Department of Pharmacology and Physiology, New Jersey Medical School, Newark, New Jersey, USA.
Diabetes. 2010 Feb;59(2):519-28. doi: 10.2337/db09-0421. Epub 2009 Nov 23.
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 N(G)-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.
在下丘脑腹内侧核（VMH）葡萄糖抑制神经元对葡萄糖反应受损的情况下（例如，反复发生低血糖），其对低血糖的代偿性反应（CRR）受损。这表明葡萄糖抑制神经元在 CRR 中起作用。我们最近发现，葡萄糖减少会增加培养的 VMH 葡萄糖抑制神经元中的一氧化氮（NO）产生。这些体外数据使我们假设 VMH 葡萄糖抑制神经元中 NO 的释放对于 CRR 至关重要。
在调节大脑 NO 信号后，评估了大鼠和小鼠对急性胰岛素诱导的低血糖和低血糖钳夹的 CRR。还评估了 VMH 葡萄糖抑制神经元的葡萄糖敏感性。
低血糖增加了大鼠下丘脑组成型一氧化氮合酶（NOS）活性和神经元 NOS（nNOS）但不增加内皮 NOS（eNOS）磷酸化。脑室和 VMH 注射非选择性 NOS 抑制剂 N(G)-单甲基-l-精氨酸（l-NMMA）可减缓低血糖后恢复至正常血糖。VMH l-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率（GIR）并减少了肾上腺素分泌。与野生型或 eNOS 敲除小鼠相比，维持低血糖平台所需的 GIR 在 nNOS 敲除小鼠中更高。最后，nNOS 敲除小鼠中几乎没有 VMH 葡萄糖抑制神经元。
我们得出结论，VMH 中的 NO 产生对于葡萄糖抑制神经元中的葡萄糖感应以及低血糖的 CRR 的完全产生是必要的。这些数据表明，增强 NO 信号可能会改善接受强化胰岛素治疗的患者因反复发生低血糖而导致的有缺陷的 CRR。
