Lactate is an important metabolic substrate for sustaining brain energy requirements when glucose supplies are limited. Recurring exposure to hypoglycemia (RH) raises lactate levels in the ventromedial hypothalamus (VMH) which contributes to counter-regulatory failure. However, the source of this lactate remains unclear. The present study investigates whether astrocytic glycogen serves as the major source of lactate in the VMH of RH rats. By decreasing the expression of a key lactate transporter in VMH astrocytes of RH rats, we reduced extracellular lactate concentrations, suggesting excess lactate was locally produced from astrocytes. To determine whether astrocytic glycogen serves as the major source of lactate, we chronically delivered either artificial extracellular fluid or 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) to inhibit glycogen turnover in the VMH of RH animals. Inhibiting glycogen turnover in RH animals prevented the rise in VMH lactate and the development of counter-regulatory failure. Lastly, we noted that RH led to an increase in glycogen shunt activity in response to hypoglycemia and elevated glycogen phosphorylase activity in the hours following a bout of hypoglycemia. Our data suggests that dysregulation of astrocytic glycogen metabolism following recurring exposure to hypoglycemia may be responsible, at least in part, for the rise in VMH lactate levels.

中文翻译：

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星形胶质细胞糖原是反复低血糖大鼠下丘脑乳酸的主要来源。

当葡萄糖供应有限时，乳酸是维持大脑能量需求的重要代谢底物。反复发生低血糖 (RH) 会导致腹内侧下丘脑 (VMH) 的乳酸水平升高，从而导致反调节失败。然而，这种乳酸的来源仍不清楚。本研究探讨星形胶质细胞糖原是否是 RH 大鼠 VMH 中乳酸的主要来源。通过降低 RH 大鼠 VMH 星形胶质细胞中关键乳酸转运蛋白的表达，我们降低了细胞外乳酸浓度，表明星形胶质细胞局部产生了过量的乳酸。为了确定星形细胞糖原是否是乳酸的主要来源，我们长期输送人工细胞外液或 1,4-二脱氧-1,4-亚氨基-d-阿拉伯糖醇 (DAB) 以抑制 RH 动物 VMH 中的糖原周转。抑制 RH 动物的糖原周转可以防止 VMH 乳酸的升高和反调节失败的发展。最后，我们注意到，RH 导致响应低血糖的糖原分流活性增加，并在低血糖发作后数小时内升高糖原磷酸化酶活性。我们的数据表明，反复发生低血糖后星形胶质细胞糖原代谢失调可能是（至少部分）VMH 乳酸水平升高的原因。