It is a long-standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose-6-phosphatase activity. Insight into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase–independent endogenous glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc^–/– mice) and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc^–/– mice using state-of-the-art stable isotope methodologies. Here we show that G6pc-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L-G6pc^–/– mice. It also showed increased glycogen phosphorylase flux in L-G6pc^–/– mice, which is coupled to the release of free glucose through glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic α-glucosidases, were unaltered in L-G6pc^−/− mice, pharmacological inhibition of α-glucosidase activity almost completely abolished residual glucose production by G6pc-deficient hepatocytes. Conclusion: Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that α-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6pc-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. (Hepatology 2017;66:2042–2054)

中文翻译：

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肝细胞有助于糖原贮积病Ia型小鼠模型中残留葡萄糖的产生

尽管糖6磷酸酶活性丧失，糖原贮积病（GSD）I型患者如何仍保留有限的内源性葡萄糖生产能力是一个长期的谜。考虑到这些患者突然死亡的风险，深入了解内源性葡萄糖残留的来源具有重要的临床意义，但到目前为止，已经提出了相互矛盾的机制。我们研究了葡萄糖-6-磷酸酶无关的内源性葡萄糖产生从肝脏特异性GSD IA小鼠模型（L-分离肝细胞G6PC ^{- / -}小鼠），并进行肝脏葡萄糖变化和糖原代谢的L-的实时分析G6PC ^{– / –}小鼠使用最先进的稳定同位素方法。在这里我们展示了G6pc缺乏的肝细胞能够产生葡萄糖。对肝葡萄糖代谢的体内分析显示，L- G6pc ^{– / –}小鼠的肝葡萄糖激酶通量降低了95％。它还显示L- G6pc ^{– / –}小鼠糖原磷酸化酶通量增加，这与通过糖原脱支释放游离葡萄糖有关。尽管在L- G6pc ^-/-小鼠中脱支酶和溶酶体酸性麦芽糖酶（两种主要的肝α-葡萄糖苷酶）的离体活性没有改变，但对α-葡萄糖苷酶活性的药理抑制作用几乎完全消除了缺乏G6pc的肝细胞产生的残余葡萄糖。结论：我们的数据表明，肝细胞有助于GSD Ia中残留的葡萄糖生成。我们表明，α-葡萄糖苷酶活性，即糖原解支和/或溶酶体糖原分解，有助于由GSD Ia肝细胞产生残余葡萄糖。L- G6pc-//-小鼠中肝GCK通量的强烈降低进一步限制了由G6pc缺陷型肝细胞合成的游离葡萄糖的磷酸化，从而允许葡萄糖释放到循环中。G6pc缺乏的肝脏中GCK通量几乎完全被废除，这也解释了GSD Ia患者残余葡萄糖生成的矛盾报道。（肝病学， 2017年； 66：2042-2054）