Madadi Golnaz, Dalvi Prasad S, Belsham Denise D
Department of Physiology, University of Toronto, Medical Science Building 3247 A, King's College Circle, Toronto, Ont., Canada M5S 1A8.
Biochem Biophys Res Commun. 2008 Nov 28;376(4):694-9. doi: 10.1016/j.bbrc.2008.09.054. Epub 2008 Sep 20.
Whether the brain synthesizes insulin is currently debated. Two clonal, immortalized mouse hypothalamic cell lines from e17, mHypoE-39 and mHypoE-46, express insulin 2 (Ins2), but not Ins1. We analyzed regions necessary for basal gene activity and found that the mouse Ins2 region -110/+183 bp stimulates promoter activity in hypothalamic neurons. The rat Ins2 showed moderate activity, whereas the human promoter construct is repressed below basal levels. In MIN6 pancreatic beta-cells, all of the Ins1 and Ins2 promoter constructs display high levels of transcriptional activity. The cell lines also express components of glucose-sensing machinery and the endogenous glucagon-like peptide 1 receptor (Glp-1R). We observed that 16.7 mM glucose induces Ins2 mRNA, while forskolin and a Glp-1 agonist, exendin-4, induce a biphasic Ins2 mRNA response in mHypoE-39 neurons. The insulin cis-regulatory regions differ between the pancreas and the hypothalamus, and glucose and Glp-1 regulate the expression of hypothalamic insulin.
大脑是否合成胰岛素目前仍存在争议。来自胚胎第17天的两种克隆的永生化小鼠下丘脑细胞系，mHypoE - 39和mHypoE - 46，表达胰岛素2（Ins2），但不表达Ins1。我们分析了基础基因活性所必需的区域，发现小鼠Ins2区域-110 / +183 bp可刺激下丘脑神经元中的启动子活性。大鼠Ins2表现出中等活性，而人类启动子构建体则被抑制至基础水平以下。在MIN6胰腺β细胞中，所有Ins1和Ins2启动子构建体均显示出高水平的转录活性。这些细胞系还表达葡萄糖感应机制的成分和内源性胰高血糖素样肽1受体（Glp - 1R）。我们观察到16.7 mM葡萄糖可诱导Ins2 mRNA表达，而福斯可林和一种Glp - 1激动剂艾塞那肽-4可在mHypoE - 39神经元中诱导双相Ins2 mRNA反应。胰腺和下丘脑之间的胰岛素顺式调节区域不同，并且葡萄糖和Glp - 1调节下丘脑胰岛素的表达。
