.Activation of the Nlrp3inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.Nat Med,2013,19:1132-1140.
[15]Chen H,Zhang X,Liao N,et al.Enhanced expression of NLRP3inflammasome-related inflammation in diabetic retinopathy.Invest Ophthalmol Visual Sci,2018,59:978-985.
[16]Lee J,Wan J,Lee L,et al.Study of the NLRP3 inflammasome component genes and downstream cytokines in patients with type2 diabetes mellitus with carotid atherosclerosis.Lipids Health Dis,2017,16:217.
[17]胡龙江,周音频,曹运兰,等.NLRP3-ASC-Caspase-1-IL-18/IL-1β-TGF信号通路与Ⅱ型糖尿病临床相关性研究.西部医学,2018,30:335-340,346.
[18]Legrandpoels S,Esser N,L'Homme L,et al.Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2diabetes.Biochem Pharmacol,2014,92:131-141.
[19]Ding T,Wang S,Zhang X,et al.Kidney protection effects of dihydroquercetin on diabetic nephropathy through suppressing ROS and NLRP3 inflammasome.Phytomedicine,2018,41:45-53.--
[2]Bonn SE,Alexandrou C,Hj?rleifsdottir SK,et al.Apptechnology to increase physical activity among patients with diabetes type 2-the DiaCert-study,a randomized controlled trial.BMC Public Health,2018,18:119.
[3]Lontchi-Yimagou E,Sobngwi E,Matsha TE,et al.Diabetes mellitus and inflammation.Curr Diabetes Rep,2013,13:435-444.
[4]Rovirallopis S,Apostolova N,Ba?uls C,et al.Mitochondria,the NLRP3 inflammasome and sirtuins in type 2 diabetes:New therapeutic targets.Antioxid Redox Signaling,2018,29:749-791.
[5]Gao L,Lu GT,Lu YY,et al.Diabetes aggravates acute pancreatitis possibly via activation of NLRP3 inflammasome in db/db mice.Am J Transl Res,2018,10:2015-2025.
[6]Jo EK,Kim JK,Shin DM,et al.Molecular mechanisms regulating NLRP3 inflammasome activation.Cell Mol Immunol,2016,13:148-159.
[7]Patel MN,Carroll RG,Galván-Pe?a S,et al.Inflammasome priming in sterile inflammatory disease.Trends Mol Med,2017,23:165-180.
[8]Qin L,Feng J,Hu C,et al.Th17/Treg imbalance mediated by IL-8 in RSV-infected bronchial epithelial cells.Med Sci,2016,41:337-344.
[9]Wu D,Yan ZB,Cheng YG,et al.Deactivation of the NLRP3inflammasome in infiltrating macrophages by duodenal-jejunal bypass surgery mediates improvement of beta cell function in type2 diabetes.Metab Clin Exp,2018,81:1-12.
[10]Park YJ,Warnock GL,Ao Z,et al.Dual role of IL-1βin islet amyloid formation and itsβ-cell toxicity:Implications in type 2diabetes and islet transplantation.Diabetes Obes Metab,2017,19:682-694.
[11]Zhao G,Dharmadhikari G,Maedler K,et al.Possible role of interleukin-1βin type 2 diabetes onset and implications for antiinflammatory therapy strategies.PloS Comput Biol,2014,10:e1003798.
[12]Stanley TL,Zanni MV,Johnsen S,et al.TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome.J Clin Endocrinol Metab,2011,96:146-150.
[13]Wada J,Makino H.Inflammation and the pathogenesis of diabetic nephropathy.Clin Sci,2013,124:139-152.
[14]Jourdan T,Godlewski G,Cinar R,et al.Activation of the Nlrp3inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.Nat Med,2013,19:1132-1140.
[15]Chen H,Zhang X,Liao N,et al.Enhanced expression of NLRP3inflammasome-related inflammation in diabetic retinopathy.Invest Ophthalmol Visual Sci,2018,59:978-985.
[16]Lee J,Wan J,Lee L,et al.Study of the NLRP3 inflammasome component genes and downstream cytokines in patients with type2 diabetes mellitus with carotid atherosclerosis.Lipids Health Dis,2017,16:217.
[17]胡龙江,周音频,曹运兰,等.NLRP3-ASC-Caspase-1-IL-18/IL-1β-TGF信号通路与Ⅱ型糖尿病临床相关性研究.西部医学,2018,30:335-340,346.
[18]Legrandpoels S,Esser N,L'Homme L,et al.Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2diabetes.Biochem Pharmacol,2014,92:131-141.
[19]Ding T,Wang S,Zhang X,et al.Kidney protection effects of dihydroquercetin on diabetic nephropathy through suppressing ROS and NLRP3 inflammasome.Phytomedicine,2018,41:45-53.--