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G6PC1和G6PC2影响G6P流量,但不影响HSD11B1活动

Emily M Hawes¹, Kayla A Boortz¹, James K Oeser¹

¹Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Journal of molecular endocrinology

|October 19, 2023

概括

葡萄糖-6-酸酶 (G6PC1/2) 抑制剂可以降低血糖,而不会增加葡萄糖皮质体信号传递. 这项研究发现G6PC1/2不会显著影响HSD11B1的活动,这表明向疗法是安全的.

科学领域:

生物化学和分子生物学
内分泌学和新陈代谢学

背景情况:

葡萄糖-6-酸酶催化子单元1和2 (G6PC1;G6PC2) 和酸脱酶 (H6PD) 是参与葡萄糖代谢的ER光酶.
11β-hydroxysteroid脱酶1型 (HSD11B1) 使用由H6PD生成的NADPH将皮质醇转化为皮质醇,影响胰岛素敏感性.
HSD11B1抑制剂改善胰岛素敏感性,而G6PC抑制剂预计会降低禁食血糖 (FBG).

研究的目的:

研究G6PC1/G6PC2和H6PD在调节葡萄糖-6-酸盐 (G6P) 流量的相互作用.
确定G6PC1/G6PC2是否影响HSD11B1活动和葡萄皮质皮质体信号传递.
评估G6PC抑制剂对代谢障碍的潜在治疗影响.

主要方法:

利用一种新型的转录试验,使用单独的融合基因来量化葡萄糖皮质体和葡萄糖信号.
过度表达的H6PD,HSD11B1,G6PC1和G6PC2在岛屿衍生的832/13和肝脏衍生的HepG2细胞系中.
研究了与11-dehydrocorticosterone (11-DHC) 治疗的野生类型和G6pc2淘汰赛小鼠的代谢变化.

主要成果:

过度表达H6PD和HSD11B1在两个细胞系中激活了葡萄糖皮质体信号传递.
在独立于G6P流量的情况下,HSD11B1的过度表达使得葡萄糖刺激的基因表达变得淡.
过度表达G6PC1/G6PC2抑制了葡萄糖信号传递,但对葡萄糖皮质体信号传递的影响很小;G6PC1/2对HepG2细胞没有影响.
动物研究表明,G6PC2的缺失不会影响代谢变化,这表明HSD11B1的活性与G6PC1/G6PC2无关.

结论:

HSD11B1的活动不受G6PC1或G6PC2的存在或不存在的显著影响.
预计G6PC1和G6PC2抑制剂可以有效降低FBG,而不会对葡萄糖皮质体信号产生不良影响.
这些发现支持G6PC抑制剂的开发,作为一种治疗策略,用于管理2型糖尿病等代谢疾病.

关键词:

11β-基类固醇脱酶1型葡萄糖的新陈代谢.葡萄糖-6-酸盐酶是什么葡萄糖-6-酸盐是一种赫索索-6-酸盐脱酶的使用小岛小岛是一个小岛.肝脏肝脏肝脏肝脏肝脏肝脏

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