Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia
Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia
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DOI：
10.1172/jci65105
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发表时间：
2013-05-01
影响因子：
15.9
通讯作者：
Behar, Kevin L.
中科院分区：
文献类型：
--
作者：
Herzog, Raimund I.;Jiang, Lihong;Behar, Kevin L.
1型和2型糖尿病患者在强化胰岛素治疗期间经常发生低血糖，并且仍然是实现严格血糖控制的最重要障碍。使用低血糖的啮齿动物模型，我们证明了暴露于先前的复发性低血糖导致脑代谢的适应，使得循环乳酸的适度增加允许脑在急性低血糖条件下正常运作。我们描述了这种影响的三个主要因素。首先，我们测量了乳酸盐进出大脑的增强运输，这导致其对总脑氧化能力的贡献仅略有增加，这表明它不是主要的燃料。第二，我们观察到在低血糖条件下葡萄糖对脑代谢的贡献加倍，使代谢活性恢复到原本仅在正常时观察到的水平。第三，我们确定乳酸升高对于维持低血糖下的葡萄糖代谢至关重要，这保护了神经元功能。这些意想不到的发现表明，虽然乳酸摄取增强，但它不足以作为替代葡萄糖的替代底物来支持代谢。然而，乳酸能够调节代谢和神经元活动，而是作为“代谢调节剂”。
Hypoglycemia occurs frequently during intensive insulin therapy in patients with both type 1 and type 2 diabetes and remains the single most important obstacle in achieving tight glycemic control. Using a rodent model of hypoglycemia, we demonstrated that exposure to antecedent recurrent hypoglycemia leads to adaptations of brain metabolism so that modest increments in circulating lactate allow the brain to function normally under acute hypoglycemic conditions. We characterized 3 major factors underlying this effect. First, we measured enhanced transport of lactate both into as well as out of the brain that resulted in only a small increase of its contribution to total brain oxidative capacity, suggesting that it was not the major fuel. Second, we observed a doubling of the glucose contribution to brain metabolism under hypoglycemic conditions that restored metabolic activity to levels otherwise only observed at euglycemia. Third, we determined that elevated lactate is critical for maintaining glucose metabolism under hypoglycemia, which preserves neuronal function. These unexpected findings suggest that while lactate uptake was enhanced, it is insufficient to support metabolism as an alternate substrate to replace glucose. Lactate is, however, able to modulate metabolic and neuronal activity, serving as a "metabolic regulator" instead.