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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健康和疾病中肝脏葡萄糖代谢的调节

肝脏对于维持正常的葡萄糖稳态至关重要——它在禁食期间产生葡萄糖并在餐后储存葡萄糖。然而，这些肝脏过程在 1 型和 2 型糖尿病中失调，这种不平衡会导致空腹和餐后状态下的高血糖。净肝葡萄糖生产是来自糖异生、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，我们强调了间接（肝外）控制肝糖异生和直接（肝）控制肝糖原代谢的重要性。我们还提出了 2 型糖尿病中亚临床肝胰岛素抵抗进展为明显空腹高血糖的机制。还讨论了对二甲双胍和胰岛素对肝糖异生的控制以及脂质诱导的肝胰岛素抵抗在改变糖异生和净肝糖原合成通量中的作用的见解。最后，我们考虑了针对肝脂肪变性、高胰高血糖素血症和脂肪分解的策略的治疗潜力。