朱　瀅　林　琳　朱海杭

江蘇省蘇北人民醫(yī)院消化科1(225001)　南京醫(yī)科大學(xué)第一附屬醫(yī)院消化科2

糖基化終末產(chǎn)物在糖尿病胃腸動力中的作用及其機制

朱瀅1*林琳2朱海杭1#

江蘇省蘇北人民醫(yī)院消化科1(225001)南京醫(yī)科大學(xué)第一附屬醫(yī)院消化科2

糖尿病(diabetes mellitus, DM)幾乎可影響消化道所有部位，約75%的DM患者伴有胃腸動力障礙，常見癥狀有惡心、嘔吐、吞咽困難、反流、腹瀉、腹痛、便秘等[1]。盡管DM胃腸動力障礙的確切機制仍不清楚，但自主神經(jīng)病變?yōu)槠錆撛跈C制的觀點已被廣泛接受，并且越來越多的證據(jù)表明，其他病理生理因素亦在其中發(fā)揮重要作用，如平滑肌病變、Cajal間質(zhì)細(xì)胞病變、腸神經(jīng)系統(tǒng)病變等[1-3]。此外，DM胃腸動力障礙可能還與腸道菌群、腸道免疫等有關(guān)，但尚待進一步證實。文獻報道糖基化終末產(chǎn)物(advanced glycation end products, AGEs)在DM患者血清和各組織器官中的含量較正常人明顯升高，可通過氧化應(yīng)激、糖基化修飾某些蛋白等，在DM并發(fā)癥的發(fā)生、發(fā)展中起重要作用[4]。目前AGEs在DM并發(fā)癥中作用的研究主要集中于DM腎病、DM血管病變方面，其與DM胃腸動力障礙的相關(guān)性少見報道。本文對AGEs在DM胃腸動力中的作用及其可能機制作一綜述。

一、AGEs及其受體和非受體依賴性作用機制

AGEs是體內(nèi)由蛋白質(zhì)、脂質(zhì)或核酸等大分子物質(zhì)經(jīng)非酶促反應(yīng)與葡萄糖或其他還原單糖反應(yīng)生成的穩(wěn)定共價化合物，該過程稱為非酶糖基化反應(yīng)[5]。AGEs的形成是一個非常復(fù)雜的級聯(lián)反應(yīng)過程，DM時的高糖環(huán)境可促進其形成，具體機制尚未完全明確。由于AGEs是一類復(fù)雜的異構(gòu)化合物的總稱，因此須采用不同方法進行檢測[6]。AGEs對機體不同部位、不同類型細(xì)胞的影響不盡相同，作為DM并發(fā)癥的重要病理基礎(chǔ)，其可能參與了DM胃腸道并發(fā)癥的發(fā)生。

生理情況下，AGEs的產(chǎn)生和清除處于平衡狀態(tài)，如產(chǎn)生超過清除，將引發(fā)多種疾病，如DM慢性并發(fā)癥、衰老、動脈粥樣硬化、高血壓、阿爾茨海默病、腫瘤等。AGEs蓄積于細(xì)胞和基質(zhì)，通過受體依賴性和非受體依賴性途徑參與病理反應(yīng)。受體依賴性途徑系通過特定的細(xì)胞表面受體調(diào)節(jié)細(xì)胞功能，非受體依賴性途徑則系通過糖基化蛋白的蓄積改變細(xì)胞外基質(zhì)結(jié)構(gòu)等發(fā)揮作用[7-10]。RAGE(receptor for advanced glycation end products)是首個被描述的AGEs受體，其為一種多配體受體，是免疫球蛋白超家族成員，存在于平滑肌細(xì)胞、巨噬細(xì)胞、內(nèi)皮細(xì)胞和星形膠質(zhì)細(xì)胞表面。RAGE由3個胞外結(jié)構(gòu)域構(gòu)成，包括一個V型的具有配體結(jié)合特性的結(jié)構(gòu)域和兩個C型的免疫球蛋白結(jié)構(gòu)域。AGEs綁定至V型結(jié)構(gòu)域，產(chǎn)生持續(xù)的受體依賴性信號，介導(dǎo)細(xì)胞活化，導(dǎo)致炎癥反應(yīng)，最終改變組織細(xì)胞功能[11-12]。AGEs/RAGE系統(tǒng)被認(rèn)為是引起DM并發(fā)癥的重要病理機制之一，參與DM心血管疾病、視網(wǎng)膜病變、腎病等的發(fā)生[13-15]。除與RAGE結(jié)合激活細(xì)胞內(nèi)信號轉(zhuǎn)導(dǎo)途徑外，AGEs還可通過修飾細(xì)胞外蛋白的結(jié)構(gòu)和功能發(fā)揮作用。糖基化蛋白的結(jié)構(gòu)對降解更為耐受，交聯(lián)產(chǎn)物蓄積于細(xì)胞和組織間，參與器官和血管功能障礙的形成；此外，糖基化蛋白還可通過破壞正常蛋白的分子構(gòu)象改變酶活性以及干擾配體與受體的識別等[16]。

二、AGEs與DM胃腸動力障礙

1. AGEs在胃腸道自主神經(jīng)中的分布及其作用：多項研究表明DM患者存在胃腸慢傳輸和蠕動異常，DM自主神經(jīng)病變被認(rèn)為是引起胃腸運動和感覺功能障礙的主要原因之一[17]。鑒于AGEs對各組織器官均有影響，因此推測其參與了DM胃腸動力障礙的發(fā)生、發(fā)展。非DM、DM個體和動物模型的整個中樞和周圍神經(jīng)系統(tǒng)均可檢出AGEs，包括神經(jīng)元、軸突、Schwann細(xì)胞、血管內(nèi)皮細(xì)胞、周細(xì)胞、基底膜等，RAGE則分布于整個中樞和周圍神經(jīng)系統(tǒng)的神經(jīng)軸[18]。AGEs的蓄積一方面直接影響蛋白結(jié)構(gòu)和功能，另一方面通過結(jié)合RAGE間接發(fā)揮功能，后者在DM神經(jīng)病變的發(fā)生、發(fā)展中起重要作用[19]。Jeyabal等[20]的研究顯示，胃腸道神經(jīng)元表達神經(jīng)元型一氧化氮合酶(nNOS)，誘導(dǎo)產(chǎn)生一氧化氮(NO)，NO是調(diào)節(jié)胃腸運動的關(guān)鍵抑制性神經(jīng)遞質(zhì)，而AGEs能抑制腸道nNOS，從而抑制NO產(chǎn)生；在DM大鼠模型中，AGEs抑制劑 ALT-711可阻止腸神經(jīng)元nNOS缺失，進而維持NO產(chǎn)生，以調(diào)節(jié)胃腸運動功能。Toth等[21]的研究證據(jù)表明，大量RAGE在神經(jīng)元軸突和神經(jīng)膠質(zhì)細(xì)胞的表達參與了DM對稱性感覺運動多發(fā)性神經(jīng)病變的信號轉(zhuǎn)導(dǎo)過程。Chen等[22]對DM大鼠模型的研究發(fā)現(xiàn)，AGEs和RAGE在小腸和結(jié)腸肌間神經(jīng)叢和黏膜下神經(jīng)叢蓄積，兩者含量均明顯增多。上述研究證據(jù)表明，AGEs/RAGE系統(tǒng)似在DM胃腸自主神經(jīng)病變中起重要作用。

2. AGEs在胃腸道肌層的分布及其作用：AGEs在上皮細(xì)胞、平滑肌細(xì)胞、肌間和黏膜下神經(jīng)叢神經(jīng)元中呈均勻分布，RAGE主要分布于上皮細(xì)胞和神經(jīng)元細(xì)胞膜，正常平滑肌細(xì)胞未觀察到RAGE陽性染色。AGEs在肌層蓄積以及神經(jīng)節(jié)RAGE表達增加可能參與了DM小腸和結(jié)直腸運動障礙的發(fā)生、發(fā)展[23]。Chen等[22]的研究表明，DM大鼠模型回腸環(huán)肌層、縱肌層增厚，絨毛、隱窩、環(huán)肌層AGEs和RAGE表達顯著上調(diào)，可能影響小腸平滑肌的收縮特性。在其他組織器官如腎臟中，AGEs可通過激活RAGE導(dǎo)致上皮細(xì)胞向肌成纖維細(xì)胞轉(zhuǎn)分化，引起組織纖維化[24]，由此推測AGEs亦可能引起胃腸組織纖維化，進而影響胃腸運動功能。但目前尚無實驗證據(jù)支持AGEs/RAGE系統(tǒng)可促進胃腸組織纖維化，該假設(shè)有待進一步研究證實。

3. AGEs在胃腸道黏膜的分布及其作用：眾所周知，小腸上皮細(xì)胞在食物的消化、吸收中起重要作用。刷狀緣是小腸消化和運輸過程中的重要位點，多種位于小腸微絨毛刷狀緣的酶類參與了碳水化合物和肽類的消化，如乳糖酶、 蔗糖酶、麥芽糖酶、α-糊精酶等。Chen等[22]的研究顯示，AGEs在空腸、回腸微絨毛和隱窩蓄積以及RAGE表達增加可能參與DM小腸消化和吸收功能障礙。DM時小腸上皮細(xì)胞微絨毛膜脂質(zhì)流動性降低[25]，膜的流動性可改變刷狀緣消化酶活性，因此AGEs可能通過影響細(xì)胞膜特性，導(dǎo)致小腸微絨毛膜流動性降低，進而影響小腸吸收功能。已證明RAGE能激活多種細(xì)胞內(nèi)信號級聯(lián)反應(yīng)，誘導(dǎo)腸上皮細(xì)胞功能改變[26]，AGEs/RAGE系統(tǒng)在DM胃腸道黏膜病變中的機制及其與DM胃腸動力障礙間是否存在直接聯(lián)系，尚需進一步研究。

三、總結(jié)與展望

綜上所述，AGEs異常蓄積在DM并發(fā)癥的發(fā)生、發(fā)展中起重要作用，但其參與DM胃腸動力障礙的具體機制尚未完全明確，關(guān)于AGEs與DM胃腸動力有以下問題亟待解決：AGEs和RAGE在胃腸道內(nèi)的分布及其作用；內(nèi)源性AGEs對胃腸動力的直接影響；胞內(nèi)第二信使信號通路、離子通道等在AGEs抑制胃腸動力中的作用等。上述問題的研究和解決，不僅對完善胃腸運動調(diào)節(jié)機制的認(rèn)知具有重要意義，而且可能為胃食管反流、便秘等DM相關(guān)胃腸動力障礙癥狀的治療提供新的靶點。

參考文獻

1 Yarandi SS, Srinivasan S. Diabetic gastrointestinal motility disorders and the role of enteric nervous system: Current status and future directions[J]. Neurogastroenterol Motil, 2014, 26 (5): 611-624.

2 Wang Y, Xu XY, Tang YR, et al. Effect of endogenous insulin-like growth factor and stem cell factor on diabetic colonic dysmotility[J]. World J Gastroenterol, 2013, 19 (21): 3324-3331.

3 Bagyanszki M, Bodi N. Diabetes-related alterations in the enteric nervous system and its microenvironment[J]. World J Diabetes, 2012, 3 (5): 80-93.

4 Wei Q, Ren X, Jiang Y, et al. Advanced glycation end products accelerate rat vascular calcification through RAGE/oxidative stress[J]. BMC Cardiovasc Disord, 2013, 13: 13.

5 Arsov S, Graaff R, van Oeveren W, et al. Advanced glycation end-products and skin autofluorescence in end-stage renal disease: a review[J]. Clin Chem Lab Med, 2014, 52 (1): 11-20.

6 Yamagishi S. Role of advanced glycation end products (AGE) and soluble receptor for AGE (sRAGE) in vascular complications in diabetes[J]. Nihon Rinsho, 2012, 70 Suppl 5: 243-247.

7 Park SY, Kim YA, Hong YH, et al. Up-regulation of the receptor for advanced glycation end products in the skin biopsy specimens of patients with severe diabetic neuropathy[J]. J Clin Neurol, 2014, 10 (4): 334-341.

8 牛軼雯，繆明遠，董煒，等. 晚期糖基化終末產(chǎn)物與其受體對糖尿病創(chuàng)面氧化應(yīng)激反應(yīng)的影響[J]. 中華燒傷雜志, 2012, 28 (1): 32-35.

9 Kalousova M, Zima T. AGEs and RAGE - advanced glycation end-products and their receptor in questions and answers[J]. Vnitr Lek, 2014, 60 (9): 720-724.

10Fukami K, Yamagishi S, Okuda S. Role of AGEs-RAGE system in cardiovascular disease[J]. Curr Pharm Des, 2014, 20 (14): 2395-2402.

11Zhu P, Ren M, Yang C, et al. Involvement of RAGE, MAPK and NF-kappaB pathways in AGEs-induced MMP-9 activation in HaCaT keratinocytes[J]. Exp Dermatol, 2012, 21 (2): 123-129.

12Kierdorf K, Fritz G. RAGE regulation and signaling in inflammation and beyond[J]. J Leukoc Biol, 2013, 94 (1): 55-68.

13Prasad A, Bekker P, Tsimikas S. Advanced glycation end products and diabetic cardiovascular disease[J]. Cardiol Rev, 2012, 20 (4): 177-183.

14Chen M, Curtis TM, Stitt AW. Advanced glycation end products and diabetic retinopathy[J]. Curr Med Chem, 2013, 20 (26): 3234-3240.

15Ishibashi Y, Yamagishi S, Matsui T, et al. Pravastatin inhibits advanced glycation end products (AGEs)-induced proximal tubular cell apoptosis and injury by reducing receptor for AGEs (RAGE) level[J]. Metabolism, 2012, 61 (8): 1067-1072.

16Zhao Z, Liu J, Shi B, et al. Advanced glycation end product (AGE) modified proteins in tears of diabetic patients[J]. Mol Vis, 2010, 16: 1576-1584.

17Chandrasekharan B, Anitha M, Blatt R, et al. Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress[J]. Neurogastroenterol Motil, 2011, 23 (2): 131-138, e126.

18King RH. The role of glycation in the pathogenesis of diabetic polyneuropathy[J]. Mol Pathol, 2001, 54 (6): 400-408.

19Singh VP, Bali A, Singh N, et al. Advanced glycation end products and diabetic complications[J]. Korean J Physiol Pharmacol, 2014, 18 (1): 1-14.

20Jeyabal PV, Kumar R, Gangula PR, et al. Inhibitors of advanced glycation end-products prevent loss of enteric neuronal nitric oxide synthase in diabetic rats[J]. Neurogastroenterol Motil, 2008, 20 (3): 253-261.

21Toth C, Rong LL, Yang C, et al. Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy[J]. Diabetes, 2008, 57 (4): 1002-1017.

22Chen P, Zhao J, Gregersen H. Up-regulated expression of advanced glycation end-products and their receptor in the small intestine and colon of diabetic rats[J]. Dig Dis Sci, 2012, 57 (1): 48-57.

23Yamagishi S. Advanced glycation end products and receptor-oxidative stress system in diabetic vascular complications[J]. Ther Apher Dial, 2009, 13 (6): 534-539.

24Oldfield MD, Bach LA, Forbes JM, et al. Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE)[J]. J Clin Invest, 2001, 108 (12): 1853-1863.

25Brasitus TA, Dudeja PK. Correction of abnormal lipid fluidity and composition of rat ileal microvillus membranes in chronic streptozotocin-induced diabetes by insulin therapy[J]. J Biol Chem, 1985, 260 (23): 12405-12409.

26Bierhaus A, Humpert PM, Morcos M, et al. Understanding RAGE, the receptor for advanced glycation end products[J]. J Mol Med (Berl), 2005, 83 (11): 876-886.

(2014-10-14收稿；2014-11-06修回)

·病例分析與個案報道·

摘要糖尿病(DM)幾乎可影響消化道所有部位，約75%的DM患者伴有胃腸動力障礙。DM胃腸動力障礙的確切機制仍不清楚，其發(fā)生系由多因素所致，可能與自主神經(jīng)病變、平滑肌病變、Cajal間質(zhì)細(xì)胞病變等有關(guān)。糖基化終末產(chǎn)物(AGEs)是體內(nèi)葡萄糖與蛋白質(zhì)、脂質(zhì)或核酸等經(jīng)非酶促反應(yīng)生成的化合物。DM時的高糖環(huán)境可促進AGEs形成，AGEs異常蓄積在DM并發(fā)癥如DM腎病、DM血管病變的發(fā)生、發(fā)展中起重要作用，但其與DM胃腸動力障礙的相關(guān)性少見報道。本文對AGEs在DM胃腸動力中的作用及其可能機制作一綜述。

關(guān)鍵詞糖尿?。晃改c活動；糖基化終產(chǎn)物，高級

Roles and Mechanisms of Advanced Glycation End Products in Diabetic Gastrointestinal MotilityZHUYing1,LINLin2,ZHUHaihang1.1DepartmentofGastroenterology,NorthernJiangsuPeople’sHospital,Yangzhou,JiangsuProvince(225001);2DepartmentofGastroenterology,theFirstAffiliatedHospitalofNanjingMedicalUniversity,Nanjing

Correspondence to: ZHU Haihang, Email: zhuhaihang@medmail.com.cn

AbstractDiabetes mellitus (DM) affects almost the whole digestive tract. Approximately 75% of the diabetic patients suffer from gastrointestinal motility disorders. The precise mechanism of diabetic gastrointestinal motility disorders is not fully clear. Its pathogenesis is considered to be multifactorial and related with autonomic neuropathy, smooth muscle myopathy and lesions of interstitial cells of Cajal. Advanced glycation end products (AGEs) are derived from the nonenzymatic reaction of glucose with proteins, lipids or nucleic acids in vivo. Hyperglycemia in DM is a favourite for formation of AGEs, and excessive accumulation of AGEs contributes to the complications of DM such as diabetic nephropathy and diabetic vascular lesions. However, the correlation of AGEs with diabetic gastrointestinal motility disorders is seldom reported. In this review article, the roles and possible mechanisms of AGEs in diabetic gastrointestinal motility were summarized.

Key wordsDiabetes Mellitus;Gastrointestinal Motility;Glycosylation End Products, Advanced

通信作者#本文，Email: zhuhaihang@medmail.com.cn

DOI:*Email: bujingzhuying@126.com