Greene H L, Wilson F A, Hefferan P, Terry A B, Moran J R, Slonim A E, Claus T H, Burr I M
J Clin Invest. 1978 Aug;62(2):321-8. doi: 10.1172/JCI109132.
Other investigators have shown that fructose infusion in normal man and rats acutely depletes hepatic ATP and P(i) and increases the rate of uric acid formation by the degradation of preformed nucleotides. We postulated that a similar mechanism of ATP depletion might be present in patients with glucose-6-phosphatase deficiency (GSD-I) as a result of ATP consumption during glycogenolysis and resulting excess glycolysis. The postulate was tested by measurement of: (a) hepatic content of ATP, glycogen, phosphorylated sugars, and phosphorylase activities before and after increasing glycolysis by glucagon infusion and (b) plasma urate levels and urate excretion before and after therapy designed to maintain blood glucose levels above 70 mg/dl and thus prevent excess glycogenolysis and glycolysis. Glucagon infusion in seven patients with GSD-I caused a decrease in hepatic ATP from 2.25 +/- 0.09 to 0.73 +/- 0.06 mumol/g liver (P <0.01), within 5 min, persisting in one patient to 20 min (1.3 mumol/g). Three patients with GSD other than GSD-I (controls), and 10 normal rats, showed no change in ATP levels after glucagon infusion. Glucagon caused an increase in hepatic phosphorylase activity from 163 +/- 21 to 311 +/- 17 mumol/min per g protein (P <0.01), and a decrease in glycogen content from 8.96 +/- 0.51 to 6.68 +/- 0.38% weight (P <0.01). Hepatic content of phosphorylated hexoses measured in two patients, showed the following mean increases in response to glucagon; glucose-6-phosphate (from 0.25 to 0.98 mumol/g liver), fructose-6-phosphate (from 0.17 to 0.45 mumol/g liver), and fructose-1,6-diphosphate (from 0.09 to 1.28 mumol/g) within 5 min. These changes, except for glucose-6-phosphate, returned toward preinfusion levels within 20 min. Treatment consisted of continuous intragastric feedings of a high glucose dietary mixture. Such treatment increased blood glucose from a mean level of 62 (range 28-96) to 86 (range 71-143) mg/dl (P <0.02), decreased plasma glucagon from a mean of 190 (range 171-208) to 56 (range 30-70) pg/ml (P <0.01), but caused no significant change in insulin levels. Urate output measured in three patients showed an initial increase, coinciding with a decrease in plasma lactate and triglyceride levels, then decreased to normal within 3 days after treatment. Normalization of urate excretion was associated with normalization of serum uric acid. We suggest that the maintenance of blood glucose levels above 70 mg/dl is effective in reducing serum urate levels and that transient and recurrent depletion of hepatic ATP due to glycogenolysis is contributory in the genesis of hyperuricemia in untreated patients with GSD-I.
其他研究人员已表明，给正常人和大鼠输注果糖会急性消耗肝脏中的三磷酸腺苷（ATP）和无机磷酸（P(i)），并通过预先形成的核苷酸降解增加尿酸生成速率。我们推测，由于糖原分解过程中ATP的消耗以及随后过度的糖酵解，葡萄糖 - 6 - 磷酸酶缺乏症（GSD - I）患者可能存在类似的ATP消耗机制。通过以下测量对这一推测进行了验证：(a) 在通过输注胰高血糖素增加糖酵解之前和之后，测量肝脏中ATP、糖原、磷酸化糖的含量以及磷酸化酶活性；(b) 在旨在将血糖水平维持在70mg/dl以上从而防止过度糖原分解和糖酵解的治疗前后，测量血浆尿酸水平和尿酸排泄量。给7例GSD - I患者输注胰高血糖素后，肝脏ATP在5分钟内从2.25±0.09微摩尔/克肝脏降至0.73±0.06微摩尔/克肝脏（P<0.01），1例患者持续到20分钟（1.3微摩尔/克）。3例非GSD - I的GSD患者（对照组）以及10只正常大鼠在输注胰高血糖素后ATP水平无变化。胰高血糖素使肝脏磷酸化酶活性从163±21微摩尔/分钟每克蛋白质增加到311±17微摩尔/分钟每克蛋白质（P<0.01），糖原含量从8.96±0.51%重量降至6.68±0.38%重量（P<0.01）。在2例患者中测量的肝脏磷酸化己糖含量显示，对胰高血糖素的反应平均增加如下：5分钟内，6 - 磷酸葡萄糖（从0.25微摩尔/克肝脏增至0.98微摩尔/克肝脏）、6 - 磷酸果糖（从0.17微摩尔/克肝脏增至0.45微摩尔/克肝脏）和1,6 - 二磷酸果糖（从0.09微摩尔/克肝脏增至1.28微摩尔/克肝脏）。除6 - 磷酸葡萄糖外，这些变化在20分钟内恢复到输注前水平。治疗包括持续胃内给予高糖饮食混合物。这种治疗使血糖从平均水平62（范围28 - 96）毫克/分升升至86（范围71 - 143）毫克/分升（P<0.02），血浆胰高血糖素从平均190（范围171 - 208）皮克/毫升降至56（范围30 - 70）皮克/毫升（P<0.01），但胰岛素水平无显著变化。在3例患者中测量的尿酸排出量显示，最初增加，与血浆乳酸和甘油三酯水平降低同时发生，然后在治疗后3天内降至正常。尿酸排泄正常化与血清尿酸正常化相关。我们认为，将血糖水平维持在70mg/dl以上可有效降低血清尿酸水平，并且在未治疗的GSD - I患者中，由于糖原分解导致的肝脏ATP短暂和反复消耗是高尿酸血症发生的原因之一。
