Genes Dev:纤毛G蛋白偶联受体调节胰岛素和胰高血糖素的分泌

2021-10-22 从医路漫漫 MedSci原创

2型糖尿病(T2D)是一种流行疾病,影响着全球4亿多患者。T2D的特征包括血糖水平升高、循环胰岛素不足和胰高血糖素过高。

背景:2型糖尿病(T2D)是一种流行疾病,影响着全球4亿多患者。T2D的特征包括血糖水平升高、循环胰岛素不足和胰高血糖素过高。虽然葡萄糖是胰岛释放胰岛素和胰高血糖素的主要介质,但循环因子包括游离脂肪酸、氨基酸、神经递质和肠促胰岛素等激素也可发挥关键作用。因此,人们对调节胰岛素和胰高血糖素分泌的药物有相当大的兴趣,特别是调节肠促胰高血糖素样肽1 (GLP-1)和葡萄糖依赖性促胰岛素肽(GIP)的G蛋白偶联受体(GPCRs)的药物。GPCRs在许多方面有助于α和β细胞发挥功能,包括调节胰岛素和胰高血糖素分泌。最近的研究表明,初生纤毛在胰岛的β细胞中发挥关键作用,但该功能的分子性质尚不清楚。

方法:利用功能表达,我们在小鼠和人胰岛α和β细胞中鉴定了多个定位于纤毛的GPCRs,包括FFAR4、PTGER4、ADRB2、KISS1R和P2RY14。

结果:游离脂肪酸受体4 (FFAR4)和前列腺素E受体4 (PTGER4)激动剂刺激纤毛cAMP信号,促进α和β细胞系以及小鼠和人胰岛胰高血糖素和胰岛素分泌。GPCRs运输到初生纤毛需要TULP3,在原代人和小鼠胰岛中,TULP3的下调会改变纤毛FFAR4和PTGER4的定位,并影响调节的胰高血糖素或胰岛素分泌,而不影响纤毛结构。

图1 纤毛型GPCRs激动剂促进GSIS和GSGS。MIN6(A)和α-TC9(B)细胞对葡萄糖的反应呈剂量依赖性。观察血糖升高(2.8~25 mM)或降低(25~1 mM)1h后GSIS(C,D)和GSGS(E,F)的变化,以及激动剂对胰岛素和胰高血糖素分泌的影响。(A-F)将等量的MIN6或α-TC9细胞接种于96孔板(1×10~5个/孔)过夜培养,然后进行分泌物测定。误差条表示平均值±SD.N=3个独立实验。单因素方差分析:(∗)P<0.0 5,(∗∗)P<0.0 1,(∗∗∗)P<0.001。

图2 FFAR4和PTGER4是由小鼠和人胰腺α和β细胞表达的纤毛状GPCR。(A,B)鼠(A)和人(B)胰岛中α,β和δ细胞纤毛。用乙酰化微管蛋白、Ar13b、胰岛素、胰高血糖素和生长抑素抗体在共聚焦荧光显微镜下观察纤毛细胞,并进行定量。(C-J)在小鼠(C,G,E,I)和人(D,H,F,J)胰岛中,内源性FFAR4和PTGER4定位于α和β细胞的初级纤毛。(E,F,I,J)显示GPCRs阳性的小鼠(E,I)和人(F,J)纤毛α,β和δ细胞(标记为Ar113b)的百分比。误差条INA、B、E、F、I、J代表平均值±SD.N=3个独立实验,每个实验评分100-300个细胞。

图3 FFAR4调控的GSIS和GSGS在胰岛中是纤毛依赖性的。GSIS(A,E)和GSGS(C,G)在Tulp3基因敲除(ShTulp3)小鼠(A,C)和人(E,G)假胰岛中与杂乱对照(ShCon)小鼠(A,C)和人(E,G)相比没有变化。(B,D,F,H)Ffar4调控的GSIS(B,F)和GSGS(D,H)在小鼠(B,D)和人(F,H)假性胰岛中具有纤毛依赖性。观察葡萄糖浓度升高(2.8~25 mM)或降低(25~1 mM)1h诱导的GSIS(A,B,E,F)和GSGS(C,D,G,H),以及激动剂对胰岛素和胰高血糖素分泌的影响。误差条Ina-H表示平均值±SD。N=4个独立实验。双尾非配对t检验:(∗)P<0.0 5,(NS)无显著性。

结论:我们的发现提供了指标证据,胰岛α和β细胞调节的激素分泌是由纤毛GPCRs控制的,为糖尿病提供了新的靶点。

原文出处:

Wu CT,  Hilgendorf KI,  Bevacqua RJ, et al.Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion.Genes Dev 2021 Aug 12

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    2021-11-20 fzwish20000
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    2022-09-15 cy0324
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  7. [GetPortalCommentsPageByObjectIdResponse(id=1750273, encodeId=5e811e50273fd, content=<a href='/topic/show?id=be7c8385345' target=_blank style='color:#2F92EE;'>#胰岛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83853, encryptionId=be7c8385345, topicName=胰岛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a7a536274692, createdName=baoya, createdTime=Tue Mar 15 13:30:22 CST 2022, time=2022-03-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1682699, encodeId=76271682699d6, content=<a href='/topic/show?id=d4d031e8074' target=_blank style='color:#2F92EE;'>#分泌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=31780, encryptionId=d4d031e8074, topicName=分泌)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=30bd35, createdName=一叶知秋, createdTime=Tue Mar 29 13:30:22 CST 2022, time=2022-03-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1811544, encodeId=2890181154476, content=<a href='/topic/show?id=552688630bf' target=_blank style='color:#2F92EE;'>#蛋白偶联#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=88630, encryptionId=552688630bf, topicName=蛋白偶联)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5c0050, createdName=lishiwen, createdTime=Thu Jun 23 22:30:22 CST 2022, time=2022-06-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1982357, encodeId=337d198235e53, content=<a href='/topic/show?id=13b658e849' target=_blank style='color:#2F92EE;'>#Dev#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5878, encryptionId=13b658e849, topicName=Dev)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bcaa382, createdName=fzwish20000, createdTime=Sat Nov 20 11:30:22 CST 2021, time=2021-11-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2049392, encodeId=c569204939223, content=<a href='/topic/show?id=4363e929ad' target=_blank style='color:#2F92EE;'>#Gene#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7929, encryptionId=4363e929ad, topicName=Gene)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=63a4277, createdName=cy0324, createdTime=Thu Sep 15 08:30:22 CST 2022, time=2022-09-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1715531, encodeId=20861e1553105, content=<a href='/topic/show?id=b1f58362e8' target=_blank style='color:#2F92EE;'>#G蛋白#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=8362, encryptionId=b1f58362e8, topicName=G蛋白)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=91a331951491, createdName=12498f1em18(暂无昵称), createdTime=Tue May 31 14:30:22 CST 2022, time=2022-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1746946, encodeId=2ca01e4694604, content=<a href='/topic/show?id=165b836349' target=_blank style='color:#2F92EE;'>#G蛋白偶联受体#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=8363, encryptionId=165b836349, topicName=G蛋白偶联受体)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=601235881674, createdName=huiwelcome, createdTime=Wed Sep 07 03:30:22 CST 2022, time=2022-09-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1261220, encodeId=3a821261220b2, content=<a href='/topic/show?id=30c6102e2607' target=_blank style='color:#2F92EE;'>#高血糖#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=102726, encryptionId=30c6102e2607, topicName=高血糖)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=55ce62, createdName=hbwxf, createdTime=Sun Oct 24 13:30:22 CST 2021, time=2021-10-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1457643, encodeId=c8d9145e6436c, content=<a href='/topic/show?id=72148400568' target=_blank style='color:#2F92EE;'>#胰高血糖素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=84005, encryptionId=72148400568, topicName=胰高血糖素)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b38f5964248, createdName=sjzlzc009, createdTime=Sun Oct 24 13:30:22 CST 2021, time=2021-10-24, status=1, ipAttribution=)]
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    2021-10-24 hbwxf
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