GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo.
GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo.
复制标题
DOI：
10.1186/s12915-021-00966-w
复制
发表时间：
2021-03-03
期刊：
影响因子：
5.4
通讯作者：
Murga C
中科院分区：
文献类型：
--
作者：
Arcones AC;Vila-Bedmar R;Mirasierra M;Cruces-Sande M;Vallejo M;Jones B;Tomas A;Mayor F Jr;Murga C
胰腺β细胞的胰岛素分泌受不同信号的精细调节，以充分控制葡萄糖稳态。肠促胰岛素激素如胰高血糖素样肽-1（GLP-1）通过与G蛋白偶联受体GLP-1 R结合，作为胰岛素释放的关键生理增强剂。胰岛素信号传导的另一个关键调节因子是丝氨酸/苏氨酸激酶G蛋白偶联受体激酶2（GRK 2）。然而，GRK 2是否影响胰岛素分泌或GRK 2是否可以控制肠促胰岛素在体内的作用仍有待分析。使用GRK 2半合子小鼠、分离的胰岛和模型β细胞系，我们已经揭示了GRK 2作为体内肠促胰岛素介导的胰岛素分泌的调节剂的相关生理作用。在GRK 2水平降低的动物（GRK 2 +/−小鼠）中喂食、口服葡萄糖灌胃或给予GLP-1 R激动剂可增强早期胰岛素释放，而不影响晚期分泌。相反，腹膜内葡萄糖诱导的胰岛素释放不受影响。这种效应在分离的胰岛中重现，并与在GRK 2 +/−小鼠中观察到的胰岛素颗粒的易释放池（RRP）的大小增加或引发功效相关。在β细胞系中使用nanoBRET，我们发现GLP-1 R的刺激促进GRK 2与该受体的结合，并且GRK 2蛋白和激酶活性是随后β抑制蛋白募集所必需的。总体而言，我们的数据表明GRK 2是GLP-1 R介导的胰岛素分泌的重要负调节剂，GRK 2干扰策略可能特别有利于早期β细胞胰岛素分泌，这种效应可能具有有趣的治疗应用。在线版本包含补充材料，可通过10.1186/s12915-021-00966-w获得。
Insulin secretion from the pancreatic β-cell is finely modulated by different signals to allow an adequate control of glucose homeostasis. Incretin hormones such as glucagon-like peptide-1 (GLP-1) act as key physiological potentiators of insulin release through binding to the G protein-coupled receptor GLP-1R. Another key regulator of insulin signaling is the Ser/Thr kinase G protein-coupled receptor kinase 2 (GRK2). However, whether GRK2 affects insulin secretion or if GRK2 can control incretin actions in vivo remains to be analyzed. Using GRK2 hemizygous mice, isolated pancreatic islets, and model β-cell lines, we have uncovered a relevant physiological role for GRK2 as a regulator of incretin-mediated insulin secretion in vivo. Feeding, oral glucose gavage, or administration of GLP-1R agonists in animals with reduced GRK2 levels (GRK2+/− mice) resulted in enhanced early phase insulin release without affecting late phase secretion. In contrast, intraperitoneal glucose-induced insulin release was not affected. This effect was recapitulated in isolated islets and correlated with the increased size or priming efficacy of the readily releasable pool (RRP) of insulin granules that was observed in GRK2+/− mice. Using nanoBRET in β-cell lines, we found that stimulation of GLP-1R promoted GRK2 association to this receptor and that GRK2 protein and kinase activity were required for subsequent β-arrestin recruitment. Overall, our data suggest that GRK2 is an important negative modulator of GLP-1R-mediated insulin secretion and that GRK2-interfering strategies may favor β-cell insulin secretion specifically during the early phase, an effect that may carry interesting therapeutic applications. The online version contains supplementary material available at 10.1186/s12915-021-00966-w.
登录
查看更多内容
影响因子：
2.2
作者：
Dolenšek J;Rupnik MS;Stožer A
通讯作者：
Stožer A
影响因子：
--
作者：
Hou, June Chunqiu;Min, Le;Pessin, Jeffrey E.
通讯作者：
Pessin, Jeffrey E.
DOI：
10.2337/ds16-0026
发表时间：
2017-08-01
期刊：
Diabetes spectrum : a publication of the American Diabetes Association
影响因子：
--
作者：
Hinnen, Deborah
通讯作者：
Hinnen, Deborah
影响因子：
64.5
作者：
Inoue, Asuka;Raimondi, Francesco;Russell, Robert B.
通讯作者：
Russell, Robert B.
影响因子：
7.7
作者：
Alenkvist, Ida;Gandasi, Nikhil R.;Tengholm, Anders
通讯作者：
Tengholm, Anders