摘要

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).

译文

尽管葡萄糖-6-磷酸酶活性下降,糖原储存病 (GSD) I 型患者维持有限的内源性葡萄糖生成能力是一个长期的谜。鉴于这些患者的猝死风险,洞察残余内源性葡萄糖产生的来源具有临床重要性,但迄今为止已经提出了矛盾的机制。我们研究了从肝脏特异性 GSD Ia 小鼠模型 (L-G6pc-/-小鼠) 中分离的肝细胞中葡萄糖-6-磷酸酶非依赖性内源性葡萄糖产生并使用最先进的稳定同位素方法对 L-G6pc-/-小鼠的肝葡萄糖通量和糖原代谢进行实时分析。在这里,我们表明 G6pc-deficient 的肝细胞能够产生葡萄糖。肝葡萄糖代谢的体内分析显示,在 L-G6pc-/-小鼠中,肝葡萄糖激酶通量降低了 95%。它还显示了 L-G6pc-/-小鼠糖原磷酸化酶通量的增加,通过糖原去分支与游离葡萄糖的释放耦合在一起。尽管在 L-G6pc-/-小鼠中,两种主要的肝 α-葡萄糖苷酶 -- 去分支酶和溶酶体酸性麦芽糖酶的离体活性没有改变, α-葡萄糖苷酶活性的药理抑制几乎完全消除了 G6pc-deficient 肝细胞产生的剩余葡萄糖。
结论: 我们的数据表明肝细胞有助于 GSD Ia 中剩余葡萄糖的产生。我们表明 α-葡萄糖苷酶活性,即糖原去分支和/或溶酶体糖原分解,有助于 GSD Ia 肝细胞产生剩余葡萄糖。L-G6pc-/-小鼠肝脏 GCK 通量的强烈减少进一步限制了 G6pc-deficient 肝细胞合成的游离葡萄糖的磷酸化,允许葡萄糖释放到循环中。几乎完全废除 GCK 在 G6pc-deficient 肝脏的流量也解释了关于 GSD Ia 患者的剩余葡萄糖产生的矛盾报道。(肝病学 2017; 66: 2042-2054)。

Glycogen storage disease

内分泌 遗传性代谢疾病 疾病
概述  :  

糖原贮积病(GSD)都被认为是遗传性代谢疾病。因此,患有代谢紊乱的人很难分解某些食物并产生能量。代谢性疾病最常见的原因是缺乏酶(或蛋白质),酶可以帮助人体将食物分解为能量。人体中有许多酶,每种酶在装配线上的作用就像一台机器,当其中一种酶无法正常工作时,分解特定食物的过程可能会更加缓慢或完全关闭。患有糖原贮积病的人缺少或缺乏负责体内糖原形成或分解的酶之一。这称为酶缺乏症。酶缺乏会导致糖原的组织浓度异常(太多或太少)或糖原的形成错误或异常(形状错误)。这取决于人患有的GSD的类型,通常,GSD的

glycogen   英/'glaɪkədʒ(ə)n/   美/'glaɪkodʒən/

释    义   n. 糖原;动物淀粉

例    句   Storing glycogen (sugar), which the body uses for energy. 储存糖原(糖),作为身体使用的能量。

 

storage   英 /ˈstɔːrɪdʒ/   美 /ˈstɔːrɪdʒ/

释    义   n. 存储;仓库;贮藏所

例    句   In the storage of the powders it increases their fluidity and stability. 在粉未的贮存中它能增大它们的流动性和稳定性。

 

disease   英 /dɪˈziːz/   美 /dɪˈziːz/

释    义   n. 病,[医] 疾病;弊病

               vt. 传染;使…有病

例    句   Your doctor will be the one to ascertain if you do in fact have the disease. 您的医生将是一个以确定如果你确实有这种疾病。

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