The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets.
The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets.
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P21激活的激酶（PAK1）参与了饮食诱导的小鼠和人类胰岛的β细胞质量扩张和存活。
DOI：
10.1007/s00125-016-4042-0
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发表时间：
2016-10
期刊：
影响因子：
8.2
通讯作者：
Thurmond DC
中科院分区：
文献类型：
--
作者：
Ahn M;Yoder SM;Wang Z;Oh E;Ramalingam L;Tunduguru R;Thurmond DC
据报道，来自2型糖尿病供体的人胰岛80%缺乏p21（Cdc 42/Rac）激活的激酶PAK 1。PAK 1与β细胞功能和β细胞群的维持有关。我们质疑PAK 1缺乏可能导致2型糖尿病易感性增加的机制。评价了在致糖尿病条件下（即使用特定细胞因子或在糖脂毒性[GLT]条件下）培养的非糖尿病人胰岛和INS 832/13 β细胞的PAK 1信号传导变化。使用经典敲除（Pak 1 −/−）小鼠评估PAK 1缺乏与GLT应激的综合效应，这些小鼠从基于脂肪/棕榈酸盐的“西方”饮食（WD）中获得45%的能量。还评估了PAK 1过表达或耗竭的INS 832/13细胞的凋亡和信号变化。非糖尿病人胰岛暴露于糖尿病应激源减弱PAK 1蛋白水平，同时增加半胱天冬酶3裂解。WD喂养的Pak 1基因敲除小鼠表现出空腹高血糖和严重的葡萄糖耐受不良。这些小鼠在急性葡萄糖激发后也未能产生胰岛素分泌反应，与WD喂养的野生型小鼠相比，β细胞质量损失43%。Pak 1基因敲除小鼠每个胰岛的总β细胞较少，与β细胞增殖减少一致。在INS 832/13 β细胞中，PAK 1缺乏联合GLT暴露相对于任一单独条件增加了β细胞死亡; PAK 1缺乏导致细胞外信号相关激酶（ERK）和B细胞淋巴瘤2（Bcl 2）磷酸化水平降低。相反，PAK 1过表达阻止GLT诱导的细胞死亡。这些发现表明PAK 1缺乏可能是糖尿病易感性增加的基础。发现通过改变PAK 1或其下游效应物来补救贫血失调的方法为疾病干预提供了有希望的机会。
Human islets from type 2 diabetic donors are reportedly 80% deficient in the p21 (Cdc42/Rac)-activated kinase, PAK1. PAK1 is implicated in beta cell function and maintenance of beta cell mass. We questioned the mechanism(s) by which PAK1 deficiency potentially contributes to increased susceptibility to type 2 diabetes. Non-diabetic human islets and INS 832/13 beta cells cultured under diabetogenic conditions (i.e. with specific cytokines or under glucolipotoxic [GLT] conditions) were evaluated for changes to PAK1 signalling. Combined effects of PAK1 deficiency with GLT stress were assessed using classic knockout (Pak1−/−) mice fed a 45% energy from fat/palmitate-based, ‘western’ diet (WD). INS 832/13 cells overexpressing or depleted of PAK1 were also assessed for apoptosis and signalling changes. Exposure of non-diabetic human islets to diabetic stressors attenuated PAK1 protein levels, concurrent with increased caspase 3 cleavage. WD-fed Pak1 knockout mice exhibited fasting hyperglycaemia and severe glucose intolerance. These mice also failed to mount an insulin secretory response following acute glucose challenge, coinciding with a 43% loss of beta cell mass when compared with WD-fed wild-type mice. Pak1 knockout mice had fewer total beta cells per islet, coincident with decreased beta cell proliferation. In INS 832/13 beta cells, PAK1 deficiency combined with GLT exposure heightened beta cell death relative to either condition alone; PAK1 deficiency resulted in decreased extracellular signal-related kinase (ERK) and B cell lymphoma 2 (Bcl2) phosphorylation levels. Conversely, PAK1 overexpression prevented GLT-induced cell death. These findings suggest that PAK1 deficiency may underlie an increased diabetic susceptibility. Discovery of ways to remediate glycaemic dysregulation via altering PAK1 or its downstream effectors offers promising opportunities for disease intervention.