The liver is crucial for the maintenance of normal glucose homeostasis — it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis.

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肝脏葡萄糖代谢在健康和疾病中的调节

肝脏对于维持正常的葡萄糖稳态至关重要，它在空腹时会产生葡萄糖，并在餐后储存葡萄糖。但是，这些肝过程在1型和2型糖尿病中失调，这种失衡会导致在空腹和餐后状态下的高血糖症。净肝葡萄糖产量是来自糖异生，糖原分解，糖原合成，糖酵解和其他途径的葡萄糖通量的总和。在这篇评论中，我们讨论了体内这些肝葡萄糖通量的调节。特别是，我们强调了肝糖原异生的间接（肝）控制和肝糖原代谢的直接（肝）控制的重要性。我们还提出了一种在2型糖尿病中亚临床肝胰岛素抵抗向明显的空腹高血糖发展的机制。还讨论了通过二甲双胍和胰岛素控制肝糖异生的见解，以及脂质诱导的肝胰岛素抵抗在修饰糖异生和净肝糖原合成通量中的作用。最后，我们考虑了针对肝脂肪变性，高血糖症和脂肪脂解的策略的治疗潜力。