Ventromedial hypothalamic nitric oxide production is necessary for hypoglycemia detection and counterregulation.
Ventromedial hypothalamic nitric oxide production is necessary for hypoglycemia detection and counterregulation.
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作者：
Fioramonti X;Marsollier N;Song Z;Fakira KA;Patel RM;Brown S;Duparc T;Pica-Mendez A;Sanders NM;Knauf C;Valet P;McCrimmon RJ;Beuve A;Magnan C;Routh VH
腹内侧下丘脑（VMH）葡萄糖抑制神经元对降低的葡萄糖的反应在对低血糖的反调节反应（CRR）受损的条件下受损（例如，复发性低血糖）。这表明葡萄糖抑制神经元在CRR中的作用。我们最近发现，在培养的VMH葡萄糖抑制神经元中，葡萄糖减少会增加一氧化氮（NO）的产生。这些体外数据使我们假设，从VMH葡萄糖抑制神经元的NO释放是关键的CRR。在大鼠和小鼠中评估CRR对急性胰岛素诱导的低血糖的响应以及在脑NO信号传导调节后的低血糖钳夹。还评估了腹内侧核葡萄糖抑制神经元的葡萄糖敏感性。低氧可增加大鼠下丘脑组织型一氧化氮合酶（NOS）活性和神经元型NOS（nNOS）磷酸化水平，但不增加内皮型NOS（eNOS）磷酸化水平。侧脑室和VMH注射非选择性NOS抑制剂NG-单甲基-L-精氨酸（L-NMMA）可减缓低血糖后恢复至正常水平。VMH I-NMMA注射还增加了大鼠高胰岛素/低血糖钳夹期间的葡萄糖输注速率（GIR）并减少了肾上腺素分泌。维持低血糖平台所需的GIR在nNOS敲除小鼠中高于野生型或eNOS敲除小鼠。最后，VMH葡萄糖抑制神经元几乎不存在nNOS敲除小鼠。我们的结论是，VMH NO的生产是必要的葡萄糖敏感的葡萄糖抑制神经元和完整的生成CRR低血糖。这些数据表明，增强NO信号可能会改善使用强化胰岛素治疗的患者中因反复低血糖而导致的CRR缺陷。
The response of ventromedial hypothalamic (VMH) glucose-inhibited neurons to decreased glucose is impaired under conditions where the counterregulatory response (CRR) to hypoglycemia is impaired (e.g., recurrent hypoglycemia). This suggests a role for glucose-inhibited neurons in the CRR. We recently showed that decreased glucose increases nitric oxide (NO) production in cultured VMH glucose-inhibited neurons. These in vitro data led us to hypothesize that NO release from VMH glucose-inhibited neurons is critical for the CRR. The CRR was evaluated in rats and mice in response to acute insulin-induced hypoglycemia and hypoglycemic clamps after modulation of brain NO signaling. The glucose sensitivity of ventromedial nucleus glucose-inhibited neurons was also assessed. Hypoglycemia increased hypothalamic constitutive NO synthase (NOS) activity and neuronal NOS (nNOS) but not endothelial NOS (eNOS) phosphorylation in rats. Intracerebroventricular and VMH injection of the nonselective NOS inhibitor NG-monomethyl-l-arginine (l-NMMA) slowed the recovery to euglycemia after hypoglycemia. VMH l-NMMA injection also increased the glucose infusion rate (GIR) and decreased epinephrine secretion during hyperinsulinemic/hypoglycemic clamp in rats. The GIR required to maintain the hypoglycemic plateau was higher in nNOS knockout than wild-type or eNOS knockout mice. Finally, VMH glucose-inhibited neurons were virtually absent in nNOS knockout mice. We conclude that VMH NO production is necessary for glucose sensing in glucose-inhibited neurons and full generation of the CRR to hypoglycemia. These data suggest that potentiating NO signaling may improve the defective CRR resulting from recurrent hypoglycemia in patients using intensive insulin therapy.
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影响因子：
7.7
作者：
Levin, Barry E.;Becker, Thomas C.;Dunn-Meynell, Ambrose A.
通讯作者：
Dunn-Meynell, Ambrose A.
影响因子：
37.8
作者：
Duplain, H;Burcelin, R;Scherrer, U
通讯作者：
Scherrer, U
影响因子：
--
作者：
HOLLINGER, BR;BRYAN, RM
通讯作者：
BRYAN, RM
DOI：
10.1097/00004647-199701000-00008
发表时间：
1997-01-01
影响因子：
6.3
作者：
Horinaka, N;Artz, N;Sokoloff, L
通讯作者：
Sokoloff, L
影响因子：
7.7
作者：
Cabou, Cendrine;Campistron, Gerard;Burcelin, Remy
通讯作者：
Burcelin, Remy