Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics.
Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics.
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DOI：
10.1042/bj20120163
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发表时间：
2012-06-15
期刊：
影响因子：
--
通讯作者：
Matschinsky FM
中科院分区：
文献类型：
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作者：
Nissim I;Horyn O;Nissim I;Daikhin Y;Wehrli SL;Yudkoff M;Matschinsky FM
葡萄糖激酶激活剂（glucokinase activators，GKA）是治疗2型糖尿病的有效药物，但其对肝脏中间代谢的影响尚不清楚。我们监测的命运13 C-标记的葡萄糖在肝脏灌注系统和分离的肝细胞。MS和NMR光谱被用来测量同位素富集。结果表明，GKA对糖酵解的刺激导致肝脏代谢的许多变化：（i）通过三尖瓣环的通量增加（三羧酸）循环，如通过将更多的13 C掺入到循环中所证明的（回补）和柠檬酸盐、谷氨酸盐和天冬氨酸盐的13 C同位素异构体的生成增加（ii）降低肝脏[Pi]和升高[ATP]，表示更大的磷酸化潜力和能量状态;（iii）刺激由葡萄糖合成糖原，但抑制由3-碳前体合成糖原;（iv）增加N-乙酰谷氨酸的合成，从而增强尿素生成;（v）增加谷氨酰胺、丙氨酸、丝氨酸和甘氨酸的合成;和（vi）增加乳酸的产生和流出。本研究提供了对GKA肝脏作用的更深入了解，并揭示了GKA治疗糖尿病的潜在获益和风险。GKA可改善肝脏生物能量学、尿素生成和糖原生成，但可降低糖原生成，并有潜在的乳酸酸中毒和脂肪肝风险。
GKAs (glucokinase activators) are promising agents for the therapy of Type 2 diabetes, but little is known about their effects on hepatic intermediary metabolism. We monitored the fate of 13C-labelled glucose in both a liver perfusion system and isolated hepatocytes. MS and NMR spectroscopy were deployed to measure isotopic enrichment. The results demonstrate that the stimulation of glycolysis by GKA led to numerous changes in hepatic metabolism: (i) augmented flux through the TCA (tricarboxylic acid) cycle, as evidenced by greater incorporation of 13C into the cycle (anaplerosis) and increased generation of 13C isotopomers of citrate, glutamate and aspartate (cataplerosis); (ii) lowering of hepatic [Pi] and elevated [ATP], denoting greater phosphorylation potential and energy state; (iii) stimulation of glycogen synthesis from glucose, but inhibition of glycogen synthesis from 3-carbon precursors; (iv) increased synthesis of N-acetylglutamate and consequently augmented ureagenesis; (v) increased synthesis of glutamine, alanine, serine and glycine; and (vi) increased production and outflow of lactate. The present study provides a deeper insight into the hepatic actions of GKAs and uncovers the potential benefits and risks of GKA for treatment of diabetes. GKA improved hepatic bioenergetics, ureagenesis and glycogenesis, but decreased gluconeogenesis with a potential risk of lactic acidosis and fatty liver.