Division of Child Development and Metabolic Disease, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Biochem J. 2012 Jun 15;444(3):537-51. doi: 10.1042/BJ20120163.
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 (13)C-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 (13)C into the cycle (anaplerosis) and increased generation of (13)C 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.
GKAs（葡萄糖激酶激活剂）是治疗 2 型糖尿病的有前途的药物，但人们对它们对肝脏中间代谢的影响知之甚少。我们在肝脏灌注系统和分离的肝细胞中监测了（13）C 标记葡萄糖的命运。MS 和 NMR 光谱用于测量同位素丰度。结果表明，GKA 刺激糖酵解导致肝脏代谢发生许多变化：（i）通过 TCA（三羧酸）循环的通量增加，这表现在更多的（13）C 掺入循环（氨甲酰磷酸）和增加生成（13）C 异头物柠檬酸、谷氨酸和天冬氨酸（脱羧）；（ii）降低肝脏[Pi]和升高[ATP]，表示更高的磷酸化潜力和能量状态；（iii）刺激葡萄糖合成糖原，但抑制 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。本研究深入了解了 GKA 在肝脏中的作用，并揭示了 GKA 治疗糖尿病的潜在益处和风险。GKA 改善了肝脏的生物能量学、尿素生成和糖异生，但降低了糖异生，可能导致乳酸酸中毒和脂肪肝。
