Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinaseaEuro2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling
Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinaseaEuro2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling
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DOI：
10.1007/s00125-012-2501-9
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发表时间：
2012-06-01
期刊：
影响因子：
8.2
通讯作者：
Vasavada, R. C.
中科院分区：
文献类型：
--
作者：
Kondegowda, N. Guthalu;Mozar, A.;Vasavada, R. C.
2型糖尿病的一个主要原因是功能性β细胞质量减少，部分原因是由糖脂毒性(GLT)等应激源引发的β细胞死亡增加。本研究评估了催乳素可以保护β细胞免受GLT的影响的假说，并探讨了促生存效应背后的机制。在INS-1细胞、啮齿类动物和人类胰岛中检测了外源性处理或内源性表达对GLT诱导的β细胞死亡的影响。通过抑制物siRNAs(显性负性突变体)和Cre-lox介导的基因缺失分析，确定了乳素促进生存的机制。乳素显著保护INS-1和原代啮齿动物β细胞免受GLT诱导的细胞死亡。催乳素对啮齿动物β细胞的促存活作用是通过激活Janus激酶-2(JAK2)/信号转导和转录激活因子-5(STAT5)信号通路来实现的。催乳素诱导的抗凋亡B细胞淋巴瘤-特大型(BCLXL)蛋白的增加是必需的，以介导其在INS-1细胞和原代啮齿动物β细胞中的促生存作用。最重要的是，催乳素对GLT诱导的人β细胞死亡有显著的保护作用，并且它们的促存活作用也是通过JAK2/STAT5通路介导的。这些研究与前人的工作一起清楚地证明了催乳素的促存活性质，并确认JAK2/STAT5通路是啮齿动物和人类β细胞这一效应的重要中介。未来的研究将确定这种多肽在体内对2型糖尿病的病理生理学的有效性。
A leading cause of type 2 diabetes is a reduction in functional beta cell mass partly due to increased beta cell death, triggered by stressors such as glucolipotoxicity (GLT). This study evaluates the hypothesis that lactogens can protect beta cells against GLT and examines the mechanism behind the pro-survival effect.The effect of exogenous treatment or endogenous expression of lactogens on GLT-induced beta cell death was examined in INS-1 cells, and in rodent and human islets. The mechanism behind the pro-survival effect of lactogens was determined using an inhibitor, siRNAs, a dominant negative (DN) mutant, and Cre-lox-mediated gene deletion analysis.Lactogens significantly protect INS-1 and primary rodent beta cells against GLT-induced cell death. The pro-survival effect of lactogens in rodent beta cells is mediated through activation of the Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling pathway. Lactogen-induced increase in the anti-apoptotic B cell lymphoma-extra large (BCLXL) protein is required to mediate its pro-survival effects in both INS-1 cells and primary rodent beta cells. Most importantly, lactogens significantly protect human beta cells against GLT-induced cell death, and their pro-survival effect is also mediated through the JAK2/STAT5 pathway.These studies, together with previous work, clearly demonstrate the pro-survival nature of lactogens and identify the JAK2/STAT5 pathway as an important mediator of this effect in both rodent and human beta cells. Future studies will determine the effectiveness of this peptide in vivo in the pathophysiology of type 2 diabetes.