Glucocorticoid-deficient corticotropin-releasing hormone knockout mice maintain glucose requirements but not autonomic responses during repeated hypoglycemia
Glucocorticoid-deficient corticotropin-releasing hormone knockout mice maintain glucose requirements but not autonomic responses during repeated hypoglycemia
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DOI：
10.1152/ajpendo.00526.2005
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发表时间：
2006-07-01
影响因子：
5.1
通讯作者：
McGuinness, Owen P.
中科院分区：
文献类型：
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作者：
Jacobson, Lauren;Ansari, Tasneem;McGuinness, Owen P.
糖皮质激素与低血糖诱导的自主神经功能衰竭有关，但也有助于正常的反调节。为了确定正常和低血糖诱导的糖皮质激素水平对急性和反复低血糖的反调节反应的影响，我们比较了雄性野生型（WT）和糖皮质激素缺乏、促肾上腺皮质激素释放激素敲除（CRH KO）小鼠的血浆儿茶酚胺、皮质酮、胰高血糖素和葡萄糖需求。清醒的、长期插管的、不受限制的WT和CRH KO小鼠在第1天经历正常血糖（Prior Eu）或低血糖钳夹（Prior Hypo），随后在第2天经历低血糖钳夹（两天的血糖均为65 +/-1 mg/dl）。CRH KO与WT小鼠的基线肾上腺素和胰高血糖素相似，去甲肾上腺素升高。CRH KO皮质酮几乎检测不到（< 1.5 μ g/dl），对低血糖无反应。尽管肾上腺素和胰高血糖素反应与WT相当或更高，但第1天低血糖期间CRH KO葡萄糖需求显著更高。高胰岛素血症性胰岛素缺乏并不增加激素或葡萄糖需求量超过基线。在第2天，既往低血糖WT组的葡萄糖需求显著较高，皮质酮和胰高血糖素反应显著较低。先前Hypo和先前Eu CRH KO小鼠具有相似的第2天葡萄糖需求。然而，先前Hypo CRH KO小鼠第2天的肾上腺素和去甲肾上腺素显著低于先前Eu CRH KO小鼠，并且胰高血糖素倾向于低于第1天。我们得出结论，CRH KO小鼠中糖皮质激素不足与1）急性低血糖期间反调节受损和2）反复低血糖后的复杂效应相关，既不能防止激素反应降低，也不能使葡萄糖需求恶化。
Glucocorticoids have been implicated in hypoglycemia-induced autonomic failure but also contribute to normal counterregulation. To determine the influence of normal and hypoglycemia-induced levels of glucocorticoids on counterregulatory responses to acute and repeated hypoglycemia, we compared plasma catecholamines, corticosterone, glucagon, and glucose requirements in male wild-type (WT) and glucocorticoid-deficient, corticotropin-releasing hormone knockout (CRH KO) mice. Conscious, chronically cannulated, unrestrained WT and CRH KO mice underwent a euglycemic (Prior Eu) or hypoglycemic clamp (Prior Hypo) on day 1 followed by a hypoglycemic clamp on day 2 (blood glucose both days, 65 +/- 1 mg/dl). Baseline epinephrine and glucagon were similar, and norepinephrine was elevated, in CRH KO vs. WT mice. CRH KO corticosterone was almost undetectable (< 1.5 mu g/dl) and unresponsive to hypoglycemia. CRH KO glucose requirements were significantly higher during day 1 hypoglycemia despite epinephrine and glucagon responses that were comparable to or greater than those in WT. Hyperinsulinemic euglycemia did not increase hormones or glucose requirements above baseline. On day 2, Prior Hypo WT had significantly higher glucose requirements and significantly lower corticosterone and glucagon responses. Prior Hypo and Prior Eu CRH KO mice had similar day 2 glucose requirements. However, Prior Hypo CRH KO mice had significantly lower day 2 epinephrine and norepinephrine vs. Prior Eu CRH KO and tended to have lower glucagon than on day 1. We conclude that glucocorticoid insufficiency in CRH KO mice correlates with 1) impaired counterregulation during acute hypoglycemia and 2) complex effects after repeated hypoglycemia, neither preventing decreased hormone responses nor worsening glucose requirements.