吉慧珍;孙琦;杨静;邢小平;

• 1:中国医学科学院北京协和医学院北京协和医院内分泌科卫生部内分泌重点实验室
• 2:山西医科大学附属第一医院内分泌科

摘要(Abstract)：

<正>胰岛β细胞功能障碍是2型糖尿病由临床前期向临床期进展的关键环节,主要表现为胰岛素合成分泌的减少以及胰岛β细胞数量的下降。研究显示,2型糖尿病患者的胰岛β细胞数量较同体重指数的肥胖以及非肥胖人群分别减少63%及41%,而β细胞凋亡水平分别是肥胖及非肥胖人群的3倍和10倍[1],因此胰岛β细胞凋亡在2型糖尿病发生发展中具有十分重要的作用。在2型糖尿病中有多种机

关键词(KeyWords)： 内质网应激;微小核糖核酸;胰岛β细胞;凋亡

Abstract:

Keywords:

基金项目(Foundation):

作者(Authors): 吉慧珍;孙琦;杨静;邢小平;

参考文献(References)：

• [1]Butler AE,Janson J,Bonner-Weir S,et al.Beta-cell deficit and increased beta-cell apoptosis in human with type 2 diabetes[J].Diabetes,2003,52:102-110.
• [2]Schroder M,Kaufman RJ.The mammalian unfolded protein response[J].Annu Rev Biochem,2005,74:739-789.
• [3]Bernales S,Papa FR,Walter P,et al.Intracellular signaling by the unfolded protein response[J].Annu Rev Cell Dev Biol,2006,22:487-508.
• [4]Ron D,Walter P.Signal integration in the endoplasmic reticulum unfolded protein response[J].Nat Rev Mol Cell Biol,2007,8:519-529.
• [5]Han D,Lerner AG,Vande Walle L,et al.IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates[J].Cell,2009,138:562-575.
• [6]Upton JP,Wang L,Han D,et al.IRE1αcleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2[J].Science,2012,338:818-822.
• [7]Lerner AG,Upton JP,Praveen PV,et al.IRE1αinduces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress[J].Cell Metab,2012,16:250-264.
• [8]Hetz C,Bernasconi P,Fisher J,et al.Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha[J].Science,2006,312:572-576.
• [9]Urano F,Wang X,Bertolotti A,et al.Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1[J].Science,2000,287:664-666.
• [10]Hu P,Han Z,Couvillon AD,et al.Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappa B activation and down-regulation of TRAF2 expression[J].Mol Cell Biol,2006,26:3071-3084.
• [11]Lange PS,Chavez JC,Pinto JT,et al.ATF4 is an oxidative stress-inducible,prodeath transcription factor in neurons in vitro and in vivo[J].J Exp Med,2008,205:1227-1242.
• [12]Hiramatsu N,Messah C,Han J,et al.Translational and posttranslational regulation of XIAP by e IF2αand ATF4 promotes ER stress-induced cell death during the unfolded protein response[J].Mol Biol Cell,2014,25:1411-1420.
• [13]Oslowski CM,Hara T,O'Sullivan-Murphy B,et al.Thioredoxin-interacting protein mediates ER stress-inducedβcell death through initiation of the inflammasome[J].Cell Metab,2012,16:265-273.
• [14]Laybutt DR,Preston AM,Akerfeldt MC,et al.Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes[J].Diabetologia,2007,50:752-763.
• [15]Lipson KL,Fonseca SG,Ishigaki S,et al.Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1[J].Cell Metab,2006,4:245-254.
• [16]Wali JA,Rondas D,Thomas HE,et al.The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity[J].Cell Death Dis,2014,5:e1124.
• [17]Zheng X,Zheng X,Pereira TS,et al.Acute hypoxia induces apoptosis of pancreaticβ-cell by activation of the unfolded protein response and upregulation of CHOP[J].Cell Death Dis,2012,3:e322.
• [18]Hirata T,Kawai T,Itoh H,et al.Palmitic acid-rich diet suppresses glucose-stimulated insulin secretion(GSIS)and induces endoplasmic reticulum(ER)stress in pancreatic islets in mice[J].Endocr Res,2015,13:1-8.
• [19]Wali JA,Gurzov EN,Thomas HE,et al.Activation of the NLRP3 inflammasome complex is not required for stress-induced death of pancreatic islets[J].PLo S One,2014,9:e113128.
• [20]Němcová-FürstováV,BaluíkováK,Srámek J,et al.Caspase-2 and JNK activated by saturated fatty acids are not involved in apoptosis induction but modulate ER stress in human pancreaticβ-cells[J].Cell Physiol Biochem,2013,31:277-289.
• [21]Song B,Scheuner D,Ron D,et al.Chop deletion reduces oxidative stress,improvesβcell function,and promotes cell survival in multiple mouse models of diabetes[J].J Clin Invest,2008,118:3378-3389.
• [22]孙琦,向若兰,张文龙,等.4-苯基丁酸抗内质网应激诱导胰岛B细胞凋亡[J].解剖学报,2012,43:784-788.
• [23]Marchetti P,Bugliani M,Lupi R,et al.The endoplasmic reticulum in pancreatic beta cells of type diabetes patients[J].Diabetologia,2007,50:2486-2494.
• [24]Omikorede O,Qi C,Herbert TP,et al.ER stress in rodent islets of Langerhans is concomitant with obesity and beta-cell compensation but not with beta-cell dysfunction and diabetes[J].Nutr Diabetes,2013,3:e93.
• [25]Chan JY,Luzuriaga J,Laybutt DR,et al.Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in beta-cell gene expression and progression to diabetes[J].Diabetes,2013,62:1557-1568.
• [26]Engin F,Nguyen T,Yermalovich A,et al.Aberrant islet unfolded protein response in type 2 diabetes[J].Sci Rep,2014,4:4054.
• [27]Chan JY,Luzuriaga J,Maxwell EL,et al.The balance between adaptive and apoptotic unfolded protein responses regulates b-cell death under ER stress conditions through XBP1,CHOP and JNK[J].Mol Cell Endocrinol,2015,413:189-201.
• [28]Friedman RC,Farh KK,Burge CB,et al.Most mammalian mRNAs are conserved targets of microRNAs[J].Genome Res,2009,19:92-105.
• [29]Roggli E,Gattesco S,Caille D,et al.Changes in microRNA expression contribute to pancreaticβ-cell dysfunction in prediabetic NOD mice[J].Diabetes,2012,61:1742-1751.
• [30]Roggli E,Britan A,Gattesco S,et al.Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic beta-cells[J].Diabetes,2010,59:978-986.
• [31]Lin X,Guan H,Huang Z,et al.Downregulation of Bcl-2expression by miR-34a mediates palmitate-induced Min6 cells apoptosis[J].J Diabetes Res,2014,2014:258695.
• [32]Ruan Q,Wang T,Kameswaran V,et al.The microRNA-21-PDCD4 axis prevents type 1 diabetes by blocking pancreatic beta cell death[J].Proc Natl Acad Sci,2011,108:12030-12035.
• [33]Jacovetti C,Abderrahmani A,Parnaud G,et al.MicroRNAs contribute to compensatory beta cell expansion during pregnancy and obesity[J].J Clin Invest,2012,122:3541-3551.
• [34]Nesca V,Guay C,Jacovetti C,et al.Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes[J].Diabetologia,2013,56:2203-2212.
• [35]Li Y,Xu X,Liang Y,et al.miR-375 enhances palmitateinduced lipoapoptosis in insulin-secreting NIT-1 cells by repressing myotrophin(V1)protein expression[J].Int J Clin Exp Pathol,2010,3:254-264.
• [36]Guay C,Menoud V,Rome S,et al.Horizontal transfer of exosomal microRNAs transduce apoptotic signals between pancreatic beta-cells[J].Cell Commun Signal,2015,19:13-17.
• [37]Hofmann S,Cherkasova V,Bankhead P,et al.Translation suppression promotes stress granule formation and cell survival in response to cold shock[J].Mol Biol Cell,2012,23:3786-3800.
• [38]Leung AK,Calabrese JM,Sharp PA.Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules[J].Proc Natl Acad Sci USA,2006,103:18125-18130.
• [39]Bartoszewska S,Kochan K,Madanecki P,et al.Regulation of the unfolded protein response by microRNAs[J].Cell Mol Biol Lett,2013,18:555-578.
• [40]Cawley K,Logue SE,Gorman AM,et al.Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion[J].PLo S One,2013,8:e73870.
• [41]Filios SR,Xu G,Chen J,et al.MicroRNA-200 is induced by thioredoxin-interacting protein and regulates Zeb1 protein signaling and beta cell apoptosis[J].J Biol Chem,2014,289:36275-36283.