Recurrent hypoglycemia increases hypothalamic glucose phosphorylation activity in rats.
Recurrent hypoglycemia increases hypothalamic glucose phosphorylation activity in rats.
复制标题
反复性低血糖会增加大鼠下丘脑葡萄糖磷酸化活性。
DOI：
10.1016/j.metabol.2010.05.009
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Evans,MarkL
中科院分区：
文献类型：
--
作者：
Osundiji,MayowaA;Hurst,Paul;Moore,StephenP;Markkula,SPauliina;Yueh,ChenY;Swamy,Ashwini;Hoashi,Shu;Shaw,JillS;Riches,ChristineH;Heisler,LoraK;Evans,MarkL
在一些反复发作低血糖的糖尿病患者中，对低血糖的防御性反调节反应受损的机制尚不清楚。先前的工作检查这是否是增加葡萄糖输送到下丘脑的结果，假设是主要的低血糖感应区，一直没有定论。在这里，我们假设，而不是增加下丘脑葡萄糖磷酸化，在葡萄糖代谢的第一个承诺的细胞内步骤，可能会发展后暴露于低血糖症。我们预计，这种适应可能倾向于在低血糖期间保持葡萄糖流量，从而减少对血糖下降的检测。我们首先验证了一个模型的复发性低血糖症的长期导管（右颈静脉）大鼠接受每日注射胰岛素。我们证实，这种反复出现的胰岛素诱导的低血糖模型导致反调节受损，关键的反调节激素肾上腺素的反应从胰岛素诱导的低血糖的第一天到第四天被显著和渐进地抑制。在另一个队列中，我们研究了反复胰岛素诱导的低血糖4天内脑葡萄糖磷酸化活性的变化。与我们的假设一致，我们发现反复低血糖以日依赖的方式显著增加下丘脑葡萄糖磷酸化活性，第4天的值比第1天高2.8 ± 0.6倍（P <0.05），而脑干和额叶皮质的葡萄糖磷酸化活性没有变化。这些发现表明，下丘脑可能通过增加葡萄糖磷酸化来适应复发性低血糖;我们推测，这种代谢适应可能至少部分地导致低血糖诱导的反调节失败。
The mechanisms underpinning impaired defensive counterregulatory responses to hypoglycemia that develop in some people with diabetes who suffer recurrent episodes of hypoglycemia are unknown. Previous work examining whether this is a consequence of increased glucose delivery to the hypothalamus, postulated to be the major hypoglycemia-sensing region, has been inconclusive. Here, we hypothesized instead that increased hypothalamic glucose phosphorylation, the first committed intracellular step in glucose metabolism, might develop following exposure to hypoglycemia. We anticipated that this adaptation might tend to preserve glucose flux during hypoglycemia, thus reducing detection of a falling glucose. We first validated a model of recurrent hypoglycemia in chronically catheterized (right jugular vein) rats receiving daily injections of insulin. We confirmed that this model of recurrent insulin-induced hypoglycemia results in impaired counterregulation, with responses of the key counterregulatory hormone, epinephrine, being suppressed significantly and progressively from the first day to the fourth day of insulin-induced hypoglycemia. In another cohort, we investigated the changes in brain glucose phosphorylation activity over 4 days of recurrent insulin-induced hypoglycemia. In keeping with our hypothesis, we found that recurrent hypoglycemia markedly and significantly increased hypothalamic glucose phosphorylation activity in a day-dependent fashion, with day 4 values 2.8 ± 0.6-fold higher than day 1 (P < .05), whereas there was no change in glucose phosphorylation activity in brain stem and frontal cortex. These findings suggest that the hypothalamus may adapt to recurrent hypoglycemia by increasing glucose phosphorylation; and we speculate that this metabolic adaptation may contribute, at least partly, to hypoglycemia-induced counterregulatory failure.