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首页> 外文期刊>American Journal of Physiology >Effects of prolonged exendin-4 administration on hypothalamic-pituitary-adrenal axis activity and water balance
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Effects of prolonged exendin-4 administration on hypothalamic-pituitary-adrenal axis activity and water balance

机译：长期服用exendin-4对下丘脑-垂体-肾上腺轴活性和水平衡的影响

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摘要

Exendin-4 (Ex-4) is a natural agonist of the glucagon-like peptide-1 (GLP-1) receptor, currently being used as a treatment for type 2 diabetes mellitus due to its insulinotropic properties. Previous studies have revealed that acute administration of both GLP-1 and, in particular, Ex-4 potently stimulates hypothalamic-pituitary-adrenal (HPA) axis activity. In this work, the effects of prolonged Ex-4 exposure on HPA function were explored. To this end, Sprague-Dawley rats were subjected to a daily regimen of two Ex-4 injections (5 μg/kg sc) for a minimum of 7 days. We found that subchronic Ex-4 administration produced a number of effects that resemble chronic stress situations, including hyperactivation of the HPA axis during the trough hours, disruption of glucocorticoid circadian secretion, hypertrophy of the adrenal gland, decreased adrenal gland sensitivity, impaired pituitaryadrenal stress responses, and reductions in both food intake and body weight. In addition, a threefold increase in diuresis was observed followed by a 1.5-fold increase in water intake; these latter effects were abolished by adrenalectomy. Together, these findings indicate that Ex-4 induces a profound dysregulation of HPA axis activity that may also affect renal function.
机译：Exendin-4（Ex-4）是胰高血糖素样肽1（GLP-1）受体的天然激动剂，由于其促胰岛素作用，目前被用于治疗2型糖尿病。先前的研究表明，急性给予GLP-1（尤其是Ex-4）均能有效刺激下丘脑-垂体-肾上腺（HPA）轴活动。在这项工作中，探索了延长Ex-4暴露对HPA功能的影响。为此，每天对Sprague-Dawley大鼠进行两次Ex-4注射（5μg/ kg sc）每天至少7天的治疗。我们发现，Ex-4的亚慢性给药产生了许多类似于慢性应激的作用，包括在低谷时段HPA轴过度活化，糖皮质激素昼夜分泌中断，肾上腺肥大，肾上腺敏感性降低，垂体肾上腺应激障碍反应，并减少食物摄入量和体重。另外，观察到利尿增加了三倍，随后的饮水量增加了1.5倍。肾上腺切除术消除了这些后一种作用。总之，这些发现表明Ex-4引起HPA轴活性的严重失调，这也可能影响肾功能。

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