李倩，馬力文

北京大學(xué)第三醫(yī)院腫瘤化療與放射病科，北京1001910

高胰島素血癥和高血糖癥是確認(rèn)的致癌風(fēng)險(xiǎn)因素，不僅因?yàn)榻堤撬幬飼?huì)影響胰島素的濃度，同時(shí)，也因其會(huì)直接影響細(xì)胞的生長、增殖與代謝，從而可能對腫瘤發(fā)生的風(fēng)險(xiǎn)有不同的影響。本文結(jié)合現(xiàn)有的研究及報(bào)道，對不同降糖藥物的機(jī)制及其對惡性腫瘤的影響作一綜述。

1 胰島素增敏劑

1.1 二甲雙胍

二甲雙胍抗腫瘤的機(jī)制主要是通過直接作用于癌細(xì)胞和間接作用于胰島素以降低血糖水平而發(fā)揮作用[1]。

1.1.1 直接作用機(jī)制MTOR信號(hào)通路是促進(jìn)癌癥發(fā)生、發(fā)展的重要通路。二甲雙胍能夠通過影響線粒體氧化磷酸化途徑，從而導(dǎo)致能量應(yīng)激和腺苷三磷酸（adenosine triphosphate，ATP）合成減少[2]。ATP水平降低會(huì)激活單磷酸腺苷活化蛋白激酶（adenosine monophosphate‐activated protein kinase，AMPK），而AMPK的激活會(huì)抑制MTOR信號(hào)通路[3]。此外，二甲雙胍可能也會(huì)通過AMPK非依賴的方式，即通過降低胰島素和胰島素樣生長因子（insu‐lin‐like growth factor，ⅠGF）水平而抑制MTOR信號(hào)通路[4]。二甲雙胍還可以通過激活肝臟激酶B1‐單磷酸腺苷活化蛋白激酶（liver kinase B1‐AMPK，LKB1‐AMPK）途徑抑制腫瘤的生長[5]。通過激活細(xì)胞周期抑制因子如p53、p21、cyclinD1，抑制腫瘤增殖和誘導(dǎo)凋亡[6‐7]。通過降低活性氧類（reactive oxygen species，ROS）物質(zhì)的產(chǎn)生、還原型輔酶Ⅰ（nicotinamide adenine dinucleotide，NADH）的利用而干擾線粒體氧化磷酸化[2]。通過抑制非折疊蛋白反應(yīng)（unfolded protein response，UPR）誘導(dǎo)凋亡，通過干擾脂肪酸代謝刺激免疫系統(tǒng)產(chǎn)生CD8T細(xì)胞[1]。通過抑制缺氧誘導(dǎo)因子‐1（hypoxia inducible factor‐1，HⅠF‐1）和血管內(nèi)皮生長因子（vascular en‐do‐thelial growth factor，VEGF）的表達(dá)，從而抑制癌細(xì)胞在低氧環(huán)境下的生長、血管生成和腫瘤轉(zhuǎn)移[8]，同時(shí)也會(huì)干擾P糖蛋白的多藥耐藥基因（multidrug resistance 1，MDR1）表達(dá)[2]。

1.1.2 間接作用機(jī)制主要的間接作用是通過抑制肝糖異生降低血糖水平，減少胃腸葡萄糖吸收和降低循環(huán)胰島素水平[6]。主要是以LKB1/AMPK依賴和（或）非依賴的方式抑制糖異生[9]。通過肝細(xì)胞的單磷酸腺苷（adenosine monophosphate，AMP）蓄積而減少胰高糖素依賴的葡萄糖分泌[10]。此外，二甲雙胍會(huì)通過減弱κ基因結(jié)合核因子（nu‐clear factor‐kappa‐gene binding，NF‐κB）的活性從而抑制炎性反應(yīng)的發(fā)生[11]，并可通過破壞腫瘤干細(xì)胞的上皮間質(zhì)轉(zhuǎn)化（epithelial mesenchymal transition，EMT）預(yù)防轉(zhuǎn)移進(jìn)程和腫瘤侵襲[12]。

1.1.3 二甲雙胍對不同癌種的影響研究顯示，二甲雙胍可降低乳腺癌、胰腺癌、肝癌、結(jié)直腸癌、前列腺癌、肺癌、卵巢癌、腎癌及頭頸部癌的發(fā)生風(fēng)險(xiǎn)[13‐22]，詳見表1?；仡櫺躁?duì)列研究顯示，二甲雙胍并不能改善晚期胰腺癌患者的生存質(zhì)量[23]，反而會(huì)增加男性患者結(jié)直腸癌的發(fā)生率[14]。然而，另一些研究認(rèn)為，二甲雙胍與喉癌等其他腫瘤的發(fā)病風(fēng)險(xiǎn)無關(guān)[24‐25]。以上爭議的原因可能是因?yàn)檠芯恐胁±x擇的偏倚及病例數(shù)量的不足所造成的：二甲雙胍常被用于患病時(shí)間短，無禁忌證（禁忌證如存在年齡大，合并肝腎功能疾病等）的患者，而這些禁忌證本身也會(huì)影響到腫瘤的發(fā)生風(fēng)險(xiǎn)。

因此，截至目前，雖然尚無明確結(jié)論表明二甲雙胍能夠降低腫瘤風(fēng)險(xiǎn)，但至少可以肯定的是，二甲雙胍不會(huì)增加其風(fēng)險(xiǎn)，因此，二甲雙胍是一種安全用藥。

1.2 噻唑烷二酮類藥物

1.2.1 機(jī)制噻唑烷二酮類屬于過氧化物酶體增生物激活受體γ（peroxisome proliferator‐activated re‐ceptor gamma，PPARγ）激動(dòng)劑。激活PPAR可降低胰島素抵抗和改善血糖控制。體內(nèi)外研究顯示，噻唑烷二酮類化合物（thiazolidinedione，TZD）（尤其是曲格列酮和環(huán)格列酮）通過影響PPARγ途徑促進(jìn)細(xì)胞周期捕獲和凋亡[26]。與此同時(shí)，還存在PPARγ非依賴的抗腫瘤作用機(jī)制：通過抑制B細(xì)胞淋巴瘤‐2基因（B‐cell lymphoma‐2，Bcl‐2）和 Bcl‐xL的抗凋亡活性，導(dǎo)致Caspase依賴的癌細(xì)胞凋亡[26]。TZD還可通過切除特異性蛋白1（specificity pro‐tein 1，Sp1）抑制癌細(xì)胞增殖、轉(zhuǎn)移，降解Sp1會(huì)使雄激素受體（androgen receptor，AR）、前列腺特異性抗原（prostate specific antigen，PSA）、雌激素受體（estrogen receptor，ER）、凋亡抑制基因survivin、表皮生長因子受體（epidermal growth factor receptor，EGFR）和細(xì)胞間黏附分子‐1（intercellular cell adhe‐sion molecule‐1，ⅠCAM‐1）和血管細(xì)胞黏附分子‐1（vascular cell adhesion molecule 1，VCAM‐1）減少[26]。

1.2.2 噻唑烷二酮類對不同癌種的影響有研究發(fā)現(xiàn)，TZD使用者可降低乳腺癌、肺癌、肝癌、卵巢癌、前列腺癌、結(jié)直腸癌、腎癌、胰腺癌和甲狀腺癌的發(fā)生風(fēng)險(xiǎn)[27‐32]，詳見表1。在甲狀腺癌和軟組織肉瘤中，聯(lián)合化療還會(huì)減少癌細(xì)胞的化療耐藥，增強(qiáng)抗腫瘤活性[33]。相反，也有報(bào)道顯示，TZD會(huì)增加膀胱癌[34]、惡性黑色素瘤及非霍奇金淋巴瘤[31]的癌癥發(fā)生風(fēng)險(xiǎn)。

2 胰島素促泌劑

磺脲類藥物通過關(guān)閉胰腺β細(xì)胞的鉀通道，一方面會(huì)導(dǎo)致空腹和餐后胰島素水平升高，進(jìn)而促進(jìn)腫瘤生長，而另一方面是關(guān)閉鉀通道本身就具有抗腫瘤效應(yīng)[35]。有研究顯示，使用磺脲類藥物的糖尿病患者的患癌風(fēng)險(xiǎn)會(huì)明顯增加，可增加結(jié)腸癌和肝癌的發(fā)生風(fēng)險(xiǎn)[36‐37]。同時(shí)也有研究顯示，胰島素或磺脲類藥物會(huì)降低28%前列腺癌的發(fā)生風(fēng)險(xiǎn)[38]。另外有研究發(fā)現(xiàn)，格列苯脲對卵巢癌細(xì)胞的浸潤和轉(zhuǎn)移有抑制作用[35]，但該結(jié)論也存在爭議[39]。一項(xiàng)來自英國的回顧性隊(duì)列研究發(fā)現(xiàn)：磺脲類較二甲雙胍的致癌風(fēng)險(xiǎn)高36%，但也不能排除其中的偏倚因素：醫(yī)務(wù)人員更傾向于給偏瘦的患者開磺脲類藥物[40]。另有來自15項(xiàng)研究的薈萃分析顯示，二甲雙胍可降低11%的結(jié)直腸癌患病風(fēng)險(xiǎn)，而磺脲類和胰島素會(huì)分別增加11%與33%結(jié)直腸癌的患病風(fēng)險(xiǎn)，但是差異無統(tǒng)計(jì)學(xué)意義[16]。

3 胰島素及胰島素類似物

Dejgaard等[41]發(fā)現(xiàn)使用胰島素類似物雖然比使用胰島素的患癌風(fēng)險(xiǎn)低，但使用長效胰島素類似物（甘精胰島素或地特胰島素）仍然存在致癌風(fēng)險(xiǎn)[42]。Karlstad等[43]發(fā)現(xiàn)使用胰島素的糖尿病患者除了前列腺癌的患病風(fēng)險(xiǎn)降低外，肝癌、胰腺癌、腎癌、胃癌和呼吸系統(tǒng)惡性腫瘤的發(fā)生風(fēng)險(xiǎn)均明顯升高；甘精胰島素使用者結(jié)腸癌的患病風(fēng)險(xiǎn)降低，而乳腺癌的患病風(fēng)險(xiǎn)升高。體外研究中，甘精胰島素在乳腺癌細(xì)胞、人類子宮內(nèi)膜癌和結(jié)直腸癌細(xì)胞中均發(fā)揮抗凋亡作用[44]。有研究顯示，甘精胰島素使用者胰腺癌和前列腺癌的患病風(fēng)險(xiǎn)會(huì)增加。另外一些研究顯示，甘精胰島素不會(huì)增加使用者的患癌風(fēng)險(xiǎn)[45‐46]。但以上研究存在隨訪時(shí)間短等局限性，結(jié)論并不十分可靠。有薈萃分析顯示，使用更高劑量的胰島素也沒有導(dǎo)致癌癥的發(fā)生率增高[47]。因此，對于未控的糖尿病，不應(yīng)該因?yàn)轭檻]患癌風(fēng)險(xiǎn)而延遲使用胰島素進(jìn)行治療。

表1 不同降糖藥物對致癌風(fēng)險(xiǎn)的影響

4 基于腸促胰素的藥物（GLP- 1激動(dòng)劑，DDP- 4-i）

腸促胰素來自于腸，攝食后的反射性分泌會(huì)使血糖升高之前刺激胰島素分泌。針對2型糖尿病患者腸促胰素活性缺乏的情況，人們研究出針對腸促胰素治療的藥物，根據(jù)其不同的作用機(jī)制分為胰升糖素樣肽 1（glucagon‐like peptide‐1，GLP‐1）受體激動(dòng)劑和二肽基肽酶4（dipeptidyl‐peptidase 4 inhibitor，DPP‐4）抑制劑兩類藥物。

基于美國食品藥品監(jiān)督管理局的分析數(shù)據(jù)報(bào)道的不良事件，GLP‐1受體激動(dòng)劑艾塞那肽以及DPP‐4抑制藥物西他列汀已受到質(zhì)疑[48]。這兩類藥物可能會(huì)增加惡性腫瘤的發(fā)生風(fēng)險(xiǎn)，尤其是增加甲狀腺癌和胰腺癌的發(fā)生風(fēng)險(xiǎn)。

GLP‐1激動(dòng)劑治療會(huì)誘導(dǎo)嚙齒類動(dòng)物甲狀腺C細(xì)胞的成癌性，但是在人類甲狀腺C細(xì)胞中并未發(fā)現(xiàn)類似效應(yīng)，可能因?yàn)镚LP‐1受體在嚙齒類動(dòng)物和人類細(xì)胞中的濃度不同（在嚙齒類動(dòng)物細(xì)胞中濃度高，在人類細(xì)胞中濃度低）[49]。Nauck等[50]發(fā)現(xiàn)GLP‐1激動(dòng)劑治療不會(huì)導(dǎo)致糖尿病患者的甲狀腺髓樣癌。

二肽基肽酶‐4抑制劑（dipeptidyl peptidase‐4 inhibitor，DDP‐4‐i）會(huì)通過抑制 DDP‐4酶阻斷對GLP‐1的降解。有研究表明，GLP‐1激動(dòng)劑或DDP‐4‐i可增加胰腺癌的發(fā)生風(fēng)險(xiǎn)[51]。但也有研究發(fā)現(xiàn)，利拉魯肽可通過抑制PⅠ3K/AKT途徑發(fā)揮對胰腺癌的抗腫瘤活性作用[52]。艾塞那肽可抑制小鼠前列腺癌細(xì)胞和結(jié)腸癌細(xì)胞的增殖，加速乳腺癌細(xì)胞的凋亡[53]。Gokhale等[54]研究發(fā)現(xiàn) DDP‐4‐i使用者胰腺癌的發(fā)生風(fēng)險(xiǎn)低于磺脲類使用者，而與TZD使用者胰腺癌的發(fā)生風(fēng)險(xiǎn)類似。有研究顯示，西他列汀也會(huì)減少鼠類的腸癌發(fā)生風(fēng)險(xiǎn)[55]。在其他研究中未發(fā)現(xiàn)DDP‐4‐i的促腫瘤活性作用[56]。GLP‐1受體激動(dòng)劑和DDP‐4‐i抑制劑還可潛在地增加急性胰腺炎的不良反應(yīng)，這可能會(huì)增加約2倍患胰腺癌的風(fēng)險(xiǎn)[48]。然而，另外一項(xiàng)回顧性分析[57]以及一項(xiàng)融合了25個(gè)研究的薈萃分析[58]均無法證明胰腺癌與艾塞那肽的相關(guān)性。

所以，基于腸促胰素的治療風(fēng)險(xiǎn)和獲益仍然是一個(gè)有爭議的問題，由于疾病的演化及進(jìn)展需要很長的時(shí)間[59]，故需要開展長期前瞻性研究設(shè)計(jì)來分析它們具體的預(yù)后（胰腺炎、胰腺癌、甲狀腺髓樣癌）[60]。目前研究的數(shù)據(jù)尚不足以證明基于腸促胰素的治療會(huì)增加癌癥的發(fā)生風(fēng)險(xiǎn)。

5 α-葡萄糖苷酶抑制劑

α‐葡萄糖苷酶抑制劑競爭性抑制位于小腸的各種α‐葡萄糖苷酶，使淀粉類分解為葡萄糖的速度減慢，從而減緩腸道內(nèi)葡萄糖的吸收，降低餐后高血糖。有研究發(fā)現(xiàn)，α‐葡萄糖苷酶抑制劑使用者會(huì)降低胃癌、肺癌的發(fā)生風(fēng)險(xiǎn)，但會(huì)增加腎癌的發(fā)生風(fēng)險(xiǎn)[19,61‐62]。

6 小結(jié)

不同種類的降糖藥物在腫瘤的發(fā)生、發(fā)展過程中可以產(chǎn)生不同的影響，相關(guān)的研究尚存在爭論。主要原因?yàn)橐陨涎芯慷酁榛仡櫺匝芯浚嬖谌虢M偏倚及隨訪時(shí)間較短的缺陷。因此，需要大規(guī)模長期隨訪的前瞻性研究來進(jìn)一步驗(yàn)證各種降糖藥物在不同癌種中可能的作用及機(jī)制。

[1]Kourelis TV,Siegel RD.Metformin and cancer:new appli‐cations for an old drug[J].Med Oncol,2012,29(2):1314‐1327.

[2]Pollak MN.Ⅰnvestigating metformin for cancer prevention and treatment:the end of the beginning[J].Cancer Discov,2012,2(9):778‐790.

[3]Schmelzle T,Hall MN.TOR,a central controller of cell growth[J].Cell,2000,103(2):253‐262.

[4]Memmott RM,Dennis PA.LKB1 and mammalian target of rapamycin as predictive factors for the anticancer efficacy of metformin[J].J Clin Oncol,2009,27(34):e226;author reply e227.

[5]Evans JM,Donnelly LA,Emslie‐Smith AM,et al.Metfor‐min and reduced risk of cancer in diabetic patients[J].Bmj,2005,330(7503):1304‐1305.

[6]Rattan R,Ali Fehmi R,Munkarah A.Metformin:an emerg‐ing new therapeutic option for targeting cancer stem cells and metastasis[J].J Oncol,2012,2012(3):928127.

[7]Rosta A.Diabetes and cancer risk:oncologic considerations[J].Orv Hetil,2011,152(29):1144‐1155.

[8]Tadakawa M,Takeda T,Li B,et al.The anti‐diabetic drug metformin inhibits vascular endothelial growth factor ex‐pression via the mammalian target of rapamycin complex 1/hypoxia‐inducible factor‐1α signaling pathway in ELT‐3 cells[J].Mol Cell Endocrinol,2015,399(5):1‐8.

[9]Pollak M.Potential applications for biguanides in oncology[J].J Clin Ⅰnvest,2013,123(9):3693‐3700.

[10]Miller RA,Chu Q,Xie J,et al.Biguanides suppress hepat‐ic glucagon signalling by decreasing production of cyclic AMP[J].Nature,2013,494(7436):256‐260.

[11]Hirsch HA,Ⅰliopoulos D,Struhl K.Metformin inhibits the inflammatory response associated with cellular transforma‐tion and cancer stem cell growth[J].Proc Natl Acad Sci USA,2013,110(3):972‐977.

[12]Mani SA,Guo W,Liao MJ,et al.The epithelial‐mesenchy‐mal transition generates cells with properties of stem cells[J].Cell,2008,133(4):704‐715.

[13]Vazquez‐Martin A,Oliveras‐Ferraros C,Del Barco S,et al.The anti‐diabetic drug metformin suppresses self‐re‐newal and proliferation of trastuzumab‐resistant tumor‐ini‐tiating breast cancer stem cells[J].Breast Cancer Res Treat,2011,126(2):355‐364.

[14]Bodmer M,Becker C,Meier C,et al.Use of antidiabetic agents and the risk of pancreatic cancer:a case‐control analysis[J].Am J Gastroenterol,2012,107(4):620‐626.

[15]Lee MS,Hsu CC,Wahlqvist ML,et al.Type 2 diabetes in‐creases and metformin reduces total,colorectal,liver and pancreatic cancer incidences in Taiwanese:a representa‐tive population prospective cohort study of 800,000 indi‐viduals[J].BMC Cancer,2011,11(1):1‐10.

[16]Singh S,Singh H,Singh PP,et al.Antidiabetic medica‐tions and the risk of colorectal cancer in patients with dia‐betes mellitus:a systematic review and meta‐analysis[J].Cancer Epidemiol Biomarkers Prev,2013,22(12):2258‐2268.

[17]Murtola TJ,Tammela TL,Lahtela J,et al.Antidiabetic medication and prostate cancer risk:a population‐based case‐control study[J].Am J Epidemiol,2008,168(8):925‐931.

[18]Tan BX,Yao WX,Ge J,et al.Prognostic influence of met‐formin as first‐line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes[J].Can‐cer,2011,117(22):5103‐5111.

[19]Lai SW,Liao KF,Chen PC,et al.Antidiabetes drugs corre‐late with decreased risk of lung cancer:a population‐based observation in Taiwan[J].Clin Lung Cancer,2012,13(2):143‐148.

[20]Gotlieb WH,Saumet J,Beauchamp MC,et al.Ⅰn vitro met‐formin anti‐neoplastic activity in epithelial ovarian cancer[J].Gynecol Oncol,2008,110(2):246‐250.

[21]Yang FQ,Wang JJ,Yan JS,et al.Metformin inhibits cell growth by upregulating microRNA‐26a in renal cancer cells[J].Ⅰnt J Clin Exp Med,2014,7(10):3289‐3296.

[22]Rêgo DF,Pavan LM,Elias ST,et al.Effects of metformin on head and neck cancer:a systematic review[J].Oral On‐col,2015,51(5):416‐422.

[23]Hwang AL,Haynes K,Hwang WT,et al.Metformin and survival in pancreatic cancer:a retrospective cohort study[J].Pancreas,2013,42(7):1054‐1059.

[24]Becker C,Jick SS,Meier CR,et al.Metformin and the risk of head and neck cancer:a case‐control analysis[J].Diabetes Obes Metab,2014,16(11):1148‐1154.

[25]Stevens RJ,Ali R,Bankhead CR,et al.Cancer outcomes and all‐cause mortality in adults allocated to metformin:systematic review and collaborative meta‐analysis of ran‐domised clinical trials[J].Diabetologia,2012,55(10):2593‐2603.

[26]Wei S,Yang J,Lee SL,et al.PPARgamma‐independent an‐titumor effects of thiazolidinediones[J].Cancer Letters,2009,276(2):119‐124.

[27]Monami M,Dicembrini Ⅰ,Mannucci E.Thiazolidinedio‐nes and cancer:results of a meta‐analysis of randomized clinical trials[J].Acta Diabetol,2014,51(1):91‐101.

[28]ColmersⅠN,Bowker SL,Johnson JA.Thiazolidinedione use and cancer incidence in type 2 diabetes:a systematic review and meta‐analysis[J].Diabetes Metab,2012,38(6):475‐484.

[29]Chang CH,Lin JW,Wu LC,et al.Association of thiazoli‐dinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus[J].Hepatology,2012,55(5):1462‐1472.

[30]Joshi H,Pal T,Ramaa CS.A new dawn for the use of thia‐zolidinediones in cancer therapy[J].Expert OpinⅠnvestig Drugs,2014,23(4):501‐510.

[31]Ferrara A,Lewis JD,Quesenberry CP Jr,et al.Cohort study of pioglitazone and cancer incidence in patients with diabetes[J].Diabetes Care,2011,34(4):923‐929.

[32]Feng YH,Velazquez‐Torres G,Gully C,et al.The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth[J].J Cell Mol Med,2011,15(4):825‐836.

[33]Fr?hlich E,Wahl R.Chemotherapy and Chemoprevention by Thiazolidinediones[J].Biomed ResⅠnt,2015,2015:1‐14.

[34]Turner RM,Kwok CS,Chen‐Turner C,et al.Thiazolidine‐diones and associated risk of bladder cancer:a systematic review and meta‐analysis[J].Br J Clin Pharmacol,2014,78(2):258‐273.

[35]Yasukagawa T,Niwa Y,Simizu S,et al.Suppression of cellular invasion by glybenclamide through inhibited se‐cretion of platelet‐derived growth factor in ovarian clear cell carcinoma ES‐2 cells[J].FEBS Lett,2012,586(10):1504‐1509.

[36]Chang CH,Lin JW,Wu LC,et al.Oral insulin secreta‐gogues,insulin,and cancer risk in type 2 diabetes mellitus[J].J Clin Endocrinol Metab,2012,97(7):E1170‐E1175.

[37]Hsieh MC,Lee TC,Cheng SM,et al.The influence of type 2 diabetes and glucose‐lowering therapies on cancer risk in the Taiwanese[J].Exp Diabetes Res,2012,2012(5):413782.

[38]González‐Pérez A,García Rodríguez LA.Prostate cancer risk among men with diabetes mellitus(Spain)[J].Cancer Causes Control,2005,16(9):1055‐1058.

[39]Pasello G,Urso L,Conte P,et al.Effects of sulfonylureas on tumor growth:a review of the literature[J].Oncologist,2013,18(10):1118‐1125.

[40]Currie CJ,Poole CD,Gale EA.The influence of glucose‐lowering therapies on cancer risk in type 2 diabetes[J].Di‐abetologia,2009.52(9):1766‐1777.

[41]Dejgaard A,Lynggaard H,R?stam J,et al.No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir:a meta‐analysis[J].Diabetolo‐gia,2009,52(12):2507‐2512.

[42]Buchs AE,Silverman BG.Ⅰncidence of malignancies in patients with diabetes mellitus and correlation with treat‐ment modalities in a largeⅠsraeli health maintenance orga‐nization:a historical cohort study[J].Metabolism,2011,60(10):1379‐1385.

[43]Karlstad O,Starup‐Linde J,Vestergaard P,et al.Use of in‐sulin and insulin analogs and risk of cancer‐systematic re‐view and meta‐analysis of observational studies[J].Curr Drug Saf,2013,8(5):333‐348.

[44]Aizen D,Sarfstein R,BruchimⅠ,et al.Proliferative and signaling activities of insulin analogues in endometrial cancer cells[J].Mol Cell Endocrinol,2015,406(18):27‐39.

[45]Lim S,Stember KG,He W,et al.Electronic medical re‐cord cancer incidence over six years comparing new users of glargine with new users of NPH insulin[J].PLoS One,2014,9(10):e109433.

[46]Bordeleau L,Gerstein HC.The association of basal insu‐lin glargine and/or n‐3 fatty acids with incident cancers in patients with dysglycemia[J].Diabetes Care,2014,37(10):e216.

[47]Johnson JA,Bowker SL.Ⅰntensive glycaemic control and cancer risk in type 2 diabetes:a meta‐analysis of major tri‐als[J].Diabetologia,2011,54(1):25‐31.

[48]Elashoff M,Matveyenko AV,Gier B,et al.Pancreatitis,pancreatic,and thyroid cancer with glucagon‐like peptide‐1‐based therapies[J].Gastroenterology,2011,141(1):150‐156.

[49]Samson SL,Garber A.GLP‐1R agonist therapy for diabe‐tes:benefits and potential risks[J].Curr Opin Endocrinol Diabetes Obes,2013,20(2):87‐97.

[50]Nauck MA,Friedrich N.Do GLP‐1‐based therapies in‐crease cancer risk?[J].Diabetes Care,2013,36 Suppl 2:S245‐S252.

[51]Tseng CH,Lee KY,Tseng FH.An updated review on can‐cer risk associated with incretin mimetics and enhancers[J].J Environ Sci Health C Environ Carcinog Ecotoxicol Rev,2015,33(1):67‐124.

[52]Chalmer T,Almdal TP,Vilsb?ll T,et al.Adverse drug reac‐tions associated with the use of liraglutide in patients with type 2 diabetes——focus on pancreatitis and pancreas can‐cer[J].Expert Opin Drug Saf,2015,14(1):171‐180.

[53]Nomiyama T,Kawanami T,Ⅰrie S,et al.Exendin‐4,a GLP‐1 receptor agonist,attenuates prostate cancer growth[J].Diabetes,2014,63(11):3891‐3905.

[54]Gokhale M,Buse JB,Gray CL,et al.Dipeptidyl‐peptidase‐4 inhibitors and pancreatic cancer:a cohort study[J].Dia‐betes Obes Metab,2014,16(12):1247‐1256.

[55]Femia AP,Raimondi L,Maglieri G,et al.Long‐term treat‐ment with Sitagliptin,a dipeptidyl peptidase‐4 inhibitor,reduces colon carcinogenesis and reactive oxygen species in 1,2‐dimethylhydrazine‐induced rats[J].Ⅰnt J Cancer,2013,133(10):2498‐2503.

[56]Simó R,Plana‐Ripoll O,Puente D,et al.Ⅰmpact of glu‐cose‐lowering agents on the risk of cancer in type 2 diabet‐ic patients.The Barcelona case‐control study[J].PLoS One,2013,8(11):e79968.

[57]Romley JA,Goldman DP,Solomon M,et al.Exenatide therapy and the risk of pancreatitis and pancreatic cancer in a privately insured population[J].Diabetes Technol Ther,2012,14(10):904‐911.

[58]Alves C,Batel‐Marques F,Macedo AF.A meta‐analysis of serious adverse events reported with exenatide and liraglu‐tide:acute pancreatitis and cancer[J].Diabetes Res Clin Pract,2012,98(2):271‐284.

[59]Yachida S,Jones S,BozicⅠ,et al.Distant metastasis oc‐curs late during the genetic evolution of pancreatic cancer[J].Nature,2010,467(7319):1114‐1117.

[60]Egan AG,Blind E,Dunder K,et al.Pancreatic safety of in‐cretin‐based drugs——FDA and EMA assessment[J].N Engl J Med,2014,370(9):794‐797.

[61]Chen YL,Cheng KC,Lai SW,et al.Diabetes and risk of subsequent gastric cancer:a population‐based cohort study in Taiwan[J].Gastric Cancer,2013,16(3)389‐396.

[62]Lai SW,Liao KF,Lai HC,et al.Kidney cancer and diabe‐tes mellitus:a population‐based case‐control study in Tai‐wan[J].Ann Acad Med Singapore,2013,42(3):120‐124.