Despite correlations between low vitamin D levels and diabetes incidence/severity, supplementation with vitamin D has not been widely effective in improving glucose parameters. This may be due to a lack of knowledge regarding how low vitamin D levels physiologically affect glucose homeostasis. We have previously shown that the brain may be a critical area for vitamin d-mediated action on peripheral glucose levels. However, the mechanisms for how vitamin D acts in the brain are unknown. We utilized a multimodal approach to determine the mechanisms by which vitamin D may act in the brain. We first performed an unbiased search (RNA-sequencing) for pathways affected by vitamin D. Vitamin D (125-dihydroxyvitamin D3; 1,25D3) delivered directly into the third ventricle of obese animals differentially regulated multiple pathways, including the insulin signaling pathway. The insulin signaling pathway includes PI3K, which is important in the brain for glucose regulation. Since others have shown that vitamin D acts through the PI3K pathway in non-neuronal cells (muscle and bone), we hypothesized that vitamin D may act in neurons through a PI3K-dependent pathway. In a hypothalamic cell-culture model (GT1-7 cells), we demonstrate that 1,25D3 increased phosphorylation of Akt in the presence of insulin. However, this was blocked with pre-treatment of wortmannin, a PI3K inhibitor. 1,25D3 increased gene transcription of several genes within the PI3K pathway, including Irs2 and p85, without affecting expression of InsR or Akt. Since we had previously shown that 1,25D3 has significant effects on neuronal function, we also tested if the PI3K pathway could mediate rapid actions of vitamin D. We found that 1,25D3 increased the firing frequency of neurons through a PI3K-dependent mechanism. Collectively, these data support that vitamin D enhances insulin signaling and neuronal excitability through PI3K dependent processes which involve both transcriptional and membrane-initiated signaling events.

中文翻译：

---

神经元中的维生素D作用需要PI3K途径来增强胰岛素信号传导和快速去极化作用。

尽管低维生素D水平与糖尿病的发生/严重程度之间存在相关性，但补充维生素D尚未广泛有效地改善葡萄糖参数。这可能是由于缺乏有关维生素D水平过低如何在生理上影响葡萄糖稳态的知识。先前我们已经表明，大脑可能是维生素D介导的对外周葡萄糖水平起作用的关键区域。但是，维生素D在大脑中的作用机理尚不清楚。我们采用了一种多峰方法来确定维生素D可能在大脑中起作用的机制。我们首先对受维生素D影响的途径进行了无偏性搜索（RNA测序）。维生素D（125-二羟基维生素D3； 1,25D3）直接递送至肥胖动物的第三脑室，通过多种途径进行差异调节，包括胰岛素信号通路。胰岛素信号传导途径包括PI3K，它在大脑中对于葡萄糖调节很重要。由于其他研究表明维生素D通过PI3K途径在非神经元细胞（肌肉和骨骼）中起作用，因此我们假设维生素D可能通过PI3K依赖性途径在神经元中起作用。在下丘脑细胞培养模型（GT1-7细胞）中，我们证明了在胰岛素存在下1,25D3增加了Akt的磷酸化。然而，这被PI3K抑制剂渥曼青霉素的预处理所阻断。1,25D3增加了PI3K途径中几个基因的基因转录，包括Irs2和p85，而没有影响InsR或Akt的表达。由于我们之前已经证明1,25D3对神经元功能有重大影响，我们还测试了PI3K途径是否可以介导维生素D的快速作用。我们发现1,25D3通过PI3K依赖性机制提高了神经元的放电频率。总体而言，这些数据支持维生素D通过PI3K依赖性过程增强胰岛素信号传导和神经元兴奋性，该过程涉及转录和膜启动信号传导事件。