Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets
Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets
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DOI：
10.3390/jcm8050674
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发表时间：
2019-05
影响因子：
3.9
通讯作者：
R. Goto;Tatsuya Kondo;Kaoru Ono;Sayaka Kitano;Nobukazu Miyakawa;Takuro Watanabe;M. Sakaguchi;Miki Sato;M. Igata;J. Kawashima;H. Motoshima;T. Matsumura;S. Shimoda;E. Araki
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作者：
R. Goto;Tatsuya Kondo;Kaoru Ono;Sayaka Kitano;Nobukazu Miyakawa;Takuro Watanabe;M. Sakaguchi;Miki Sato;M. Igata;J. Kawashima;H. Motoshima;T. Matsumura;S. Shimoda;E. Araki
由于肾素-血管紧张素-醛固酮系统影响葡萄糖稳态，胰岛的矿化皮质激素受体（MR）信号可能调节葡萄糖负荷下的胰岛素反应。胰高血糖素样肽-1 （GLP-1）的产生受白细胞介素-6 （IL-6）的刺激。为了确定MR、IL-6和GLP-1在胰岛中的相互作用是如何调节葡萄糖稳态的，我们对原发性醛固酮增生症（PA）模型啮齿动物的胰岛进行了葡萄糖耐量和组织学分析，并使用α-细胞系进行了体外实验。我们测量了原发性醛固酮增多症（PA）患者在服用MR拮抗剂epleenone前后的活性GLP-1浓度。在PA模型啮齿动物中，醛固酮降低了胰岛素分泌，胰岛/胰腺面积比和加入醛固酮（E+A）的依普利酮（eplerenone）恢复了α-细胞中IL-6的诱导。E+A处理α-细胞后，IL-6、GLP-1浓度升高，抗凋亡信号增强。E+ a处理也显著增加了MR和IL-6 mRNA，这些上调被使用小干扰RNA （siRNA）沉默MR所钝化。通过E+ a处理IL-6基因启动子的转录激活需要启动子中完整的MR结合元件。eperenone治疗后，PA患者活性GLP-1浓度显著升高。α-细胞中的MR信号可能刺激IL-6的产生，增加GLP-1的分泌，从而保护胰腺β细胞，改善葡萄糖稳态。
Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic α-cells. To determine how glucose homeostasis is regulated by interactions of MR, IL-6 and GLP-1 in islets, we performed glucose tolerance and histological analysis of islets in primary aldosteronism (PA) model rodents and conducted in vitro experiments using α-cell lines. We measured active GLP-1 concentration in primary aldosteronism (PA) patients before and after the administration of MR antagonist eplerenone. In PA model rodents, aldosterone decreased insulin-secretion and the islet/pancreas area ratio and eplerenone added on aldosterone (E+A) restored those with induction of IL-6 in α-cells. In α-cells treated with E+A, IL-6 and GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA (siRNA). Transcriptional activation of the IL-6 gene promoter by E+A-treatment required an intact MR binding element in the promoter. Active GLP-1 concentration was significantly increased in PA patients after eplerenone treatment. MR signal in α-cells may stimulate IL-6 production and increase GLP-1 secretion, thus protecting pancreatic β-cells and improving glucose homeostasis.