炎性反应介导2型糖尿病患者相关肿瘤标志物升高的临床研究:倾向性匹配研究和中介模型研究

Clinical study on inflammatory response mediated tumor marker elevation in patients with type 2 diabetes mellitus:propensity matching study and mediating model study

目的比较2型糖尿病(T2DM)患者与非糖尿病患者癌抗原19-9(CA19-9)、癌胚抗原(CEA)表达情况,探讨白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)和高敏C反应蛋白(hs-CRP)在调节CA19-9和CEA中的作用。方法选取2016年1—12河北省秦皇岛军工医院T2DM患者146例(T2DM组),根据年龄、性别、体质量指数(BMI)、腰围和臀围进行倾向评分匹配,按照1∶1不取代的最近邻匹配法完成健康对照组匹配共146例。将T2DM患者根据糖化血红蛋白(HbA1c)水平分为四组:HbA1c<7%16例(A亚组),7%≤HbA1c<9%38例(B亚组),9%≤HbA1c<11%44例(C亚组),HbA1c≥11%48例(D亚组)。采用逐步线性回归确定T2DM患者CA19-9、CEA水平升高机制中IL-6、TNF-α、hs-CRP的中介效应。结果T2DM组空腹血糖(FBG)、HbA1c、IL-6、TNF-α、hs-CRP、CA19-9、CEA均明显高于健康对照组[(9.95±2.98)mmol/L比(4.89±0.77)mmol/L、(9.85±2.18)%比(5.71±1.91)%、(46.51±13.17)ng/L比(32.41±13.74)ng/L、(45.41±17.25)ng/L比(21.54±15.01)ng/L、(4.99±3.51)mg/L比(3.19±3.15)mg/L、(13.35±5.34)U/L比(8.58±1.08)U/L和(2.51±1.04)μg/L比(2.14±1.01)μg/L],差异有统计学意义(P<0.01)。A亚组、B亚组、C亚组和D亚组性别构成、腰围、臀围、病程和FBG比较差异无统计学意义(P>0.05);四亚组年龄、BMI、IL-6、TNF-α、hs-CRP、CA19-9和CEA比较差异有统计学意义(P<0.01或<0.05)。T2DM患者HbA1c与IL-6、TNF-α、hs-CRP、CA19-9和CEA呈正相关性(r=0.863、0.802、0.495、0.883和0.766,P<0.01)。IL-6、TNF-α、hs-CRP在HbA1c调节CA19-9中起着部分中介效应[分别为20.5%(0.181/0.883)、17.8%(0.157/0.883)、8.2%(0.072/0.883)],TNF-α在HbA1c调节CEA中起着部分中介效应[24.0%(0.184/0.766)]。结论T2DM患者的肿瘤标志物水平升高与血糖有相关性,其中炎性反应是二者之间潜在调节变量。

Objective To compare the expression of carbohydrate antigen 19-9(CA19-9)and carcinoembryonic antigen(CEA)between type 2 diabetes mellitus(T2DM)and non-diabetic patients,and investigate the role of interleukin-6(IL-6),tumor necrosis factor-α(TNF-α)and high sensitive C-reactive protein(hs-CRP)in the regulation of CA19-9 and CEA.Methods From January to December 2016,a total of 146 patients with T2DM(T2DM group)were selected in Qinhuangdao Military Hospital of Hebei Province.According to age,gender,body mass index(BMI),waist circumference and hip circumference,propensity score was matched.A total of 146 healthy control group matches were completed according to the nearest neighbor matching method of 1∶1.According to the glycated hemoglobin(HbA1c),the patients with T2DM were divided into 4 groups:HbA1c<7%16 cases(A subgroup),7%≤HbA1c<9%38 cases(B subgroup),9%≤HbA1c<11%44 cases(C subgroup),HbA1c≥11%48 cases(D subgroup).The mediating effects of IL-6,TNF-αand hs-CRP in CA19-9 and CEA levels in patients with T2DM were determined by stepwise linear regression.Results The fasting plasma glucose(FBG),HbA1c,IL-6,TNF-α,hs-CRP,CA19-9 and CEA in T2DM group were significantly higher than those in control group:(9.95±2.98)mmol/L vs.(4.89±0.77)mmol/L,(9.85±2.18)%vs.(5.71±1.91)%,(46.51±13.17)ng/L vs.(32.41±13.74)ng/L,(45.41±17.25)ng/L vs.(21.54±15.01)ng/L,(4.99±3.51)mg/L vs.(3.19±3.15)mg/L,(13.35±5.34)U/L vs.(8.58±1.08)U/L and(2.51±1.04)μg/L vs.(2.14±1.01)μg/L,and there were statistical differences(P<0.01).There were no statistical differences in gender composition,waist circumference,hip circumference,disease course and FBG among A subgroup,B subgroup,C subgroup and D subgroup(P>0.05).There were statistical differences in the age,BMI,IL-6,TNF-α,hs-CRP,CA19-9 and CEA among 4 subgroups(P<0.01 or<0.05).In patients with T2DM,the HbA1c was positively correlated with IL-6,TNF-α,hs-CRP,CA19-9 and CEA(r=0.863,0.802,0.495,0.883 and 0.766;P<0.01).The IL-6,TNF-αand hs-CRP had some mediating effects in HbA1c regulation of CA19-9:20.5%(0.181/0.883),17.8%(0.157/0.883)and 8.2%(0.072/0.883),respectively;the TNF-αhad some mediating effect in HbA1c regulation of CEA:24.0%(0.184/0.766).Conclusions There is a correlation between the levels of tumor markers and blood glucose in patients with T2DM,and inflammatory response is a potential regulatory variable.