Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion
Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion
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DOI：
10.1073/pnas.1008859107
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Napoli, Joseph L.
中科院分区：
文献类型：
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作者：
Kane, Maureen A.;Folias, Alexandra E.;Napoli, Joseph L.
全反式维甲酸（atRA）异构体9-顺式维甲酸（9 cRA）在体外激活维甲酸受体（RAR）和类维生素A X受体（RXR）。RAR控制多个基因，而RXR作为RAR和其他调节代谢的核受体的伴侣。尚未确定9 cRA的生理功能，因为使用经分析验证的检测方法在血清或多种组织中未检出9 cRA。在这里，我们通过液相色谱/串联质谱（LC/MS/MS）鉴定了小鼠胰腺中的9 cRA，并表明9 cRA随着进食和葡萄糖给药后而降低，并与血清胰岛素呈反比。9 cRA通过降低葡萄糖转运蛋白2（Glut 2）和葡萄糖激酶（GK）活性，在15分钟内降低小鼠胰岛和大鼠β细胞系832/13中葡萄糖刺激的胰岛素分泌（GSIS）。9 cRA还降低Pdx-1和HNF 4 α mRNA表达，分别降低8倍和80倍：Pdx-1或HNF 4a缺陷导致年轻人成熟期糖尿病（分别为MODY 4和1），GK基因缺陷（MODY 2）也是如此。胰腺β细胞产生9 cRA，β细胞数量减少的小鼠模型、杂合秋田小鼠和链脲霉素处理的小鼠具有减少的9 cRA。9 cRA在具有β细胞肥大的葡萄糖不耐受小鼠中异常高，包括具有饮食诱导的肥胖（DIO）的小鼠以及ob/ob和db/db小鼠。这些数据确立了9 cRA作为具有多种作用机制的胰腺特异性autacoid，并提供了对GSIS的独特见解。
The all-trans-retinoic acid (atRA) isomer, 9-cis-retinoic acid (9cRA), activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in vitro. RARs control multiple genes, whereas RXRs serve as partners for RARs and other nuclear receptors that regulate metabolism. Physiological function has not been determined for 9cRA, because it has not been detected in serum or multiple tissues with analytically validated assays. Here, we identify 9cRA in mouse pancreas by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and show that 9cRA decreases with feeding and after glucose dosing and varies inversely with serum insulin. 9cRA reduces glucose-stimulated insulin secretion (GSIS) in mouse islets and in the rat beta-cell line 832/13 within 15 min by reducing glucose transporter type 2 (Glut2) and glucokinase (GK) activities. 9cRA also reduces Pdx-1 and HNF4 alpha mRNA expression, similar to 8- and 80-fold, respectively: defects in Pdx-1 or HNF4a cause maturity onset diabetes of the young (MODY4 and 1, respectively), as does a defective GK gene (MODY2). Pancreas beta-cells generate 9cRA, and mouse models of reduced beta-cell number, heterozygous Akita mice, and streptozotocin-treated mice have reduced 9cRA. 9cRA is abnormally high in glucose-intolerant mice, which have beta-cell hypertropy, including mice with diet-induced obesity (DIO) and ob/ob and db/db mice. These data establish 9cRA as a pancreas-specific autacoid with multiple mechanisms of action and provide unique insight into GSIS.