Mechanistic Investigation of GHS-R Mediated Glucose-Stimulated Insulin Secretion in Pancreatic Islets.
Mechanistic Investigation of GHS-R Mediated Glucose-Stimulated Insulin Secretion in Pancreatic Islets.
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DOI：
10.3390/biom12030407
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发表时间：
2022-03-06
期刊：
影响因子：
5.5
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Pradhan G;Lee JH;Wu CS;Wang H;Lin L;Donti T;Graham BH;Rajan AS;Balasubramanyam A;Samson SL;Guo S;Sun Y
Ghrelin受体是一种生长激素促分泌素受体（GHS-R），在胰腺中表达。新出现的证据表明，GHS-R参与葡萄糖刺激的胰岛素分泌（GSIS）的调节，但GHS-R调节胰腺中GSIS的机制尚不清楚。在这项研究中，我们研究了GHS-R对GSIS的作用，详细使用全球Ghsr−/−小鼠（体内）和Ghsr消融的胰岛（离体）。GSIS在Ghsr−/−小鼠和Ghsr消融的胰岛中均减弱，而WT和Ghsr−/−小鼠之间的胰岛形态相似。为了阐明Ghsr介导的GSIS的机制，我们研究了GSIS信号级联的关键步骤。在Ghsr消融的胰岛中，葡萄糖转运蛋白2（Glut 2）和葡萄糖代谢中间产物葡萄糖-6-磷酸（G6 P）的基因表达减少，支持葡萄糖摄取减少。WT和Ghsr−/−小鼠胰岛中线粒体DNA含量无差异，但Ghsr−/−胰岛中ATP/ADP比值显著低于WT胰岛。此外，胰腺和十二指肠同源框1（Pdx 1）以及胰岛素受体（IR）和胰岛素受体底物1和2（IRS 1/IRS 2）的胰岛素信号转导基因的表达在Ghsr−/−胰岛中下调。Akt是胰岛素信号级联反应的关键介质。同时，在胰岛素刺激和稳态条件下，Ghsr−/−小鼠胰腺中Akt磷酸化水平降低。这些发现表明，GHS-R消融影响胰腺中胰岛素信号通路的关键组分，表明GHS-R和胰岛中胰岛素信号通路之间存在串扰，GHS-R可能通过Akt-Pdx 1-GLUT 2通路调节GSIS。
Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global Ghsr−/− mice (in vivo) and Ghsr-ablated pancreatic islets (ex vivo). GSIS was attenuated in both Ghsr−/− mice and Ghsr-ablated islets, while the islet morphology was similar between WT and Ghsr−/− mice. To elucidate the mechanism underpinning Ghsr-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (Glut2) and the glucose-metabolic intermediate—glucose-6-phosphate (G6P) were reduced in Ghsr-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and Ghsr−/− mice, but the ATP/ADP ratio in Ghsr−/− islets was significantly lower than that of WT islets. Moreover, the expression of pancreatic and duodenal homeobox 1 (Pdx1), as well as insulin signaling genes of insulin receptor (IR) and insulin receptor substrates 1 and 2 (IRS1/IRS2), was downregulated in Ghsr−/− islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of Ghsr−/− mice under both insulin-stimulated and homeostatic conditions. These findings demonstrate that GHS-R ablation affects key components of the insulin signaling pathway in the pancreas, suggesting the existence of a cross-talk between GHS-R and the insulin signaling pathway in pancreatic islets, and GHS-R likely regulates GSIS via the Akt-Pdx1-GLUT2 pathway.
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影响因子：
5.8
作者：
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通讯作者：
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影响因子：
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DOI：
10.1152/ajpendo.00330.2007
发表时间：
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作者：
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