本文受兩項中華醫(yī)學會臨床醫(yī)學專項資金資助,基金編號13020120397和13040630448,并受第三軍醫(yī)大學青年人才基金項目資助,編號swh2013qn02.作者…

1、<p><b>　　腸促胰素與糖尿病</b></p><p>　　吳綺楠 綜述 陳兵 審校</p><p>　　QiNan Wu, Bing Chen*</p><p>　　第三軍醫(yī)大學第一附屬醫(yī)院內分泌科，重慶，400038</p><p>　　Endocrinology Department, the Fi

2、rst affiliated Hospital of the Third Military Medical University,</p><p>　　ChongQing 400038, China</p><p><b>　　通訊作者：陳兵</b></p><p>　　E-mail：chenbing3@medmail.com.cn</p

3、><p>　　Telephone：+86-23-68754138</p><p>　　本文受兩項中華醫(yī)學會臨床醫(yī)學專項資金資助，基金編號：13020120397和13040630448，并受第三軍醫(yī)大學青年人才基金項目資助，編號：SWH2013QN02 。</p><p>　　作者簡介：吳綺楠，男，1978.12-，副主任醫(yī)師，在讀博士，研究方向：糖尿病及其慢

4、性并發(fā)癥的防治</p><p>　　通訊作者簡介：陳兵，男，1960.11-，主任醫(yī)師，教授，博士生導師，研究方向：增齡性內分泌代謝疾病的防治</p><p>　　摘要：隨著胰高血糖素樣肽-1、二肽基肽酶-IV抑制劑以及胃轉流術在糖尿病治療領域的應用，越來越多的證據(jù)顯示糖尿病的發(fā)生發(fā)展與胃腸道分泌的一組激素-腸促胰素有關，本文將對腸促胰素在糖尿病中的研究進展和爭論做一綜述。</p&g

5、t;<p><b>　　Abstract</b></p><p>　　With the application of glucagon like peptide-1, dipeptidyl peptidase-IV inhibitor and gastric bypass in the treatment of diabetes, more and more evidence

6、reveals that diabetes is associated with a group of gut secretion hormone which called as incretin. This article reviews recent advances and controversies of incretins in diabetes.</p><p><b>　　概述</b

7、></p><p>　　腸促胰素（incretin）是一類由胃腸道K細胞和L細胞分泌的一類胃腸激素，其中主要包括胰高血糖素樣肽-1（glucagon like peptide-1， GLP-1），葡萄糖依賴性促胰島素激素(glucose-dependent insulinotropic polypeptide, GIP)以及胃腸釋放肽（Gastrin-releasing peptide GRP）等。早在20

8、世紀五十年代，有學者發(fā)現(xiàn)較之靜脈注射葡萄糖而言，口服葡萄糖刺激的胰島素分泌更顯著，這種效應稱之為腸促胰素效應（incretin effect），隨后發(fā)現(xiàn)，該效應所產(chǎn)生的胰島素占到了生理分泌的胰島素一半左右，其中以GLP-1促胰島素分泌效應最強[1]。而對于GLP-1的研究也是最多的，在GLP-1的研究基礎上，學者們提出胃腸-胰島素軸，進一步的研究發(fā)現(xiàn)GLP-1不僅具有調控進食后胰島素的分泌，還可抑制胰高血糖素的分泌，并參與下丘腦對食欲的

9、控制，延緩胃排空，減輕體重等功能。其中，GLP-1由胰高血糖素原產(chǎn)生，生理情況下GLP-1濃度較低，是因為其產(chǎn)生后迅速被二肽基肽酶-IV（dipeptidyl peptida</p><p>　　Incretin與胰島細胞功能和數(shù)量</p><p>　　胰島β細胞在數(shù)量和功能上的缺陷是1型糖尿病和2型糖尿病共同的重要發(fā)病機制之一，β細胞對葡萄糖和incretin如 GLP-1和GIP的反應

10、減弱時糖尿病的主要特征[3]。其中GLP-1激動劑對胰島β細胞功能和數(shù)量有顯著影響，其中包括：1）有效促進胰島細胞的增殖，減少胰島β細胞的凋亡率：由于GLP-1受體屬于α跨膜受體，通過激活Gsα蛋白，可進一步激活多條促進胰島β細胞增殖的信號通路，當小鼠被敲除Gsα后，可表現(xiàn)出胰島β細胞在數(shù)量上和功能上的缺失[4]。GLP-1尚可作用于FoxO1, PDX-1, Foxa2等一些對胰島β細胞數(shù)量和功能有影響的轉錄因子[5,6]。在健康小鼠

11、中，2周的Exendin-4治療可增加1.76倍的胰島體積[7]，相似的是，每日2次的Exendin-4治療較之未治療組的小鼠，胰島增殖速度達到2倍[8]。在Zucker大鼠體內，也得到了相似的結論[9]。進一步的研究發(fā)現(xiàn)，GLP-1促進胰島細胞增殖和防止凋亡主要的信號通路包括PKA，PI3K-Akt[10]，雖然這是GLP-1實現(xiàn)其生理功能研究最多的2個信號途徑，而近年多項研究均提示GLP-1通過這兩條信號途徑促進胰</p>

12、;<p>　　以上的研究說明，GLP-1主要通過促進胰島細胞增殖，減少其凋亡，誘導胰腺外分泌細胞分化成為胰島素分泌細胞對胰島細胞數(shù)量和功能產(chǎn)生影響，但這些過程涉及的具體機制尚需進一步研究。如由于wnt途徑是典型的致癌信號途徑，GLP-1激活wnt信號途徑在促進胰島細胞增殖及抑制凋亡中的作用可能是以后的研究熱點，糖尿病和一些癌癥在發(fā)病機制上是否有相同之處尚需進一步探討。再如無論是尸體來源、動物來源還是干細胞來源，可用于胰島移

13、植的細胞來源非常有限，GLP-1可促進胰腺導管細胞分化為胰島樣細胞的功能可為胰島移植提供另一個有希望的細胞來源，GLP-1可增加移植的胰島細胞存活率和功能也為未來胰島移植治療糖尿病帶來了新的希望。此外，長期單獨使用GLP-1很可能打破機體代謝平衡，由于GIP，GLP-1和胰高血糖素均參與了血糖和胰島素的調控，目前已經(jīng)有學者制成GLP-1，GIP和胰高血糖素三聯(lián)制劑并將之用于糖尿病動物和人并取得了良好的療效，這也是今后的研究熱點之一[29

14、]。</p><p>　　Incretin與1型糖尿病</p><p>　　1型糖尿病是一種自身免疫疾病，T淋巴細胞可自發(fā)攻擊本身的胰島β細胞導致其凋亡，造成胰島素分泌的絕對缺乏，大多數(shù)患者需要胰島素維持生命，而且在1型糖尿病患者中，仍然存在著胰高血糖素異常和胃排空異常。由于一系列針對2型糖尿病的臨床前和基礎研究中發(fā)現(xiàn)GLP-1可減少胰島β細胞凋亡和誘導胰島β細胞增殖的作用，因此對于1型糖

15、尿病來說，incretin制劑尤其是GLP-1有著潛在的重要治療價值，可有效對抗由自身免疫所誘導的胰島β細胞凋亡。其次，GLP-1可減少胰高血糖素的分泌，抑制胃排空，有助于有效的降低血糖，這也有助于1型糖尿病患者病情進展的控制。在NOD小鼠的研究中，人們發(fā)現(xiàn)持續(xù)的輸注GLP-1可增加胰島細胞再生，減少其凋亡，延緩1型糖尿病發(fā)展歷程[30]。但作者認為，單一的GLP-1治療在人類中不太可能取得類似的效應，聯(lián)合治療仍然是糖尿病治療的基本思路

16、，當在NOD小鼠中將GLP-1聯(lián)合其他藥物如抗-CD3，利索茶堿，抗人胸腺淋巴細胞血清以及胃泌素時，可明顯改善或逆轉糖尿病，尤其是在Exendin-4聯(lián)合抗人胸腺淋巴細胞血清后NOD小鼠的糖尿病改善率達到了88%[30]。有趣的是，有學者發(fā)現(xiàn)抗</p><p>　　綜合以上，迄今為止的證據(jù)表明，GLP-1受體激動劑可以促進1型糖尿病患者β細胞的恢復和血糖控制。GLP-1激動劑與一些免疫調節(jié)劑的聯(lián)用可更好的保護β細

17、胞和改善血糖控制。雖然缺乏較大規(guī)模的臨床試驗證實，但可以想象的是，GLP-1激動劑很有可能得到美國FDA批準在1型糖尿病患者中使用。</p><p>　　Incretin與2型糖尿病</p><p>　　GLP-1和GIP分泌和對胰島素的反應缺陷是2型糖尿病的特征之一[36]，GLP-1的分泌缺陷以及GLP-1對胰島素反應的缺陷（GLP-1抵抗）存在于很多2型糖尿病患者中，這是補充GLP-

18、1類似物和GLP-1受體激動劑的基礎，多項研究顯示，補充GLP-1和GLP-1受體激動劑可以改善2型糖尿病試驗動物和人的胰島素分泌，其機制仍然是GLP-1具有葡萄糖依賴性促胰島素分泌效應（glucose-stimulated insulin secretion GSIS），抑制胃排空，抑制胰高血糖素以及改善胰島β細胞功能[37]。眾所周知，胰島素抵抗在2型糖尿病發(fā)病中的重要一環(huán)，炎癥反應是胰島素抵抗的原因之一，Lee及同事發(fā)現(xiàn)GLP-1

19、可減輕脂肪細胞中的炎癥反應，并認為有助于改善胰島素抵抗[38]。另有研究發(fā)現(xiàn)每日皮下注射利拉魯肽可上調ob/ob小鼠海馬的Mash1基因表達，并通過上調脂聯(lián)素（一種能改善胰島素抵抗、高血糖、高血脂等代謝紊亂的脂肪因子），PPARα, PPARγ的表達，減輕肝臟和外周的胰島素抵抗，改善血糖控制和血脂[39,40]。有學者通過給小鼠注射表達Exendin-4的腺病毒，發(fā)現(xiàn)其</p><p>　　綜合以上，incret

20、in在2型糖尿病發(fā)病機制和病理生理進展中可能占有重要地位，2型糖尿病中存在GLP-1的分泌和抵抗，大規(guī)模的臨床試驗已證實GLP-1激動劑和DPP-IV抑制劑應用于2型糖尿病的療效與安全，胃腸道手術治療2型糖尿病的機制也主要在于激動incretin，但仍需大規(guī)模隨機對照的臨床研究以明確其長期效應和安全性，而GIP在2型糖尿病中的作用和地位尚需進一步研究以證實。</p><p><b>　　展望</b

21、></p><p>　　腸促胰素為基礎的治療在很大程度上已經(jīng)改變了人們對糖尿病的認識和治療。對腸促胰素的基礎研究也不斷的發(fā)現(xiàn)其對于胰島細胞增殖、凋亡、分化的影響，以上可能會對如何維持胰島細胞數(shù)量和功能以及胰島移植的細胞來源提供可能的方向。對GLP-1聯(lián)合免疫調節(jié)劑在1型糖尿病動物及患者中的研究正不斷的證明其對1型糖尿病的療效，并有助于更好的了解1型糖尿病發(fā)病的機制。2型糖尿病患者中廣泛存在著GLP-1和GI

22、P的分泌異常和作用異常，GLP-1類似物和受體激動劑可有效降低2型糖尿病患者空腹和餐后血糖水平而不引起低血糖。除了控制血糖，還有研究發(fā)現(xiàn)GLP-1為基礎的化合物也可有效降低體重，減少心血管疾病的危險因素，糾正能量代謝紊亂。這也有助于人們理解并發(fā)現(xiàn)2型糖尿病的發(fā)病機制，找到新的防治靶點。</p><p><b>　　參考文獻</b></p><p>　　Drucker

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