Zhang Xueping, Yang Shanshan, Chen Jinglu, Su Zhiguang
Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
Front Endocrinol (Lausanne). 2019 Jan 24;9:802. doi: 10.3389/fendo.2018.00802. eCollection 2018.
Hepatic gluconeogenesis, glucose synthesis from available precursors, plays a crucial role in maintaining glucose homeostasis to meet energy demands during prolonged starvation in animals. The abnormally increased rate of hepatic gluconeogenesis contributes to hyperglycemia in diabetes. Gluconeogenesis is regulated on multiple levels, such as hormonal secretion, gene transcription, and posttranslational modification. We review here the molecular mechanisms underlying the transcriptional regulation of gluconeogenesis in response to nutritional and hormonal changes. The nutrient state determines the hormone release, which instigates the signaling cascades in the liver to modulate the activities of various transcriptional factors through various post-translational modifications like phosphorylation, methylation, and acetylation. AMP-activated protein kinase (AMPK) can mediate the activities of some transcription factors, however its role in the regulation of gluconeogenesis remains uncertain. Metformin, a primary hypoglycemic agent of type 2 diabetes, ameliorates hyperglycemia predominantly through suppression of hepatic gluconeogenesis. Several molecular mechanisms have been proposed to be metformin's mode of action.
肝糖异生，即利用可用前体合成葡萄糖，在动物长期饥饿期间维持葡萄糖稳态以满足能量需求方面发挥着关键作用。肝糖异生速率异常增加会导致糖尿病患者出现高血糖。糖异生在多个层面受到调控，如激素分泌、基因转录和翻译后修饰。我们在此综述响应营养和激素变化时糖异生转录调控的分子机制。营养状态决定激素释放，激素释放会引发肝脏中的信号级联反应，通过磷酸化、甲基化和乙酰化等各种翻译后修饰来调节各种转录因子的活性。AMP激活的蛋白激酶（AMPK）可以介导某些转录因子的活性，但其在糖异生调节中的作用仍不确定。二甲双胍是2型糖尿病的主要降糖药物，主要通过抑制肝糖异生来改善高血糖。已经提出了几种分子机制作为二甲双胍的作用方式。
