郭 穎，吳 波

二甲雙胍對(duì)2型糖尿病患者血清PSA水平的影響及其與前列腺癌的關(guān)系

郭 穎，吳 波*

目的 觀察二甲雙胍對(duì)2型糖尿病(T2DM)患者PSA水平的影響，并探討二甲雙胍與前列腺癌的關(guān)系。方法 將2014年1-8月在我院內(nèi)分泌科住院的178例T2DM男性患者和96例健康體檢男性分為糖尿病組和健康對(duì)照組。糖尿病組和健康對(duì)照組(年齡和民族匹配)均排除既往或同時(shí)患有前列腺疾病或其他惡性腫瘤、急性感染(包括活動(dòng)性的結(jié)核)和嚴(yán)重的肝腎功能損害者，對(duì)收集的臨床資料和相關(guān)的輔助檢查結(jié)果行回顧性的病例對(duì)照分析。結(jié)果 ①糖尿病組PSA水平低于對(duì)照組(P<0.05)。②T2DM患者中，應(yīng)用二甲雙胍者的總PSA水平及游離PSA水平低于非二甲雙胍組(P<0.01，P<0.05)。結(jié)論 T2DM 患者血清PSA水平低于健康人群，二甲雙胍可能有降低前列腺癌風(fēng)險(xiǎn)的作用。

二甲雙胍；2型糖尿病；PSA；前列腺癌

0 引言

流行病學(xué)研究顯示，2型糖尿病(T2DM)與多種腫瘤的發(fā)生密切相關(guān)[1-3]。2010年美國糖尿病學(xué)會(huì)(ADA)和美國癌癥學(xué)會(huì)(ACS)聯(lián)合發(fā)表共識(shí)[4]指出，糖尿病(主要是T2DM)患者罹患癌癥的風(fēng)險(xiǎn)增高，而罹患前列腺癌的風(fēng)險(xiǎn)較正常人群減低，機(jī)制未明。血清總前列腺特異性抗原(Total prostate-specific antigen，TPSA)是目前診斷前列腺癌(Carcinoma of prostate，PCa)的最佳腫瘤標(biāo)記物，本文觀察二甲雙胍對(duì)糖尿病患者TPSA及TPSA與游離前列腺特異性抗原(Free prostate specific antigen，F(xiàn)PSA)的比值(TPSA/FPSA)的影響，并與健康人群進(jìn)行對(duì)比分析。

1 資料與方法

1.1 資料 收集2014年1-8月在我院內(nèi)分泌科住院的178例T2DM男性患者(糖尿病組)，年齡50～80歲，平均(64.5±15.5)歲，診斷符合WHO (1999年)標(biāo)準(zhǔn)，排除已明確診斷為前列腺癌等其他前列腺疾病的患者。分為二甲雙胍組(80例)和非二甲雙胍組(98例)。并選取同期我院健康體檢中心的96例男性(健康對(duì)照組)，排除已明確診斷為前列腺疾病及其他惡性腫瘤的患者，均為我院健康體檢合格者。

1.2 方法

1.2.1 檢測(cè)方法 仔細(xì)詢問受試者的病史，進(jìn)行查體并記錄病程、應(yīng)用藥物種類，晨抽取空腹靜脈血，高效液相色譜法測(cè)定HbA1c，CA19-9測(cè)定采用ROCHE Modular Analytics E170型自動(dòng)電化學(xué)發(fā)光免疫分析儀及其配套試劑。HbA1c正常值參考范圍：4.8%～6.0%；總PSA正常值參考范圍：0～4；游離PSA正常值參考范圍：0～0.934。

2 結(jié)果

2.1 糖尿病組與健康對(duì)照組PSA水平比較 糖尿病組TPSA、FPSA均低于健康對(duì)照組(P<0.05)，而兩組TPSA/FPSA比較差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。見表1。

表1 糖尿病組與健康對(duì)照組PSA水平比較

注：與健康對(duì)照組比較，*P<0.05

2.2 糖尿病患者中，二甲雙胍組患者的TPSA、FPSA水平均低于非二甲雙胍組(P<0.01，P<0.05)。兩組TPSA/FPSA比較差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。見表2。

表2 二甲雙胍組與非二甲雙胍組PSA水平比較

注：與非二甲雙胍組比較，*P<0.05，**P<0.01

3 討論

本研究結(jié)果顯示，T2DM患者總PSA水平較健康人群水平較低，由于TPSA是目前診斷前列腺癌的最佳腫瘤標(biāo)記物，推斷T2DM患者罹患前列腺癌的風(fēng)險(xiǎn)可能降低。而在T2DM患者中，應(yīng)用二甲雙胍的患者TPSA、FPSA水平均明顯低于非二甲雙胍組，推斷二甲雙胍可能會(huì)降低罹患前列腺的風(fēng)險(xiǎn)。其根本作用機(jī)制可能在于以下方面：二甲雙胍是一種AMP 活化蛋白激酶(AMPK)[5-6]，AMPK可以抑制激活雷帕霉素靶蛋白(mTOR)，而后者是調(diào)控惡性細(xì)胞增殖活化的重要因子，并與對(duì)抗抗癌藥物有關(guān)[7-8]。此外，二甲雙胍可以通過調(diào)節(jié)某些細(xì)胞周期蛋白(cycling A /B /D等)誘導(dǎo)細(xì)胞周期停滯和凋亡[9-10]，干擾Vcap 細(xì)胞進(jìn)入S期，使其停留在G0/G1期。此外，二甲雙胍能抑制線粒體complex1 活性來改變細(xì)胞呼吸功能，進(jìn)而影響細(xì)胞能量代謝[11-12]。Vazquez-Martin等[13]也對(duì)此進(jìn)行了研究，結(jié)果顯示，二甲雙胍可用于清除上皮起源的非侵入性的腫瘤，即早期原位癌。EMT 指上皮細(xì)胞通過特定程序轉(zhuǎn)化為具有間質(zhì)表型細(xì)胞的生物學(xué)過程，從而使其獲得侵襲和轉(zhuǎn)移的能力[14]。E-cadherin和Vimentin分別是上皮細(xì)胞和間質(zhì)細(xì)胞的重要生物標(biāo)志物[15-16]。Vazquez-Martin等[17]發(fā)現(xiàn)，在高侵襲性乳腺癌細(xì)胞中，二甲雙胍對(duì)由TGFβ信號(hào)通路誘導(dǎo)的EMT 過程有抑制作用，表現(xiàn)為TGFβ介導(dǎo)的E-cadherin下調(diào)與Vimentin上調(diào)消失。因此，二甲雙胍在mRNA 和蛋白水平上，可抑制前列腺癌Vcap細(xì)胞的EMT，并顯著抑制腫瘤細(xì)胞的侵襲和遷移能力[18]。本試驗(yàn)為回顧性研究，可能存在選擇性偏倚，但對(duì)糖尿病與前列癌關(guān)系的總體結(jié)論影響不大。本研究結(jié)果表明，二甲雙胍在有效控制血糖的同時(shí)，可以降低前列腺癌的發(fā)病率。因此，二甲雙胍可能會(huì)為前列腺癌特別是伴有糖尿病的患者提供新的臨床治療選擇。既往研究多基于動(dòng)物模型，只有少部分為已明確診斷為前列腺癌的回顧性研究。本研究首次從前列腺癌相關(guān)腫瘤標(biāo)記物角度探討糖尿病與前列腺癌的關(guān)系，且從血糖水平及其相關(guān)藥物等多方面綜合性分析了二者的關(guān)系。糖尿病降低前列腺癌風(fēng)險(xiǎn)的機(jī)制一直是研究的熱點(diǎn)。Jayachan-dran曾提出糖尿病降低前列腺癌風(fēng)險(xiǎn)可能與肥胖和種族有關(guān)[19]，也有學(xué)者認(rèn)為HNF1B 和JAZF1是糖尿病和前列癌的關(guān)系所在[20]，總之，糖尿病與前列癌的關(guān)系仍需進(jìn)一步探討。

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Effect of metformin on plasma PSA level of type 2 diabetes and the relationship between metformin and prostate cancer

GUO Ying,WU Bo*

(The First Endocrinology Ward,Shengjing Hospital of China Medical University,Shenyang 110004,China)

Objective To observe the effect of metformin on plasma PSA of T2DM patients,and explore the relationship between metformin and prostate cancer.Methods 178 cases of T2DM male patients of Department of Endocrinology in our hospital from January to August 2014 were collected as experimental group,and 96 healthy men were chose as control group.Patients with previous or simultaneous with prostate disease or other malignant tumor,acute infection (including active tuberculosis) and serious liver and kidney injury were excluded.The retrospective case-control analysis for the clinical data and related auxiliary examination results of the cases in the two groups were done.Results ①The level of PSA in experimental group was lower than that of control group (P<0.05).②In T2DM patients,the total PSA and free PSA levels in patients using metformin were obviously lower than the patients without using metformin group (P<0.01,P<0.05).Conclusion The plasma PSA level in patients with T2DM was lower than that of healthy people,and metformin may reduce the risk of prostate cancer.

Metformin;Type 2 diabetes;PSA;Prostate cancer

2014-05-11

中國醫(yī)科大學(xué)附屬盛京醫(yī)院第一內(nèi)分泌病房，沈陽 110004

*通信作者

10.14053/j.cnki.ppcr.201504010