Pais Isabel, Hubold Christian, Hallschmid Manfred, Letterer Sebastian, Oltmanns Kerstin, Schultes Bernd, Born Jan, Peters Achim
Department of Internal Medicine I, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Psychoneuroendocrinology. 2008 Sep;33(8):1069-76. doi: 10.1016/j.psyneuen.2008.04.002. Epub 2008 Jul 23.
In animals, blocking of glutamate signaling at the N-methyl-D-aspartate (NMDA) receptor reduces the neuroendocrine counterregulation to hypoglycemia. Hence, it has been proposed that increased excitatory glutamatergic input to the hypothalamus signals enforced central nervous energy demand under conditions of reduced supply. We examined the effect of the NMDA receptor antagonist memantine on hypoglycemia counterregulation in healthy humans. Hypoglycemic clamp experiments were performed in 10 healthy men after oral administration of 20 mg memantine and placebo. Counterregulatory hormones were measured during baseline and a clamp period of 120 min with hypoglycemia of 2.4 mmol/l lasting for 50 min. In addition, symptoms related to glycemic changes were assessed. Unexpectedly, the counterregulatory responses to hypoglycemia of adrenocorticotropin, cortisol and epinephrine were not decreased but tended to be increased by memantine, while norepinephrine and growth hormone were not affected. Glucagon levels were increased by memantine treatment during baseline and throughout the hypoglycemic period. After memantine administration, subjects also experienced more neuroglycopenic symptoms during hypoglycemia, whereas differences in autonomic symptoms did not reach significance. Contrasting with findings in animals, blocking the NMDA receptor does not decrease the counterregulatory responses to hypoglycemia in humans. Our data do not support the view that in humans, enhanced glutamate signaling during hypoglycemia supports the satisfaction of increased central nervous energy demands by enforcing hormonal counterregulation.
在动物中，阻断N-甲基-D-天冬氨酸（NMDA）受体处的谷氨酸信号传导可降低对低血糖的神经内分泌反调节作用。因此，有人提出，在下丘脑供应减少的情况下，谷氨酸能兴奋性输入增加表明中枢神经系统能量需求增强。我们研究了NMDA受体拮抗剂美金刚对健康人低血糖反调节的影响。在10名健康男性口服20 mg美金刚和安慰剂后进行了低血糖钳夹实验。在基线期和持续120分钟的钳夹期内测量反调节激素，其中低血糖（2.4 mmol/l）持续50分钟。此外，评估与血糖变化相关的症状。出乎意料的是，美金刚并未降低促肾上腺皮质激素、皮质醇和肾上腺素对低血糖的反调节反应，反而有增加的趋势，而去甲肾上腺素和生长激素则未受影响。在基线期及整个低血糖期，美金刚治疗均可使胰高血糖素水平升高。服用美金刚后，受试者在低血糖期间还出现了更多的神经低血糖症状，而自主神经症状的差异未达到显著水平。与动物研究结果相反，阻断NMDA受体并不会降低人类对低血糖的反调节反应。我们的数据不支持以下观点：在人类中，低血糖期间谷氨酸信号增强通过加强激素反调节来满足中枢神经系统增加的能量需求。
