Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia
Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia
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DOI：
10.2337/db07-1755
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发表时间：
2008-05-01
期刊：
影响因子：
7.7
通讯作者：
Dunn-Meynell, Ambrose A.
中科院分区：
文献类型：
--
作者：
Levin, Barry E.;Becker, Thomas C.;Dunn-Meynell, Ambrose A.
胰岛素诱导的低血糖的反调节反应是由腹内侧下丘脑（VMH）介导的，其中包含专门的葡萄糖敏感神经元，其中许多使用葡萄糖激酶（GK）作为葡萄糖调节神经元活动的限速步骤。由于与VMH GK表达增加相关的条件与钝化的反调节反应相关，我们测试了增加VMH GK活性将类似地减弱的假设，研究设计和方法-在Sprague-Dawley大鼠双侧VMH注射1）GK激活剂药物（化合物A）以增加VMH GK活性，2）低剂量四氧嘧啶（4 μ g）以急性抑制GK活性，3）高剂量四氧嘧啶（24 μ g），或4）表达GK短发夹RNA（shRNA）的腺病毒以慢性降低GK表达和活性。而胰高血糖素在体内注射到VMH时对胰岛素诱导的低血糖的反应为40-62%。另一方面，在一项研究中，VMH GK mRNA或活性的急性和慢性降低对主要增加肾上腺素对胰岛素诱导的低血糖的反应具有较小和更多的选择性作用。结论-这些研究表明，VMH GK活性是对胰岛素诱导的低血糖的反调节反应的重要调节剂，并且特异性抑制胰岛素诱导的低血糖后下丘脑GK活性升高的药物-诱导的低血糖可能改善在严格控制的糖尿病受试者中观察到的抑制的反调节反应。
OBJECTIVE-The counterregulatory response to insulin-induced hypoglycemia is mediated by the ventromedial hypothalamus (VMH), which contains specialized glucosensing neurons, many of which use glucokinase (GK) as the rate-limiting step in glucose's regulation of neuronal activity. Since conditions associated with increased VMH GK expression are associated with a blunted counterregulatory response, we tested the hypothesis that increasing VMH GK activity would similarly attenuate, while decreasing GK activity would enhance the counterregulatory response to insulin-induced hypoglycemia.RESEARCH DESIGN AND METHODS-The counterregulatory response to insulin-induced hypoglycemia was evaluated in Sprague-Dawley rats after bilateral VMH injections of 1) a GK activator drug (compound A) to increase VMH GK activity, 2) low-dose alloxan (4 jig) to acutely inhibit GK activity, 3) high-dose alloxan (24 mu g), or 4) an adenovirus expressing GK short hairpin RNA (shRNA) to chronically reduce GK expression and activity.RESULTS-Compound A increased VMH GK activity sixfold in vitro and reduced the epinephrine, norepinephrine, and glucagon responses to insulin-induced hypoglycemia by 40-62% when injected into the VMH in vivo. On the other hand, acute and chronic reductions of VMH GK mRNA or activity had a lesser and more selective effect on increasing primarily the epinephrine response to insulin-induced hypoglycemia by 23-50%.CONCLUSIONS-These studies suggest that VMH GK activity is an important regulator of the counterregulatory response to insulin-induced hypoglycemia and that a drug that specifically inhibited the rise in hypothalamic GK activity after insulin-induced hypoglycemia might improve the dampened counterregulatory response seen in tightly controlled diabetic subjects.