張磊 綜述 何飛 審校

(鄭州大學(xué)第一附屬醫(yī)院心內(nèi)科， 河南 鄭州450052)

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他汀類藥物致新發(fā)糖尿病機(jī)制的研究進(jìn)展

張磊 綜述 何飛 審校

(鄭州大學(xué)第一附屬醫(yī)院心內(nèi)科， 河南 鄭州450052)

大量的臨床實(shí)驗(yàn)結(jié)果證實(shí)，他汀類藥物不僅能大幅度降低膽固醇，還可以顯著減少心血管事件，如心絞痛、心肌梗死、冠心病死亡等。然而，近期的臨床研究提示他汀類藥物可以增加患者新發(fā)糖尿病的風(fēng)險(xiǎn)，他汀類藥物與新發(fā)糖尿病的關(guān)系引起廣泛關(guān)注。目前，他汀類藥物引發(fā)糖尿病的具體機(jī)制仍不清楚?，F(xiàn)對近年來有關(guān)他汀類藥物引發(fā)糖尿病的機(jī)制研究進(jìn)展予以綜述。

他汀類藥物；糖尿?。粰C(jī)制

他汀類藥物，即3-羥-3-甲基戊二酰輔酶A(3-hydroxy-3-methyglutaryl coenzyme A, HMG-COA)還原酶抑制劑，因能有效降低人體內(nèi)低密度脂蛋白膽固醇(low-density lipoprotein cholesterol, LDL-C)水平，而廣泛應(yīng)用于心血管的一級和二級預(yù)防。而新近的研究發(fā)現(xiàn)，他汀類藥物也可能對人體血糖水平產(chǎn)生影響，導(dǎo)致患者血糖水平升高，增加新發(fā)糖尿病的風(fēng)險(xiǎn)。但他汀類藥物致新發(fā)糖尿病的具體機(jī)制仍不清楚，現(xiàn)簡要綜述他汀類藥物致新發(fā)糖尿病的相關(guān)機(jī)制。

1 他汀類藥物對胰腺β細(xì)胞胰島素分泌的作用

1.1 抑制β細(xì)胞內(nèi)ATP等代謝產(chǎn)物的生成

他汀類藥物主要抑制HMG-COA還原酶，因而減少了中間產(chǎn)物甲羥戊酸的合成。甲羥戊酸為類異戊二烯的前體，也是合成輔酶Q10的必需物。當(dāng)甲羥戊酸缺乏時(shí)，必然導(dǎo)致細(xì)胞內(nèi)類異戊二烯和輔酶Q10合成障礙。輔酶Q10是線粒體電子傳遞鏈中重要的電子載體，其含量的降低使電子傳遞減緩，致胰腺β細(xì)胞ATP生成減少，從而使胰島素分泌受抑制[1]。

1.2 抑制β細(xì)胞L型鈣通道

葡萄糖經(jīng)葡萄糖轉(zhuǎn)運(yùn)體-2(glucose transporters-2,GLUT-2)攝入β細(xì)胞，由葡萄糖激酶磷酸化為6-磷酸葡萄糖后啟動(dòng)級聯(lián)反應(yīng)，使ATP依賴的鉀通道關(guān)閉，細(xì)胞膜去極化，L型鈣通道開放，鈣離子內(nèi)流，致含有胰島素的微粒分泌[2]。葡萄糖可以刺激β細(xì)胞內(nèi)游離鈣離子升高，他汀類藥物則可能抑制此過程，阻斷電壓門控鈣通道，減少葡萄糖誘導(dǎo)的胰島素分泌。辛伐他汀能抑制胰島素分泌，但普伐他汀則無此作用[3]。Yada等[3]利用大鼠進(jìn)行的實(shí)驗(yàn)表明：當(dāng)胰腺β細(xì)胞攝取他汀后，胰島素分泌會減少，這是由于受葡萄糖激動(dòng)引起的胞漿中鈣離子和L型鈣通道的開放增加這一過程被抑制所致，且這些抑制作用與他汀的脂溶性高低相平行，而水溶性他汀沒有類似效應(yīng)。細(xì)胞膜上的膽固醇具有調(diào)控細(xì)胞功能的效應(yīng)。膽固醇能維持β細(xì)胞電壓鈣通道的正常功能，且對于胰島素顆粒的動(dòng)員及其與細(xì)胞膜的融合至關(guān)重要。他汀類藥物的降脂作用可能導(dǎo)致β細(xì)胞膜膽固醇異常[4]。Xia 等[5]通過抑制β細(xì)胞株MIN6細(xì)胞的鯊烯環(huán)氧酶來減少膽固醇分泌，發(fā)現(xiàn)膽固醇缺乏時(shí)會抑制細(xì)胞膜上的電壓門控鈣通道，減少由葡萄糖刺激的胰島素釋放。而膽固醇充足時(shí)，這一現(xiàn)象會逆轉(zhuǎn)，提示胰島素分泌減少可能與細(xì)胞內(nèi)膽固醇耗盡有關(guān)。由于他汀類藥物能大幅度降低膽固醇，因而可能會導(dǎo)致胰島素釋放減少。

1.3 誘導(dǎo)β細(xì)胞程序性細(xì)胞死亡

與機(jī)體其他組織細(xì)胞相比，胰腺β細(xì)胞容易受到氧化和炎癥損傷并且極易程序性細(xì)胞死亡[6]，而脂蛋白可調(diào)節(jié)β細(xì)胞的生存[7]。Rütti等[8]發(fā)現(xiàn)， LDL-C不但減少由葡萄糖刺激的胰島素分泌，還可抑制β細(xì)胞增殖。高密度脂蛋白膽固醇(high-density lipoprotein cholesterol,HDL-C)則可以保護(hù)β細(xì)胞，避免程序性細(xì)胞死亡。盡管他汀類藥物具有降膽固醇和抗炎作用，但其在抑制內(nèi)源性膽固醇合成的同時(shí)，還可能會促使外源性膽固醇激活β細(xì)胞內(nèi)有害的免疫炎癥反應(yīng)[7]。此外，氧化LDL-C可以刺激細(xì)胞內(nèi)的免疫應(yīng)答，激活炎癥的級聯(lián)反應(yīng)，損傷β細(xì)胞的結(jié)構(gòu)與功能，導(dǎo)致胰島素分泌減少[9]。這種炎癥、氧化、程序性細(xì)胞死亡之間的相互作用，被血漿來源的LDL-C進(jìn)一步強(qiáng)化。

1.4 對腺苷三磷酸結(jié)合盒轉(zhuǎn)運(yùn)體1的影響

miRNA-33a是腺苷三磷酸結(jié)合盒轉(zhuǎn)運(yùn)體1(ATP-binding cassette transporter A1,ABCA1)重要調(diào)節(jié)基因，其表達(dá)與胰島細(xì)胞和β細(xì)胞中的ABCA1水平呈負(fù)相關(guān)[10-11]。研究[11-13]發(fā)現(xiàn)胰島細(xì)胞內(nèi)ABCA1水平的變化影響胰島細(xì)胞內(nèi)膽固醇穩(wěn)態(tài)進(jìn)而影響胰島素分泌和誘導(dǎo)β細(xì)胞功能障礙。Allen等[14]證實(shí)辛伐他汀和阿托伐他汀誘導(dǎo)肝細(xì)胞內(nèi)miRNA-33a的表達(dá)，提示他汀類藥物可能通過增加miRNA-33a的表達(dá)進(jìn)而導(dǎo)致胰島素分泌減少最終引發(fā)糖尿病。

2 他汀類藥物對周圍組織攝取、利用葡萄糖的影響

2.1 對脂聯(lián)素的影響

脂聯(lián)素是脂肪細(xì)胞分泌的具有增加胰島素敏感性和抗炎作用的細(xì)胞因子。Koh等[15]薈萃分析了24個(gè)他汀類藥物試驗(yàn)中糖尿病患者和非糖尿病患者胰島素敏感性以及相關(guān)因素(如脂聯(lián)素)的改變，發(fā)現(xiàn)普伐他汀可增加冠心病患者和葡萄糖耐量受損患者的胰島素敏感性和脂聯(lián)素分泌，甚至對無癥狀的高膽固醇血癥患者也有相同作用[16]，但對健康的非糖尿病患者無此作用。有研究[17]證實(shí)瑞舒伐他汀有降低血漿脂聯(lián)素水平和胰島素敏感性的作用，而普伐他汀卻有升高二者的作用。研究[18]發(fā)現(xiàn)匹伐他汀可以改善成熟脂肪細(xì)胞內(nèi)激素敏感脂肪酶的表達(dá)，增加脂聯(lián)素分泌，從而升高胰島素敏感性。

2.2 對周圍組織攝取葡萄糖的影響

葡萄糖轉(zhuǎn)運(yùn)蛋白(glucose transporters，GLUT)是一組協(xié)助轉(zhuǎn)運(yùn)葡萄糖進(jìn)入組織的重要蛋白質(zhì)。其中GLUT1主要分布于腦內(nèi)血管內(nèi)皮細(xì)胞，GLUT2分布于體內(nèi)肝臟、腸、腎臟及胰腺β細(xì)胞，GLUT3分布于神經(jīng)細(xì)胞，GLUT4則主要分布于脂肪細(xì)胞、心肌細(xì)胞和骨骼肌細(xì)胞，而GLUT4活性降低通常被認(rèn)為與胰島素抵抗有關(guān)[19]。當(dāng)胰島素釋放至細(xì)胞外液后，激活胰島素受體(酪氨酸蛋白激酶)，使胰島素受體底物磷酸化，這會增加細(xì)胞膜外GLUT4水平，導(dǎo)致血糖攝取增加。而類異戊二烯化合物能夠上調(diào)細(xì)胞膜上的GLUT4使脂肪細(xì)胞對葡萄糖的攝取增加。Nakata等[20]研究發(fā)現(xiàn)阿托伐他汀可通過抑制類異戊二烯化合物生成，進(jìn)而阻礙2型糖尿病小鼠模型的脂肪細(xì)胞分化成熟和GLUT4表達(dá)，導(dǎo)致脂肪細(xì)胞攝取葡萄糖的顯著減少進(jìn)而引起胰島素抵抗。

2.3 抑制外周組織的胰島素信號轉(zhuǎn)導(dǎo)

他汀類藥物還可能通過影響外周胰島素信號轉(zhuǎn)導(dǎo)來抑制胰島素分泌。動(dòng)物實(shí)驗(yàn)[21]發(fā)現(xiàn)高劑量他汀暴露下調(diào)骨骼肌中Akt和Foxol的表達(dá)，Akt和Foxol是激活胰島素受體底物磷酸化的信號轉(zhuǎn)導(dǎo)通路，進(jìn)而減少GLUT4的表達(dá)，使糖耐量受損。

2.4 對周圍組織的毒性作用

β細(xì)胞[22]、骨骼肌細(xì)胞[23]及脂肪細(xì)胞[24]的線粒體功能障礙被認(rèn)為與糖尿病的發(fā)病機(jī)制有關(guān)。有研究[25]表明他汀類藥物能產(chǎn)生肌肉毒性作用，導(dǎo)致骨骼肌細(xì)胞線粒體功能障礙，影響骨骼肌細(xì)胞對葡萄糖的攝取和利用，從而導(dǎo)致胰島素抵抗及糖尿病。

2.5 對解偶聯(lián)蛋白3的影響

解偶聯(lián)蛋白3被認(rèn)為能阻止線粒體中非酯化型脂肪酸的聚集[26]，研究[27-28]發(fā)現(xiàn)肌細(xì)胞內(nèi)三酰甘油的聚集能降低骨骼肌對胰島素的敏感性。Larsen等[29]發(fā)現(xiàn)服用辛伐他汀降低解偶聯(lián)蛋白3水平進(jìn)而導(dǎo)致胰島素抵抗。有關(guān)解偶聯(lián)蛋白3在服用他汀類藥物致糖尿病中的作用仍需進(jìn)一步研究。

3 結(jié)語

他汀類藥物升高血糖的機(jī)制主要與其影響胰腺β細(xì)胞分泌胰島素及周圍組織對葡萄糖的攝取、利用這兩方面機(jī)制有關(guān)，但具體機(jī)制仍不詳，仍需要進(jìn)一步深入探討。

[1] Sasaki J, Iwashita M, Kono S. Statins: beneficial or adverse for glucose metabolism[J]. J Atheroscler Thromb,2006,13(3):123-129.

[2] Kruit JK, Brunham LR, Verchere CB, et al. HDL and LDL cholesterol significantly influence beta-cell function in type 2 diabetes mellitus[J]. Curr Opin Lipidol,2010,2l(3):178-185.

[3] Yada T, Nakata M, Shiraishi T, et al. Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+signalling and insulin secretion due to blockade of L-type Ca2+channels in rat islet beta-cells[J]. Br J Pharmacol,1999,126(5):1205-1213.

[4] Mascitelli L, Goldstein MR. Statins, cholesterol depletion and risk of incident diabetes[J]. Int J Cardiol, 2011,152(2):275-276.

[5] Xia F, Xie L, Mihic A, et al. Inhibition of cholesterol biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic beta-cells[J]. Endocrinology,2008,149(10):5136-5145.

[6] Sj?holm A, Berggren PO, Cooney RV. Gamma-tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide[J]. Biochem Biophys Res Commun,2000,277(2):334-340.

[7] Roehrich ME, Mooser V, Lenain V, et al. Insulin-secreting beta-cell dysfunction induced by human lipoproteins[J]. J Biol Chem,2003,278(20):18368-18375.

[8] Rütti S, Ehses JA, Sibler RA, et al. Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells[J]. Endocrinology,2009,150(10):4521-4530.

[9] Kruit JK, Kremer PH, Dai L, et al. Cholesterol efflux via ATP-binding cassette transporter A1(ABCAl) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice[J]. Diabetologia,2010,53(6):1110-1119.

[10]Rayner KJ, Suarez Y, Davalos A, et al. MiR-33 contributes to the regulation of cholesterol homeostasis[J]. Science,2010,328(5985):1570-1573.

[11]Wijesekara N, Zhang LH, Kang MH, et al. miR-33a modulates ABCA1 expression, cholesterol accumulation, and insulin secretion in pancreatic islets[J]. Diabetes,2012,61(3):653-658.

[12]Brunham LR, Kruit JK, Pape TD, et al. Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment[J]. Nat Med,2007,13(3):340-347.

[13]Kruit JK, Wijesekara N, Fox JE,et al. Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules[J]. Diabetes,2011,60(12):3186-3196.

[14]Allen RM, Marquart TJ, Albert CJ, et al. miR-33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity[J]. EMBO Mol Med,2012,4(9):882-895.

[15]Koh KK, Sakuma I, Quon MJ. Differential metabolic effects of distinct statins[J]. Atherosclerosis, 2011,215(1):1-8.

[16]Takagi T, Matsuda M, Abe M, et al.Effect of pravastatin on the development of diabetes and adiponectin production[J]. Atherosclerosis,2008,196(1):114-121.

[17]Koh KK, Quon MJ, Sakuma I, et al.Differential metabolic effects of rosuvastatin and pravastatin in hypercholesterolemic patients[J]. Int J Cardiol,2013,166(2):509-515.

[18]Arnaboldi L, Corsini A. Could changes in adiponectin drive the effect of statins on the risk of new-onset diabetes? The case of pitavastatin[J]. Atheroscler Suppl,2015,16:1-27.

[19]Doehner W, Gathercole D, Cicoira M, et al.Reduced glucose transporter GLUT4 in skeletal muscle predicts insulin resistance in non-diabetic chronic heart failure patients independently of body composition[J]. Int J Cardiol,2010,138(1):19-24.

[20]Nakata M, Nagasaka S, Kusaka I, et al. Effects of statins on the adipocyte maturation and expression of glucose transporter 4(SLC2A4): implications in glycaemic control[J].Diabetologia,2006,49(8):1881-1892.

[21]Preiss D, Sattar N. Statins and the risk of new-onset diabetes:a review of recent evidence[J]. Curr Opin Lipidol,2011,22(6):460-466.

[22]Supale S, Li N, Brun T, et al. Mitochondrial dysfunction in pancreatic β cells[J]. Trends Endocrinol Metab,2012,23(9):477-487.

[23]Phielix E, Mensink M. Type 2 diabetes mellitus and skeletal muscle metabolic function[J]. Physiol Behav,2008,94(2):252-258.

[24]Wang CH,Wang CC, Huang HC, et al. Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes[J]. FEBS J,2013,280(4):1039-1050.

[25]Sirvent P, Fabre O, Bordenave S, et al. Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins[J]. Toxicol Appl Pharmacol,2012,259(2):263-268.

[26]Schrauwen P, Saris WH, Hesselink MK. An alternative function for human uncoupling protein 3: protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix[J]. FASEB J,2001,15(13):2497-2502.

[27]Krssak M, Falk Petersen K, Dresner A, et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a1H NMR spectroscopy study[J]. Diabetologia,1999,42(1):113-116.

[28]Moro C, Bajpeyi S, Smith SR. Determinants of intramyocellular triglyceride turnover: implications for insulin sensitivity[J]. Am J Physiol Endocrinol Metab,2008,294(2):e203-e213.

[29]Larsen S, Stride N, Hey-Mogensen M, et al. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance[J]. J Am Coll Cardiol,2013,61(1):44-53.

Progress in Research of Mechanism of New-onset Diabetes Mellitus Induced by Statins

ZHANG Lei, HE Fei

(Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China)

A series of large-scale clinical trials have shown that statins can not only greatly reduce cholesterol, but also significantly reduce cardiovascular events, such as angina pectoris, myocardial infarction and coronary heart disease death. However, some recent clinical researches have indicated that statins increase the risk of new-onset diabetes mellitus. Therefore, the relationship between diabetes mellitus and statins has been of concern. At present, the mechanism of new-onset diabetes mellitus induced by statins is still unclear. This article reviews the recent progress in research of mechanism of new-onset diabetes mellitus induced by statins.

statins; diabetes mellitus; mechanism

河南省衛(wèi)生科技創(chuàng)新型人才工程中青年科技創(chuàng)新人才項(xiàng)目(201403029)；河南省醫(yī)學(xué)科技攻關(guān)計(jì)劃(201403030)

張磊(1989—)，在讀碩士，主要從事冠心病及心力衰竭研究。Email:zdyxyzhanglei@sina.com

何飛(1971—)，醫(yī)學(xué)博士后，副主任醫(yī)師，主要從事心臟電生理及心力衰竭研究。Email:hefeihn71@sina.com

R972+.6;R

A

10.3969/j.issn.1004-3934.2015.05.025

2015-03-17