Diabetes impairs hypothalamo-pituitary-adrenal (HPA) responses to hypoglycemia, and insulin treatment normalizes HPA but not epinephrine responses
Diabetes impairs hypothalamo-pituitary-adrenal (HPA) responses to hypoglycemia, and insulin treatment normalizes HPA but not epinephrine responses
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DOI：
10.2337/diabetes.51.6.1681
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发表时间：
2002-06-01
期刊：
影响因子：
7.7
通讯作者：
Vranic, M
中科院分区：
文献类型：
--
作者：
Chan, O;Chan, S;Vranic, M
我们最近发现，除了血浆促肾上腺皮质激素（ACTH）和皮质酮，下丘脑促肾上腺皮质激素释放激素（CRH）mRNA和海马1型糖皮质激素受体（GR 1）mRNA也上调不受控制的链脲佐菌素诱导的糖尿病。在本研究中，对照，糖尿病，胰岛素治疗的糖尿病大鼠进行了高胰岛素-低血糖葡萄糖钳夹，以评估下丘脑-垂体-肾上腺（HPA）的中枢机制和胰岛素诱导的低血糖的反调节反应。糖尿病大鼠血浆ACTH、皮质酮和肾上腺素的增加显著低于对照组。胰岛素治疗恢复了糖尿病大鼠对低血糖的ACTH和皮质酮反应，但不能恢复肾上腺素反应。胰高血糖素和去甲肾上腺素对低血糖的反应不受糖尿病或胰岛素治疗的影响。低血糖时，对照组和胰岛素治疗组大鼠下丘脑CRH mRNA和垂体前阿黑皮素mRNA表达增加，但未治疗组大鼠没有增加。精氨酸加压素mRNA在所有组中均未因低血糖而改变。有趣的是，低血糖降低对照组和胰岛素治疗的糖尿病大鼠海马GR 1 mRNA的表达，而不是在糖尿病大鼠。与此相反，2型糖皮质激素受体（GR 2）的mRNA没有改变低血糖。总之，尽管基础HPA活性增加，HPA对低血糖的反应在未控制的糖尿病中显著降低。我们推测CRH反应的缺陷可能与GR 1反应的缺陷有关。有趣的是，胰岛素治疗恢复了HPA对低血糖的反应，但令人惊讶的是，没有恢复肾上腺素反应不足。这一点很重要，因为在严重低血糖期间，肾上腺素是一种重要的反调节激素。
We recently established that in addition to plasma adrenocorticotrophic hormone (ACTH) and corticosterone, hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal type 1 glucocorticoid receptor (GR1) mRNA were also upregulated in uncontrolled streptozotocin-induced diabetes. In the current study, control, diabetic, and insulin-treated diabetic rats underwent a hyperinsulinemic-hypoglycemic glucose clamp to evaluate central mechanisms of hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulin-induced hypoglycemia. Increases in plasma ACTH, corticosterone, and epinephrine were significantly lower in diabetic rats versus controls. Insulin treatment restored ACTH and corticosterone but not epinephrine responses to hypoglycemia in diabetic rats. Glucagon and norepinephrine responses to hypoglycemia were not affected by diabetes or insulin treatment. In response to hypoglycemia, hypothalamic CRH mRNA and pituitary proopiomelanocortin mRNA expression increased in control and insulin-treated but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal GR1 mRNA expression in control and insulin-treated diabetic rats but not in diabetic rats. In contrast, type 2 glucocortoid receptor (GR2) mRNA was not altered by hypoglycemia. In conclusion, despite increased basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that the defect in CRH response could be related to the defective GR1 response. It is intriguing that insulin treatment restored the HPA response to hypoglycemia but, surprisingly, not the deficient epinephrine response. This is important because during severe hypoglycemia, epinephrine is an important counterregulatory hormone.