花生四烯酸P450表氧化酶代谢物-EETs通过抑制肝脏炎症及刺激肝脏神经信号调控胰腺β细胞增殖及功能

Studies have shown that pancreatic β-cell proliferation and insulin secretion could be regulated by neuronal signals from the liver, proved the presence of vago-insulin system. Cytochrome P450 (CYP450) epoxygenases which is highly expressed in the cardiovascular system and hepacytes metabolize arachidonic acid to rich EETs. Our previous study found that CYP-EETs overexpression in diabetic animals models significantly reduced blood glucose, improved hepatic insulin resistance and inflammation, and inhibited islet injury. Accordingly, we proposed the hypothesis: In type 2 diabetes, CYP-EETs could regulate the function of pancreatic β-cell and improved insulin resistance through the inhibited hepatic infalammation and neuronal signals from the liver. To verify our hypothesis, our project adopted different vagotomy and nerve blockade, bilateral midbrain transfection in mouse model of type 2 diabetes with selective hepatic CYP44 gene knockout and overexpression, to clarify the role of CYP-EETs on islet in diabetes by inhibited hepatic infalammation and activated neural signals from liver. To investigate the neural signals mechanism of EETs implicated in pancreatic function and diabetes. This study would provide a new prospective for type 2 daibetes and it’s complication prevention and treatment from the inflammatory and neuronal pathway.

研究表明肝脏可通过迷走神经信号调节胰岛β细胞增殖与胰岛素分泌，即迷走-胰岛系统。花生四烯酸P450表氧化酶在心血管系统和肝细胞中高表达，代谢花生四烯酸产生丰富的代谢物-EETs。我们前期系列研究发现表氧化酶-EETs能非常显著降低糖尿病模型动物的血糖水平，改善肝脏胰岛素抵抗和炎症，并减轻胰岛细胞损伤。据此提出假说：在2型糖尿病中，表氧化酶-EETs可以通过抑制肝脏炎症和刺激迷走神经信号调控胰岛β细胞功能，改善胰岛素抵抗。为了验证这一假说，本项目将利用CYP44肝脏选择性基因敲除和高表达鼠建立2型糖尿病模型，通过不同的迷走神经切断术及阻滞术、中脑截断术等手段，明确表氧化酶-EETs经过抑制肝脏炎症和经过神经信号实现其在糖尿病发生中对胰岛系统的作用；探讨EETs调控胰岛功能背后的神经信号通路和改善糖尿病的神经信号机制。本研究将从炎症和神经信号途径出发为2型糖尿病及其并发症的防治提供新的思路。