Diabetes:选择性Epac激动剂可恢复2型糖尿病胰岛的葡萄糖诱导的Cdc42-Pak1激活和胰岛素分泌

2018-07-24 MedSci MedSci原创

葡萄糖代谢刺激胰腺β细胞的Cdc42-Pak1活动、启动F-肌动蛋白细胞骨架重塑,进而将胞质内的分泌颗粒转运至细胞膜,完成胰岛素外分泌。在β细胞中,葡萄糖代谢还可生成cAMP,cAMP信号与Cdc42-Pak1激活交联可能是葡萄糖刺激胰岛素分泌(GSIS)的基础。既往已明确cAMP调节的鸟嘌呤核氨酸交换因子Epac2可通过cAMP升高剂介导增强GSIS。近期,Rajakrishnan Veluth

葡萄糖代谢刺激胰腺β细胞的Cdc42-Pak1活动、启动F-肌动蛋白细胞骨架重塑,进而将胞质内的分泌颗粒转运至细胞膜,完成胰岛素外分泌。在β细胞中,葡萄糖代谢还可生成cAMP,cAMP信号与Cdc42-Pak1激活交联可能是葡萄糖刺激胰岛素分泌(GSIS)的基础。既往已明确cAMP调节的鸟嘌呤核氨酸交换因子Epac2可通过cAMP升高剂介导增强GSIS。

近期,Rajakrishnan Veluthakal等人发现用选择性Epca激动剂8-pCPT-2’-O-Me-cAMP-AM处理非糖尿病(ND)人类胰岛和INS-1 832/13β细胞后,葡萄糖浓度1mM时,Cdc42-Pak1即可激活,该效应的强度相当于在缺乏8-pCPT-2’-O-Me-cAMP-AM的情况下,葡萄糖浓度20mM时所检测到的Cdc42-Pak1激活。而与之相反,cAMP拮抗剂Rp-8-Br-cAMPS-pAB可阻断葡萄糖诱导的Cdc42-Pak1激活,从而阻断GSIS,同时还可增加细胞内F-肌动蛋白含量。

来源于2型糖尿病(T2D)患者的胰岛细胞表现出明显的葡萄糖诱导的Cdc42-Pak1激活缺陷和胰岛素分泌障碍,Epac激活剂可拯救上述缺陷,进而恢复GSIS。

总而言之,本研究揭示了cAMP作为直接代谢耦合因子在Epac2和Cdc42-Pak1所调控的GSIS过程中发挥出乎意料的作用。

原始出处:

Rajakrishnan Veluthakal,et al. Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets. Diabetes  2018 Jul;  db171174. https://doi.org/10.2337/db17-1174

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    2018-08-05 gwc392
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  5. 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  6. 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createdBy=95bc21134754, createdName=medscijoin, createdTime=Thu Jul 26 13:34:00 CST 2018, time=2018-07-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1564463, encodeId=736c1564463b8, content=<a href='/topic/show?id=1c59438679' target=_blank style='color:#2F92EE;'>#CDC42#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4386, encryptionId=1c59438679, topicName=CDC42)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=23db14986201, createdName=hongbochen, createdTime=Thu Jul 26 13:34:00 CST 2018, time=2018-07-26, status=1, ipAttribution=)]
    2019-04-15 baoya
  8. 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    2018-07-26 hongbochen
  9. 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  10. 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    2018-07-26 hongbochen

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强化血压(BP)治疗是否有助于预防心血管事件,包括2型糖尿病患者的心衰?现有学者对此展开研究。研究人员利用ACCORD BP试验的数据,根据Cox风险率模型计算心血管事件的风险比,对比采取标准疗法(2362人)和强化血糖控制(2371人)的患者首次发生心血管事件的时间。总体平均随访4.5年,随访期间有528位患者确诊发生心血管事件。对于采用标准血糖控制的患者,强化BP治疗组的心血管事件风险明显低于