呂承安，王若然，孟卓賢

綜 述

2型糖尿病進(jìn)程中胰島β細(xì)胞功能變化的分子機(jī)制

呂承安1,2，王若然1,2，孟卓賢1,2

1. 浙江大學(xué)醫(yī)學(xué)院病理學(xué)與病理生理學(xué)系，杭州 310058 2. 浙江大學(xué)醫(yī)學(xué)院浙江省疾病蛋白質(zhì)組學(xué)重點(diǎn)實(shí)驗(yàn)室，杭州 310058

近年來(lái)，2型糖尿病(type 2 diabetes，T2D)發(fā)病率迅速上升，已成為全球性的健康危機(jī)。最近的臨床和基礎(chǔ)研究表明，胰島β細(xì)胞功能障礙是導(dǎo)致T2D及其相關(guān)并發(fā)癥的重要原因。在2型糖尿病的自然病程中，胰島β細(xì)胞經(jīng)歷從代償?shù)绞Т鷥數(shù)膭?dòng)態(tài)變化；其中，代謝應(yīng)激反應(yīng)，如內(nèi)質(zhì)網(wǎng)應(yīng)激(endoplasmic reticulum stress，ER stress)、氧化應(yīng)激(oxidative stress)和炎癥(inflammation)是β細(xì)胞功能變化的關(guān)鍵調(diào)控機(jī)制。本文總結(jié)了β細(xì)胞功能在2型糖尿病病程中動(dòng)態(tài)變化的研究進(jìn)展，以期深化對(duì)2型糖尿病分子機(jī)制的理解，為精準(zhǔn)診斷和臨床干預(yù)2型糖尿病提供參考。

胰島β細(xì)胞；2型糖尿??；分子機(jī)制

2型糖尿病(type 2 diabetes，T2D)是當(dāng)今世界上最嚴(yán)重的公共衛(wèi)生問(wèn)題之一，然而其具體發(fā)病機(jī)制仍不清楚，治療效果遠(yuǎn)不理想[1]。T2D的主要特征是胰島素分泌相對(duì)缺乏、外周組織胰島素抵抗和隨之而來(lái)的高血糖。長(zhǎng)期高血糖將引起微血管和大血管并發(fā)癥，導(dǎo)致心臟病、中風(fēng)和糖尿病視網(wǎng)膜病變等嚴(yán)重疾病[2]。早期的研究曾認(rèn)為外周組織胰島素抵抗是T2D的主要病因；然而隨著對(duì)胰島生理功能和病理機(jī)制的深入了解，人們逐漸認(rèn)識(shí)到胰島β細(xì)胞(pancreatic β-cell)在T2D的發(fā)生發(fā)展過(guò)程中起到關(guān)鍵性作用[3]。全基因組關(guān)聯(lián)研究(genome wide association study，GWAS)現(xiàn)已確定的T2D風(fēng)險(xiǎn)位點(diǎn)中，與β細(xì)胞功能受損相關(guān)的風(fēng)險(xiǎn)位點(diǎn)遠(yuǎn)多于與胰島素抵抗相關(guān)的風(fēng)險(xiǎn)位點(diǎn)，進(jìn)一步從遺傳風(fēng)險(xiǎn)角度強(qiáng)調(diào)了胰島β細(xì)胞在T2D中的核心作用[4]。

胰島β細(xì)胞是人體血糖的主要調(diào)控者，通過(guò)對(duì)葡萄糖的精確感受分泌胰島素，一方面促使外周組織攝取葡萄糖，另一方面抑制內(nèi)源性葡萄糖生成，從而控制機(jī)體血糖穩(wěn)態(tài)。在T2D的發(fā)病過(guò)程中，β細(xì)胞經(jīng)歷了從功能代償(compensation)到失代償(decompensation)的動(dòng)態(tài)變化[5～7]。在糖尿病前期，雖然機(jī)體出現(xiàn)了輕度高血糖和外周組織胰島素抵抗；但β細(xì)胞通過(guò)增加單個(gè)細(xì)胞胰島素分泌量[7]和自我增殖等代償反應(yīng)克服這些障礙，維持了機(jī)體糖脂代謝穩(wěn)態(tài)，延緩了糖尿病的發(fā)生[5,8]。然而，日積月累的代謝應(yīng)激(metabolic stress)，如內(nèi)質(zhì)網(wǎng)應(yīng)激(endoplasmic reticulum stress，ER stress)、氧化應(yīng)激(oxidative stress)和炎癥(inflammation)會(huì)逐漸對(duì)β細(xì)胞造成損傷。隨著這些因素的持續(xù)作用，β細(xì)胞代償?shù)哪芰χ饾u減弱，最終發(fā)展為β細(xì)胞失代償[7]。在失代償階段，β細(xì)胞分泌的胰島素不足以滿(mǎn)足身體的需求，機(jī)體糖脂代謝穩(wěn)態(tài)被打破，糖尿病并發(fā)癥逐一出現(xiàn)[5,8]。值得注意的是，除了代謝應(yīng)激外，染色質(zhì)重塑(chromatin remodeling)和組蛋白修飾(histone modification)也可能在胰島β細(xì)胞功能從代償?shù)绞Т鷥數(shù)霓D(zhuǎn)變中發(fā)揮關(guān)鍵作用[7]；胰島β細(xì)胞的去分化(dedifferentiation)和轉(zhuǎn)分化(trans- differentiation)也在近年間被視為β細(xì)胞在應(yīng)激條件下逃避細(xì)胞死亡命運(yùn)的一種保護(hù)機(jī)制，與β細(xì)胞數(shù)量減少密切相關(guān)[9]。本文對(duì)胰島β細(xì)胞動(dòng)態(tài)變化機(jī)制的研究進(jìn)展展開(kāi)綜述，討論β細(xì)胞胰島素分泌在生理狀態(tài)下的調(diào)控，并進(jìn)一步分別總結(jié)T2D前期促使β細(xì)胞代償和晚期導(dǎo)致β細(xì)胞功能障礙和失代償?shù)姆肿訖C(jī)制。

1 β細(xì)胞胰島素分泌的生理調(diào)節(jié)

β細(xì)胞正常合成和分泌胰島素是機(jī)體調(diào)節(jié)血糖能力的重要保障。在正常情況下，胰島素基因被轉(zhuǎn)錄，翻譯為前胰島素原(preproinsulin)并運(yùn)輸?shù)絻?nèi)質(zhì)網(wǎng)管腔；隨后切除信號(hào)肽，剩余的肽鏈折疊并形成二硫鍵，形成胰島素原(proinsulin)；胰島素原隨后被轉(zhuǎn)移到高爾基體，在高爾基體中被剪切為C肽(C-peptide)和胰島素，然后被儲(chǔ)存在分泌顆粒中，直到血糖的升高促使分泌顆粒與β細(xì)胞膜融合，胰島素被釋放進(jìn)入血液循環(huán)[10]。

1.1 葡萄糖刺激胰島素分泌通路

葡萄糖刺激胰島素分泌(glucose-stimulated insulin secretion，GSIS)通路是發(fā)現(xiàn)最早且研究最透徹的胰島素分泌通路。在GSIS通路中，血糖升高使β細(xì)胞膜葡萄糖轉(zhuǎn)運(yùn)體GLUT1(嚙齒動(dòng)物為GLUT2)將葡萄糖轉(zhuǎn)運(yùn)到胞內(nèi)，隨后葡萄糖激酶(glucose kinase, GK)將細(xì)胞內(nèi)葡萄糖磷酸化為葡萄糖6-磷酸，這是β細(xì)胞中葡萄糖代謝的關(guān)鍵限速步驟。進(jìn)一步在細(xì)胞質(zhì)中進(jìn)行糖酵解，產(chǎn)生丙酮酸(pyruvate)、還原性輔酶1(reduced form of nicotinamide-adenine dinucleotide，NADH)和少量腺苷三磷酸(adenosine triphosphate，ATP)。丙酮酸和NADH隨后被運(yùn)輸?shù)骄€(xiàn)粒體中，并通過(guò)三羧酸循環(huán)(tricarboxylic acid cycle)和電子傳遞鏈(electron transport chain，ETC)，在此過(guò)程中產(chǎn)生大量的ATP；ATP轉(zhuǎn)運(yùn)復(fù)合物隨后將這些ATP轉(zhuǎn)運(yùn)到細(xì)胞質(zhì)中；細(xì)胞質(zhì)中ATP/ADP比值的上升抑制了細(xì)胞膜上的ATP敏感鉀離子(K+)的通道，并使細(xì)胞膜去極化；細(xì)胞膜去極化導(dǎo)致電壓依賴(lài)性的鈣離子(Ca2+)通道打開(kāi)，胞外大量Ca2+流入；胞內(nèi)Ca2+濃度的增加促進(jìn)胰島素的釋放[10]。

由于被β細(xì)胞吸收的氨基酸和脂肪酸可以通過(guò)分解代謝形成三羧酸循環(huán)的中間產(chǎn)物，氨基酸和脂肪酸直接增強(qiáng)胰島素分泌的作用可能可以部分歸因于如上所述的鉀通道-鈣通道途徑。例如，亮氨酸可以通過(guò)谷氨酸代謝途徑產(chǎn)生α-酮戊二酸，然后進(jìn)入三羧酸循環(huán)；同樣，血液中的脂肪酸可以通過(guò)特殊的轉(zhuǎn)運(yùn)蛋白進(jìn)入β細(xì)胞，被活化生成乙酰輔酶A(acetyl coenzyme A，acetyl-CoA)，隨后通過(guò)肉堿穿梭途徑進(jìn)入線(xiàn)粒體[11]。在線(xiàn)粒體基質(zhì)中，乙酰輔酶A可被氧化，通過(guò)三羧酸循環(huán)和ETC產(chǎn)生ATP[11]。

1.2 胰島素分泌的“放大通路”

除了經(jīng)典的GSIS通路，氨基酸、脂肪酸以及胃腸道內(nèi)分泌細(xì)胞分泌的肽類(lèi)可以通過(guò)獨(dú)立于GSIS通路的“放大通路”(amplifying pathways)來(lái)調(diào)控胰島素的合成和分泌。雖然這些通路對(duì)β細(xì)胞胰島素分泌功能有重要影響，但它們發(fā)現(xiàn)較晚，目前研究還不透徹。mTOR蛋白復(fù)合體1(mammalian target of rapamycin complex 1，mTORC1)對(duì)于β細(xì)胞感知氨基酸至關(guān)重要[12]。氨基酸可通過(guò)Rag和Rab1A蛋白激活β細(xì)胞的mTORC1，促進(jìn)胰十二指腸同源框1(pancreatic and duodenal homeobox 1，PDX1)轉(zhuǎn)錄因子進(jìn)入細(xì)胞核，提高胰島素基因的表達(dá)水平[13]。G蛋白偶聯(lián)受體40(G protein-coupled receptor 40，GPR40)是一種在β細(xì)胞表面高表達(dá)的脂肪酸受體；脂肪酸可結(jié)合并活化該受體，在胞內(nèi)激活蛋白激酶C(protein kinase C，PKC)，促使磷脂酰肌醇二磷酸(phosphatidylinositol diphosphate，PIP2)水解為三磷酸肌醇(triphosphoinositide，IP3)和二酰甘油(diacylglycerol，DAG)；IP3結(jié)合并打開(kāi)位于內(nèi)質(zhì)網(wǎng)膜上的IP3門(mén)控Ca2+通道，釋放內(nèi)質(zhì)網(wǎng)中儲(chǔ)存的Ca2+，增加胞漿Ca2+的濃度并促進(jìn)胰島素顆粒與細(xì)胞膜的融合。與此同時(shí)，DAG激活PKC和蛋白激酶D1 (protein kinase D1，PKD1)，進(jìn)而激發(fā)下游信號(hào)通路，導(dǎo)致胰島素顆粒胞吐增強(qiáng)[14,15]。

抑胃肽(gastric inhibitory polypeptide，GIP)和胰高血糖素樣肽1(glucagon-like peptide 1，GLP1)是兩種重要的腸促胰激素，由腸道K細(xì)胞和L細(xì)胞分泌，對(duì)β細(xì)胞的正常分泌功能有重要作用。另外，生理?xiàng)l件下，胰島中有少部分GLP1來(lái)源于胰島α細(xì)胞[16]。GIP和GLP1與β細(xì)胞上的特定受體結(jié)合，介導(dǎo)腺苷酸環(huán)化酶(adenylate cyclase)將ATP轉(zhuǎn)化為環(huán)磷酸腺苷(cyclic adenosine monophosphate，cAMP)。cAMP在胰島β細(xì)胞中可以激活蛋白激酶A(protein kinase A，PKA)和Epac2。一方面，PKA抑制ATP敏感的鉀通道，增加胰島素分泌；另一方面，激活的Epac2誘導(dǎo)了內(nèi)質(zhì)網(wǎng)膜上的Ca2+通道RYR的開(kāi)放，提升了胞內(nèi)Ca2+的濃度[17]。也有研究表明，激活的Epac2可以與Rim2[18]、Piccolo和Rab3[19]等相互作用，誘導(dǎo)胰島素的釋放。

分泌到胞外的胰島素可以通過(guò)自分泌的方式影響β細(xì)胞，對(duì)β細(xì)胞功能的正常發(fā)揮不可或缺[20]。胰島素與β細(xì)胞膜上具有內(nèi)在酪氨酸激酶特性的受體，如胰島素受體(insulin receptor，IR)或胰島素樣生長(zhǎng)因子-1受體(insulin-like growth factor 1 receptor，IGF-1R)結(jié)合，隨后受體自磷酸化；激活的受體磷酸化胰島素受體底物(insulin receptor substrate，IRS)，IRS激活多個(gè)下游信號(hào)蛋白，包括Erk1/2、PI3K、Akt、mTORC1、p70s6K和PLC[20]。在生理?xiàng)l件下，胰島素通過(guò)PI3K/p70s6K和CaMK等途徑促進(jìn)自身的轉(zhuǎn)錄[21]。此外，由于胰島素可以通過(guò)PI3K-Akt通路激活mTORC1，mTORC1-PDX1介導(dǎo)的胰島素表達(dá)也可能是胰島素自分泌調(diào)節(jié)通路的另一個(gè)分支[20]。近期的研究進(jìn)一步發(fā)現(xiàn)，胰島素抑制受體Inceptor在胰島素的自分泌調(diào)控中發(fā)揮著重要作用。β細(xì)胞表達(dá)的Inceptor可以促進(jìn)網(wǎng)格蛋白介導(dǎo)的IR和IGF1R內(nèi)吞，使得分泌出去的胰島素不能激活自分泌調(diào)節(jié)通路；在小鼠中敲除Inceptor后，小鼠迅速出現(xiàn)了高胰島素血癥，并死于低血糖[22]。Inceptor的發(fā)現(xiàn)表明胰島素自分泌反饋調(diào)節(jié)通路的負(fù)調(diào)控也具有重要的生理意義；適當(dāng)抑制Inceptor，增強(qiáng)胰島素自分泌調(diào)節(jié)可能是增強(qiáng)β細(xì)胞功能的新思路。

1.3 腸道菌群對(duì)β細(xì)胞胰島素分泌的調(diào)控

作為人體內(nèi)重要的微生態(tài)系統(tǒng)，腸道菌群對(duì)人體代謝、免疫、內(nèi)分泌等具有深刻的影響，與T2D的關(guān)系十分密切[23,24]。近年來(lái)，多項(xiàng)研究證實(shí)了腸道菌群對(duì)胰島β細(xì)胞功能的調(diào)控作用。腸道細(xì)菌受腸道溶菌酶作用產(chǎn)生的胞質(zhì)肽聚糖可以進(jìn)入血液循環(huán)，最終與β細(xì)胞膜上的受體Nod1結(jié)合，招募Rip2及Rab1a至β細(xì)胞內(nèi)的分泌囊泡表面，促進(jìn)胰島素的成熟與轉(zhuǎn)運(yùn)；而在失去腸道菌群的無(wú)菌小鼠中，胰島素的成熟和囊泡的正常轉(zhuǎn)運(yùn)過(guò)程受阻[25]。膳食纖維的攝入可以促進(jìn)腸道內(nèi)產(chǎn)短鏈脂肪酸(short-chain fatty acid，SCFA)細(xì)菌的繁盛；這些細(xì)菌產(chǎn)生的SCFA有助于促進(jìn)β細(xì)胞分泌胰島素[26,27]。一些研究把SCFA的這種生理效應(yīng)歸因于其對(duì)腸促胰激素GLP1的促進(jìn)作用[26]，也有一些研究認(rèn)為某些SCFA是通過(guò)腦-腸軸刺激宿主的迷走神經(jīng)，迷走神經(jīng)促進(jìn)β細(xì)胞分泌胰島素[27]。此外，一種名為BefA的腸道細(xì)菌蛋白可以促進(jìn)斑馬魚(yú)β細(xì)胞增殖[28]。這項(xiàng)研究深化了人們對(duì)腸-胰互作的認(rèn)知，不過(guò)BefA在哺乳類(lèi)和人類(lèi)體內(nèi)是否有相同的生理功能尚需進(jìn)一步探究。

1.4 胰島微環(huán)境對(duì)β細(xì)胞胰島素分泌的調(diào)控

研究表明，在β細(xì)胞調(diào)控血糖的過(guò)程中，胰島中的各種細(xì)胞，包括α細(xì)胞、δ細(xì)胞、免疫細(xì)胞以至胰島神經(jīng)細(xì)胞均發(fā)揮了作用。這樣一個(gè)整合內(nèi)分泌、免疫、神經(jīng)調(diào)節(jié)因子的復(fù)雜系統(tǒng)被稱(chēng)作胰島微環(huán)境[29]。胰島內(nèi)部的α細(xì)胞和δ細(xì)胞對(duì)β細(xì)胞具有重要的內(nèi)分泌調(diào)節(jié)作用。α細(xì)胞產(chǎn)生的胰高血糖素(glucagon)，δ細(xì)胞產(chǎn)生的生長(zhǎng)抑素(somatostatin)等都可以通過(guò)旁分泌的形式作用于β細(xì)胞[30]。一方面，胰高血糖素可以促進(jìn)β細(xì)胞分泌胰島素；另一方面，胰高血糖素作用于δ細(xì)胞，刺激δ細(xì)胞產(chǎn)生生長(zhǎng)抑素，對(duì)胰島素的分泌起抑制作用；生長(zhǎng)抑素反過(guò)來(lái)又抑制了胰高血糖素的分泌[30]。在這一經(jīng)典模型之外，最近發(fā)現(xiàn)白細(xì)胞介素18(interleukin 18, IL18)也是β細(xì)胞功能的重要調(diào)控因子：IL18主要由α細(xì)胞分泌，可結(jié)合β細(xì)胞上的受體NCC，調(diào)控PDX1的表達(dá)，進(jìn)而增強(qiáng)胰島素合成與分泌[31]。免疫系統(tǒng)亦參與調(diào)節(jié)胰島微環(huán)境。生理?xiàng)l件下，胰島免疫細(xì)胞產(chǎn)生的炎癥因子，如白細(xì)胞介素1β(interleukin 1β，IL1β)可以促進(jìn)胰島β細(xì)胞分泌胰島素，參與維持餐后胰島素分泌；IL1β信號(hào)缺失的小鼠出現(xiàn)了胰島素分泌不足[32]。此外，神經(jīng)對(duì)β胰島也存在精細(xì)的調(diào)控。胰島內(nèi)部存在多種分泌不同神經(jīng)遞質(zhì)的神經(jīng)元[33]，而它們分泌的神經(jīng)遞質(zhì)對(duì)胰島素分泌的影響不同：乙酰膽堿可以刺激胰島素的分泌[34]，而腎上腺素的生理效應(yīng)則相反[35]。

2 T2D中胰島β細(xì)胞的代償機(jī)制

正常糖耐量個(gè)體中，胰島素分泌量和胰島素敏感性之間呈現(xiàn)出負(fù)相關(guān)：胰島素敏感性低的個(gè)體需要更高的胰島素分泌量才能實(shí)現(xiàn)正常的血糖控制。胰島素分泌量的提升源自單個(gè)β細(xì)胞的胰島素分泌水平提升和胰島β細(xì)胞的數(shù)量提升[36]。β細(xì)胞增生的來(lái)源尚存在爭(zhēng)議；許多研究表明胰島α細(xì)胞[37]、δ細(xì)胞[38]以及胰腺導(dǎo)管細(xì)胞[39]均有轉(zhuǎn)分化為β細(xì)胞的可能，也有研究表明生理和病理?xiàng)l件下新生的β細(xì)胞主要來(lái)源于已有β細(xì)胞的增殖[40]。經(jīng)典理論認(rèn)為代償過(guò)程受β細(xì)胞對(duì)高糖的感知和響應(yīng)調(diào)控；體內(nèi)和體外實(shí)驗(yàn)均證明，在高糖刺激下，β細(xì)胞通過(guò)增大自身體積和增殖來(lái)增加胰島素的合成和分泌量[41,42]。事實(shí)上，調(diào)控β細(xì)胞代償?shù)囊蛩乇姸?，這些因素的組合被統(tǒng)稱(chēng)為代謝應(yīng)激[36]。β細(xì)胞代謝應(yīng)激是由高血糖、高脂血癥和高胰島素血癥介導(dǎo)的綜合概念，由過(guò)多的能量攝入和外周組織胰島素抵抗引起，主要包括內(nèi)質(zhì)網(wǎng)應(yīng)激、氧化應(yīng)激和炎癥三大方面[43,44](圖1)。β細(xì)胞代謝應(yīng)激的來(lái)源十分廣泛，涉及大腦、肝臟、肌肉、脂肪、腎臟和腸道等器官，也與胰島的微環(huán)境有關(guān)[45]。

2.1 代償期的內(nèi)質(zhì)網(wǎng)應(yīng)激

胰島素合成和分泌量的增加給β細(xì)胞帶來(lái)了更重的蛋白質(zhì)折疊任務(wù)，蛋白質(zhì)折疊分子機(jī)器的超載最終導(dǎo)致未折疊及錯(cuò)誤折疊蛋白質(zhì)的大量積累[43]，觸發(fā)內(nèi)質(zhì)網(wǎng)應(yīng)激。在高糖和外周胰島素抵抗的情況下，高胰島素需求刺激β細(xì)胞胰島素的合成，并可能促進(jìn)胰島素的錯(cuò)誤折疊[46]。高糖刺激顯著增加了β細(xì)胞中內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)基因的表達(dá)，而過(guò)度刺激內(nèi)質(zhì)網(wǎng)應(yīng)激通路可能是高糖對(duì)β細(xì)胞產(chǎn)生毒性的重要機(jī)制[47]。此外，內(nèi)質(zhì)網(wǎng)應(yīng)激可能不僅由未折疊或錯(cuò)誤折疊蛋白質(zhì)積累引發(fā)：高脂則會(huì)刺激eIF-2磷酸化，誘導(dǎo)β細(xì)胞中ATF6、CHOP和BiP的表達(dá)，表明游離脂肪酸也參與了β細(xì)胞內(nèi)質(zhì)網(wǎng)應(yīng)激[48,49]。有機(jī)制研究表明，飽和脂肪酸可能通過(guò)干擾和中斷蛋白質(zhì)從內(nèi)質(zhì)網(wǎng)到高爾基體的運(yùn)輸來(lái)觸發(fā)內(nèi)質(zhì)網(wǎng)應(yīng)激[50]。相反，高密度脂蛋白帶來(lái)的脂質(zhì)代謝改善恢復(fù)了內(nèi)質(zhì)網(wǎng)-高爾基轉(zhuǎn)運(yùn)穩(wěn)態(tài)，緩解了β細(xì)胞內(nèi)質(zhì)網(wǎng)應(yīng)激[51]。另外，棕櫚酸誘導(dǎo)羧肽酶E(carboxypeptidase E，一種胰島素原轉(zhuǎn)化為成熟胰島素所需的酶)的鈣依賴(lài)性降解，從而導(dǎo)致胰島素原的積累[52]。在過(guò)量的胰島淀粉樣多肽(islet amyloid polypeptide，IAPP)作用下，內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)也可以被激活[53,54]。

圖1 胰島β細(xì)胞代謝應(yīng)激

三種主要的內(nèi)質(zhì)網(wǎng)信號(hào)分子，PERK、ATF6和IRE1α作為傳感器觸發(fā)細(xì)胞適應(yīng)內(nèi)質(zhì)網(wǎng)應(yīng)激的反應(yīng)[55]。在β細(xì)胞代償期內(nèi)，內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)水平較低，持續(xù)時(shí)間較短，有助于維持蛋白質(zhì)正常表達(dá)和折疊，包括抑制蛋白質(zhì)翻譯[56]，誘導(dǎo)mRNA降解[57]，激活自噬[58]，促進(jìn)內(nèi)質(zhì)網(wǎng)生成[59]，上調(diào)伴侶蛋白表達(dá)水平[60]和降解錯(cuò)誤折疊的蛋白[61]?？傮w來(lái)講，代償期的內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)從多方面保護(hù)β細(xì)胞內(nèi)蛋白合成分子機(jī)器的正常運(yùn)轉(zhuǎn)，維持胰島素的正常表達(dá)和分泌。代償期的內(nèi)質(zhì)網(wǎng)應(yīng)激對(duì)調(diào)控β細(xì)胞增殖也有重要意義。IRE1α可以通過(guò)調(diào)控轉(zhuǎn)錄因子X(jué)BP1的活性，促進(jìn)細(xì)胞周期關(guān)鍵調(diào)控因子細(xì)胞周期素D1(cyclinD1)的轉(zhuǎn)錄表達(dá)；同時(shí)在內(nèi)質(zhì)網(wǎng)應(yīng)激出現(xiàn)不久，IRE1α-XBP1信號(hào)通路即被激活，而IRE1α缺失，該條通路被抑制后，β細(xì)胞的代償性增殖顯著受損。這提示IRE1α-XBP1通路可能是代償期β細(xì)胞增殖的重要調(diào)控因子[62]。也有研究證明ATF6亦有促進(jìn)β細(xì)胞增殖的作用[63]。

2.2 代償期的氧化應(yīng)激

以活性氧(reactive oxygen species，ROS)水平升高為特征的氧化應(yīng)激也是代償期β細(xì)胞經(jīng)歷的一種代謝應(yīng)激[60,64]。ROS是各種細(xì)胞生理活動(dòng)的副產(chǎn)物，主要由線(xiàn)粒體有氧呼吸產(chǎn)生[65]。由于生理?xiàng)l件下β細(xì)胞的乳酸代謝水平很低[66]，葡萄糖進(jìn)入細(xì)胞時(shí)將被完全氧化；在高血糖條件下，如前所述，β細(xì)胞中糖氧化水平上升，同時(shí)ROS生成水平提高[64]。游離脂肪酸可能通過(guò)多種途徑引起β細(xì)胞氧化應(yīng)激。一方面，β-細(xì)胞中脂質(zhì)氧化代謝的增加可能導(dǎo)致游離脂肪酸氧化不完全，導(dǎo)致ROS生成增加[64]；另一方面，脂質(zhì)介導(dǎo)的細(xì)胞氧化應(yīng)激也可能與其抑制KIF12的作用有關(guān)[67]。KIF12是一種參與β細(xì)胞抗氧化活性的微管馬達(dá)，可以作為轉(zhuǎn)錄因子Sp1的支架。KIF12-Sp1復(fù)合體通過(guò)提高Hsc70的表達(dá)，增強(qiáng)過(guò)氧化物酶體功能，從而緩解氧化應(yīng)激[67]。同時(shí)，β細(xì)胞鈣通道的持續(xù)激活和高胰島素刺激都與其氧化應(yīng)激水平有關(guān)[68,69]。

生理?xiàng)l件下，ROS作為信號(hào)分子，在信號(hào)轉(zhuǎn)導(dǎo)中發(fā)揮著重要的作用[70]。在代償期的氧化應(yīng)激條件下，β細(xì)胞仍可以通過(guò)去除或中和過(guò)量的活性氧來(lái)自我保護(hù)。促進(jìn)自噬，上調(diào)抗氧化酶和還原性抗氧化伴侶分子，如蛋白二硫異構(gòu)酶(Protein disulfide isomerase，PDI)，內(nèi)質(zhì)網(wǎng)氧化還原素1(endoplasmic reticulum oxidoreductins 1，ERO1)或谷胱甘肽(glutathione，GSH)等的表達(dá)[64,71]是β細(xì)胞對(duì)抗氧化應(yīng)激的主要方法。在代償階段，β細(xì)胞內(nèi)的抗氧化系統(tǒng)可以有效保護(hù)其免受ROS造成的種種損傷。Forkhead轉(zhuǎn)錄因子1(forkhead box O1，F(xiàn)oxo1)在β細(xì)胞強(qiáng)化抗氧化系統(tǒng)，應(yīng)對(duì)氧化應(yīng)激的過(guò)程中發(fā)揮了重要作用。在正常生理?xiàng)l件下，F(xiàn)oxo1可被Akt磷酸化，遷移到胞質(zhì)并失活；而在氧化應(yīng)激中，F(xiàn)oxo1被JNK等轉(zhuǎn)錄因子在另一位點(diǎn)磷酸化并入核，調(diào)控其下游基因表達(dá)，包括過(guò)氧化氫酶(catalase)和超氧化物歧化酶(superoxide dismutase，Sod2)，發(fā)揮抗氧化作用[72]。β細(xì)胞也可能通過(guò)線(xiàn)粒體自噬以降解受損線(xiàn)粒體，從而維持線(xiàn)粒體穩(wěn)態(tài)[73]。對(duì)健康小鼠的胰島β細(xì)胞單細(xì)胞測(cè)序顯示，ROS的產(chǎn)生可能可以通過(guò)下游的Srf、Jun、Fos等轉(zhuǎn)錄因子誘導(dǎo)β細(xì)胞增殖[74]；提示ROS可能也在代償期的β細(xì)胞增殖中發(fā)揮了重要作用。此外，也有研究認(rèn)為ROS通過(guò)轉(zhuǎn)錄因子Nrf2參與β細(xì)胞代償[75]。沒(méi)有氧化應(yīng)激時(shí)，Nrf2與抑制因子如Keap1結(jié)合，處于未激活狀態(tài)，會(huì)被泛素化而降解；出現(xiàn)氧化應(yīng)激時(shí)，Keap1被氧化使得對(duì)Nrf2的靶向結(jié)合能力下降，從而使Nrf2激活并轉(zhuǎn)移至核內(nèi)[75]。Nrf2一方面保護(hù)細(xì)胞免受ROS的損傷，抑制β細(xì)胞凋亡，另一方面促進(jìn)β細(xì)胞增殖相關(guān)基因的表達(dá)[75]。

2.3 代償期的胰島炎癥

糖尿病胰島的炎癥特征包括巨噬細(xì)胞浸潤(rùn)和炎癥因子釋放增加[76,77]。一方面，營(yíng)養(yǎng)過(guò)剩刺激外周組織，如脂肪組織、肌肉和肝臟釋放炎癥因子進(jìn)入血液循環(huán)，這些炎癥因子隨血流進(jìn)入胰島，導(dǎo)致胰島炎癥[78]。另一方面，營(yíng)養(yǎng)過(guò)剩相關(guān)的高血糖和高血脂可以直接作用于胰島，并觸發(fā)炎癥反應(yīng)。相較于失代償期，代償期的胰島炎癥程度輕微。胰島炎性細(xì)胞因子如IL1β、腫瘤壞死因子α(tumor necrosis factor α，TNFα)和干擾素γ(interferon γ，IFNγ)可以降低心肌肌漿網(wǎng)Ca2+-ATP酶(sarco endoplasmic reticulum Ca2+-ATPase，SERCA)的表達(dá)[79]；由于SERCA的功能是將胞漿中的Ca2+轉(zhuǎn)運(yùn)到內(nèi)質(zhì)網(wǎng)中，這種調(diào)控可以在暫時(shí)將胞漿中的Ca2+維持在較高水平，從而促進(jìn)胰島素的分泌。此外，炎癥因子還可通過(guò)調(diào)節(jié)Nrf2/NF-ΚB和SAPK/JNK通路誘導(dǎo)氧化應(yīng)激[80]，因此炎癥和氧化應(yīng)激的下游通路有可能存在交叉。在β細(xì)胞炎癥和氧化應(yīng)激通路的交互中，二價(jià)金屬離子轉(zhuǎn)運(yùn)體1(divalent metal-ion transporter1，DMT1)可能發(fā)揮了重要作用[81]。

3 T2D中胰島β細(xì)胞的失代償機(jī)制

β細(xì)胞功能的代償總是與不斷增長(zhǎng)的胰島素需求相抗衡。后者的不斷增長(zhǎng)，連同T2D進(jìn)程中其他因素，包括內(nèi)質(zhì)網(wǎng)應(yīng)激、氧化應(yīng)激和炎癥水平的增加，使得β細(xì)胞的負(fù)擔(dān)日益加重，最后導(dǎo)致代償能力喪失，也即β細(xì)胞功能失代償?？梢哉f(shuō)，β細(xì)胞的代償和失代償分別是由短期和長(zhǎng)期的代謝應(yīng)激的結(jié)果：短期的代謝應(yīng)激會(huì)激發(fā)β細(xì)胞代償反應(yīng)；長(zhǎng)期的代謝應(yīng)激會(huì)對(duì)β細(xì)胞造成不可逆的損傷，包括凋亡和β細(xì)胞特性的喪失(去分化和轉(zhuǎn)分化)，是β細(xì)胞數(shù)量減少和功能損傷的直接原因(圖2)。下面將對(duì)β細(xì)胞失代償過(guò)程中三個(gè)方面的代謝應(yīng)激和β細(xì)胞去分化、轉(zhuǎn)分化的機(jī)制進(jìn)行分別討論。

3.1 失代償期的內(nèi)質(zhì)網(wǎng)應(yīng)激

在β細(xì)胞從代償?shù)绞Т鷥數(shù)倪^(guò)渡過(guò)程中，胰島素原的分泌顯著增加，這表明β細(xì)胞中內(nèi)質(zhì)網(wǎng)或高爾基體中的胰島素加工系統(tǒng)受損[60]。從已有的證據(jù)來(lái)看，β細(xì)胞從代償?shù)绞Т鷥數(shù)霓D(zhuǎn)變可能對(duì)應(yīng)于內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)從保護(hù)性到細(xì)胞毒性的轉(zhuǎn)變。雖然代償期的內(nèi)質(zhì)網(wǎng)應(yīng)激具有一定的保護(hù)作用，失代償期高水平、長(zhǎng)期的內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)反而成為了β細(xì)胞凋亡的重要推手[55]。C/EBP同源蛋白(C/EBP homolog protein，CHOP)是PERK的下游因子，可能參與了內(nèi)質(zhì)網(wǎng)應(yīng)激誘導(dǎo)的細(xì)胞凋亡。抑制CHOP基因可以緩解內(nèi)質(zhì)網(wǎng)應(yīng)激[82]，并減輕內(nèi)質(zhì)網(wǎng)應(yīng)激后的β細(xì)胞凋亡；過(guò)表達(dá)CHOP則具有相反的作用[83]。此外，內(nèi)質(zhì)網(wǎng)應(yīng)激可能通過(guò)干擾β細(xì)胞內(nèi)質(zhì)網(wǎng)膜上的鈣離子通道，蘭尼堿受體(ryanodine receptor，RyR)的功能，導(dǎo)致內(nèi)質(zhì)網(wǎng)鈣離子滲漏[54]；鈣離子穩(wěn)態(tài)的喪失導(dǎo)致胰島素分泌功能受損，并進(jìn)一步促進(jìn)β細(xì)胞死亡。持久的內(nèi)質(zhì)網(wǎng)應(yīng)激會(huì)減弱ATF6和IRE1α通路的活性，但PERK通路卻不受影響[84]，這意味著不同的應(yīng)激反應(yīng)通路在內(nèi)質(zhì)網(wǎng)應(yīng)激壓力下決定細(xì)胞命運(yùn)方面發(fā)揮了不同的作用。結(jié)合上文對(duì)ATF6和IRE1α對(duì)β細(xì)胞的保護(hù)和促增殖效應(yīng)的討論[62,63]，對(duì)這兩條通路的抑制可能是失代償期β細(xì)胞增殖功能減弱、凋亡增加的機(jī)制。

圖2 T2D病程中胰島β細(xì)胞從代償?shù)绞Т鷥數(shù)墓δ茏兓?/p>

3.2 失代償期的氧化應(yīng)激

在病理?xiàng)l件下，過(guò)量的ROS會(huì)對(duì)細(xì)胞的核酸、蛋白質(zhì)和脂質(zhì)造成損傷，導(dǎo)致線(xiàn)粒體功能障礙，甚至誘導(dǎo)細(xì)胞死亡。正常的胰島細(xì)胞會(huì)表達(dá)Sod2、catalase等過(guò)氧化物酶來(lái)清除過(guò)量的ROS，同時(shí)也會(huì)表達(dá)其他對(duì)氧化應(yīng)激具有保護(hù)作用的因子，如Rheb1和Fam3a；然而在糖尿病個(gè)體的β細(xì)胞中，這些抗氧化酶和保護(hù)因子均出現(xiàn)了下調(diào)[85,86]。在失代償期入核的Foxo1在長(zhǎng)時(shí)間代謝應(yīng)激下的耗竭可能參與助推β細(xì)胞抗氧化系統(tǒng)失效[72,87]。失代償階段，ROS過(guò)量，抗氧化系統(tǒng)受損，導(dǎo)致ROS破除β細(xì)胞的抗氧化防線(xiàn)，胞內(nèi)的抗氧化劑耗竭[88]。此外，由于線(xiàn)粒體DNA(mitochondrial DNA，mtDNA)裸露在外，對(duì)ROS具有固有脆弱性，容易被氧化應(yīng)激產(chǎn)生的ROS損傷。事實(shí)上，糖尿病患者常出現(xiàn)mtDNA損傷伴隨線(xiàn)粒體功能障礙[89]。ROS還可能通過(guò)干擾線(xiàn)粒體形態(tài)損傷線(xiàn)粒體功能：體外研究表明，ROS抑制線(xiàn)粒體裂變的調(diào)節(jié)因子Fis1，并導(dǎo)致產(chǎn)生細(xì)長(zhǎng)和巨大的線(xiàn)粒體[90]。聯(lián)系Fis-1在β細(xì)胞功能中發(fā)揮的重要作用[91]，提示ROS可能會(huì)通過(guò)抑制Fis-1導(dǎo)致異常的線(xiàn)粒體融合，進(jìn)而損傷β細(xì)胞功能。綜上，失代償階段發(fā)生的不可逆損傷，包括β細(xì)胞DNA損傷[92,93]和引發(fā)的細(xì)胞凋亡，可能是由ROS及其下游分子直接介導(dǎo)的。

3.3 失代償期的炎癥

生理情況下，炎癥對(duì)維持β細(xì)胞功能發(fā)揮了重要作用；代償期的炎癥可以臨時(shí)增加胰島素分泌量；在失代償期，過(guò)度的炎癥反而促進(jìn)β細(xì)胞功能損傷。雖然IL1β、TNFα和IFNγ等對(duì)SERCA的抑制作用可以短時(shí)間內(nèi)增加細(xì)胞質(zhì)鈣的濃度，促進(jìn)胰島素分泌[79]，長(zhǎng)期暴露于這些炎癥細(xì)胞因子之下會(huì)使得內(nèi)質(zhì)網(wǎng)鈣離子儲(chǔ)庫(kù)耗竭，導(dǎo)致胰島素分泌受損[79]。在這種情況下，Ca2+依賴(lài)的蛋白質(zhì)加工和β細(xì)胞凋亡也會(huì)被促進(jìn)[43]。胞外炎癥因子的刺激之外，Eguchi等[94]的研究證明飽和游離脂肪酸-可以通過(guò)TLR4/MyD88通路觸發(fā)胰島內(nèi)的炎癥過(guò)程，導(dǎo)致β細(xì)胞功能障礙，而抑制促炎激酶IKK可以部分抵消這種游離脂肪酸誘導(dǎo)的β細(xì)胞功能障礙[95]。炎癥會(huì)激活氧化應(yīng)激，而氧化應(yīng)激則會(huì)刺激NF-κB通路，反過(guò)來(lái)加劇β細(xì)胞炎癥[96]。2015年的另一項(xiàng)研究表明，炎癥通過(guò)Nrf2/NF-κB和SAPK/JNK途徑誘導(dǎo)ROS產(chǎn)生并促進(jìn)β細(xì)胞死亡[80]，表明促炎細(xì)胞因子引發(fā)的炎癥反應(yīng)與內(nèi)質(zhì)網(wǎng)應(yīng)激和氧化應(yīng)激密切相關(guān)。最新研究表明，炎癥誘導(dǎo)β細(xì)胞死亡也需要胰島免疫細(xì)胞的參與：炎癥狀態(tài)的胰島中，胰島內(nèi)的巨噬細(xì)胞可與胰島β細(xì)胞接觸并誘導(dǎo)其增加中性粒細(xì)胞趨化因子Cxcl8a的表達(dá)；募集到的中性粒細(xì)胞攻擊并殺死巨噬細(xì)胞接觸過(guò)的β細(xì)胞[97]。

健康的腸道菌群可以維護(hù)β細(xì)胞的功能；反之，腸道菌群失調(diào)也是造成T2D中胰島β細(xì)胞功能受損的因素[23]。目前的研究提示腸道菌群失調(diào)損傷胰島β細(xì)胞功能的主要機(jī)制是加劇胰島炎癥。血液循環(huán)中對(duì)胰島有促炎和損傷效果的細(xì)菌脂多糖(lipopolysaccharide，LPS)的增多與T2D患者出現(xiàn)的腸道菌群失調(diào)有關(guān)[98]。LPS會(huì)被免疫細(xì)胞識(shí)別，激活Toll樣受體，通過(guò)NF-κB通路促進(jìn)免疫細(xì)胞表達(dá)和分泌促炎性細(xì)胞因子[99]。另有研究表明，來(lái)源于腸道，含有細(xì)菌DNA的細(xì)胞外囊泡(microbial DNA- containing extracellular vesicles, mEV)在T2D患者的胰島內(nèi)富集；這些微囊泡以通過(guò)激活cGAS/STING導(dǎo)致炎癥，進(jìn)一步損傷β細(xì)胞功能[100]。mEV入侵胰島可能與胰島內(nèi)Vsig4+巨噬細(xì)胞缺失有關(guān)[100]；而mEV的產(chǎn)生與腸道菌群穩(wěn)態(tài)之間的關(guān)系還不清楚，需要更深入的研究。

3.4 β細(xì)胞去分化與轉(zhuǎn)分化

2012年，Talchai等[87]報(bào)道了T2D模型的小鼠胰島中，高比例的β細(xì)胞分化程度出現(xiàn)了倒退，回到了前體細(xì)胞的狀態(tài)，失去了胰島素分泌的功能；這種丟失分化狀態(tài)的獨(dú)特生理學(xué)現(xiàn)象被命名為去分化。有研究顯示T2D患者損失的β細(xì)胞大部分都是通過(guò)去分化途徑，而不是通過(guò)凋亡途徑損失的[101]。Foxo1對(duì)β細(xì)胞分化狀態(tài)的維持具有重要的意義。在失代償期，代償期入核Foxo1的耗竭可能是β細(xì)胞去分化的重要推手：敲除Foxo1會(huì)導(dǎo)致只在前體β細(xì)胞中表達(dá)的基因，如Neurogenin3、Oct4、Nanog和L-Myc等在β細(xì)胞中表達(dá)，從而加速β細(xì)胞去分化[87]。

細(xì)胞譜系追蹤實(shí)驗(yàn)表明，T2D患者的β細(xì)胞可能會(huì)轉(zhuǎn)而分化為其他種類(lèi)的細(xì)胞，如α細(xì)胞[102]和δ細(xì)胞[101]；這種細(xì)胞命運(yùn)的改變被命名為轉(zhuǎn)分化[102]。發(fā)生這種轉(zhuǎn)換的原因是在α細(xì)胞和δ細(xì)胞中特征性表達(dá)的基因在β細(xì)胞中被異常激活；如β細(xì)胞中Arx基因的激活會(huì)抑制β細(xì)胞特征性的Pax4基因，使其帶有α細(xì)胞的特征[103,104]。目前尚不清楚β細(xì)胞轉(zhuǎn)分化是一步到位抑或是需要經(jīng)歷去分化的中間階段。雖然尚處在探索階段，去分化和轉(zhuǎn)分化現(xiàn)象的發(fā)現(xiàn)為T(mén)2D的干預(yù)和胰島β功能的保護(hù)提供了新的思路。

4 結(jié)語(yǔ)與展望

β細(xì)胞在2型糖尿病中的動(dòng)態(tài)變化在糖尿病的精準(zhǔn)診斷和治療中具有廣闊的應(yīng)用前景，已受到廣泛的關(guān)注。但目前仍并沒(méi)有技術(shù)能夠準(zhǔn)確地跟蹤胰島β細(xì)胞在人類(lèi)糖尿病患者發(fā)病過(guò)程的縱向變化。這主要存在三方面的困境：第一是胰腺的解剖位置復(fù)雜，第二是具有內(nèi)分泌功能的胰島在胰腺中占比極低，第三是通過(guò)血液循環(huán)中胰島素水平的變化來(lái)反映胰島β細(xì)胞的功能，無(wú)法避免外周組織胰島素敏感性對(duì)結(jié)果的干擾?；趪X動(dòng)物模型，目前已經(jīng)清楚β細(xì)胞在T2D中功能變化分為代償和失代償兩個(gè)階段(圖2)，但是尚沒(méi)有找到這兩個(gè)階段之間的明確分界。鑒于有研究表明進(jìn)入失代償期前的β細(xì)胞仍有逆轉(zhuǎn)的可能，探究這兩個(gè)時(shí)期之間的界限，開(kāi)發(fā)出相應(yīng)的分子標(biāo)志物，對(duì)糖尿病干預(yù)策略的制定和及時(shí)、精準(zhǔn)的治療可能大有裨益。

β細(xì)胞功能變化的調(diào)節(jié)可以在多個(gè)尺度上進(jìn)行研究。T2D的進(jìn)展會(huì)對(duì)多種器官組織產(chǎn)生復(fù)雜精細(xì)的影響，這些反過(guò)來(lái)又與β細(xì)胞發(fā)生深刻的相互作用，使β細(xì)胞不斷調(diào)整自己的生理活動(dòng)和分泌功能。與T2D進(jìn)程中β細(xì)胞功能動(dòng)態(tài)變化相關(guān)的有多種相互關(guān)聯(lián)的途徑，包括內(nèi)質(zhì)網(wǎng)應(yīng)激、氧化應(yīng)激、炎癥及β細(xì)胞去分化、轉(zhuǎn)分化。目前已有的藥物大多將治療策略定為增加β細(xì)胞的胰島素分泌，長(zhǎng)期用藥勢(shì)必使得β細(xì)胞超負(fù)荷工作，進(jìn)一步加重其代謝應(yīng)激，長(zhǎng)遠(yuǎn)來(lái)看是一種竭澤而漁的做法；而對(duì)胰島β細(xì)胞不同階段的代謝特征和代謝應(yīng)激通路的進(jìn)一步探究將有助于新治療靶點(diǎn)的發(fā)現(xiàn)和對(duì)應(yīng)藥物的開(kāi)發(fā)，以β細(xì)胞代謝應(yīng)激的逐漸緩解和功能的逐漸恢復(fù)為目的，為減輕T2D患者的胰島β細(xì)胞功能損傷提供“治本”的方案。近期刊登于的研究靶向參與β細(xì)胞氧化應(yīng)激的缺氧誘導(dǎo)因子-1α(hypoxia-inducible factor 1α，HIF1α)，通過(guò)抑制HIF1α實(shí)現(xiàn)了β細(xì)胞代謝應(yīng)激的緩解和功能的保護(hù)[105]，是對(duì)這種新治療思路的有效探索。近年來(lái)的新技術(shù)，諸如單細(xì)胞轉(zhuǎn)錄組學(xué)/表觀基因組分析和基于CRISPR的基因組編輯等新技術(shù)可以在這方面為人們提供新的見(jiàn)解。鑒于單細(xì)胞轉(zhuǎn)錄組學(xué)/表觀基因組技術(shù)目前只適用于新鮮組織，而大多數(shù)臨床樣本被固定包埋在石蠟中，因此開(kāi)發(fā)固定后石蠟包埋或其他常見(jiàn)儲(chǔ)存條件相兼容的新技術(shù)仍待解決[106]。

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Molecular mechanism of islet β-cell functional alternations during type 2 diabetes

Chengan Lv1,2, Ruoran Wang1,2, Zhuo-Xian Meng1,2

In recent years, the incidence rate of type 2 diabetes (T2D) has risen rapidly and has become a global health crisis. Recent experimental and clinical studies have shown that islet β-cell dysfunction is an important cause of T2D and its related complications. β-cells undergo dynamic compensation and decompensation in the course of T2D. In this process, metabolic stress responses, such as ER stress, oxidative stress and inflammation, are key regulators of β-cell functional alternations. In this review, we summarize the research progress on the β-cell functional dynamics in the course of T2D, in order to deepen the understanding of the molecular mechanism of T2D, and provide reference for its precise diagnosis and clinical intervention.

β-cell;type 2 diabetes; molecular mechanism

2022-08-04;

2022-09-02;

2022-09-30

國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：91857110，81722012，81670740)，科技部國(guó)家重點(diǎn)研發(fā)計(jì)劃項(xiàng)目(編號(hào)：2018YFA0800403，2021YFC20701903)，浙江省自然科學(xué)基金項(xiàng)目(編號(hào)：LZ21H070001)和杭州市醫(yī)學(xué)重點(diǎn)學(xué)科建設(shè)基金項(xiàng)目(No.OO20200055)資助 [Supported by the National Natural Science Foundation of China (Nos. 91857110, 81722012, 81670740), the National Key R&D Program of the Ministry of Science and Technology (Nos. 2018YFA0800403, 2021YFC20701903), the Zhejiang Provincial Natural Science Foundation of China (No. LZ21H070001), and the Construction Fund of Medical Key Disciplines of Hangzhou (No. OO20200055)]

呂承安，在讀臨床醫(yī)學(xué)八年制本科生，專(zhuān)業(yè)方向：糖尿病的分子機(jī)制。E-mail: 3190100992@zju.edu.cn

孟卓賢，博士，研究員，研究方向：糖尿病的分子機(jī)制。E-mail: zxmeng@zju.edu.cn

10.16288/j.yczz.22-265

(責(zé)任編委: 周紅文)