Chan Owen, Inouye Karen, Akirav Eitan, Park Edward, Riddell Michael C, Vranic Mladen, Matthews Stephen G
Department of Physiology, University of Toronto, Medical Sciences Building, Room 3240, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Endocrinology. 2005 Mar;146(3):1382-90. doi: 10.1210/en.2004-0607. Epub 2004 Nov 24.
Diabetes is associated with increased basal hypothalamo-pituitary-adrenal (HPA) activity and impaired stress responsiveness. Previously, we demonstrated that the HPA response to hypoglycemia is significantly impaired in diabetic rats. In this study our goals were to 1) differentiate between the effects of hyperinsulinemia and those of hypoglycemia per se, and 2) establish whether diabetes lowers peak stress responses. Normal and streptozotocin-diabetic rats were subjected to hyperinsulinemic-euglycemic glucose clamps to evaluate central and peripheral responses. These were compared with peak ACTH and corticosterone responses to restraint and hypoglycemia. Hyperinsulinemia increased CRH and vasopressin mRNA, and plasma ACTH and corticosterone in normal and diabetic rats. In normal animals, insulin-induced activation of ACTH and corticosterone was lower than the responses during either restraint or hypoglycemia. In contrast, ACTH and corticosterone activation in diabetic rats was similar with all three stressors. Pituitary-adrenal axis activation in diabetic animals was also much lower compared with that in normal controls. The response to hyperinsulinemia (euglycemia) was associated with increases in glucocorticoid receptor mRNA in the anterior pituitary and paraventricular nucleus. Hippocampal mineralocorticoid receptor mRNA expression was increased in normal, but not in diabetic, animals. We speculate that the ability to appropriately match the HPA response to the potency of a stressor is related to the ability to alter hippocampal mineralocorticoid receptor expression. In diabetes, this ability is impaired; hence, maximal HPA activation is greatly diminished. This is a novel observation that may have important implications in the treatment of impaired counterregulatory mechanisms in human diabetes.
糖尿病与下丘脑 - 垂体 - 肾上腺（HPA）基础活性增加及应激反应受损有关。此前，我们证明糖尿病大鼠对低血糖的HPA反应显著受损。在本研究中，我们的目标是：1）区分高胰岛素血症和低血糖本身的影响；2）确定糖尿病是否会降低应激反应峰值。对正常大鼠和链脲佐菌素诱导的糖尿病大鼠进行高胰岛素 - 正常血糖钳夹实验，以评估中枢和外周反应。将这些反应与对束缚和低血糖的促肾上腺皮质激素（ACTH）和皮质酮峰值反应进行比较。高胰岛素血症会增加正常大鼠和糖尿病大鼠的促肾上腺皮质激素释放激素（CRH）和血管加压素mRNA水平，以及血浆ACTH和皮质酮水平。在正常动物中，胰岛素诱导的ACTH和皮质酮激活低于束缚或低血糖期间的反应。相比之下，糖尿病大鼠中ACTH和皮质酮的激活在所有三种应激源下相似。与正常对照组相比，糖尿病动物的垂体 - 肾上腺轴激活也低得多。对高胰岛素血症（正常血糖）的反应与垂体前叶和室旁核中糖皮质激素受体mRNA的增加有关。正常动物海马盐皮质激素受体mRNA表达增加，但糖尿病动物未增加。我们推测，使HPA反应与应激源强度相匹配的能力与改变海马盐皮质激素受体表达的能力有关。在糖尿病中，这种能力受损；因此，HPA的最大激活大大减弱。这是一项新的观察结果，可能对人类糖尿病中反调节机制受损的治疗具有重要意义。
