Malendowicz Ludwik K, Neri Giuliano, Nussdorfer Gastone G, Nowak Krzysztof W, Zyterska Agnieszka, Ziolkowska Agnieszka
Department of Histology and Embryology, Karol Marcinkowski University of Medical Sciences, PL-60781 Poznan, Poland.
Int J Mol Med. 2003 Oct;12(4):593-6.
Evidence is available that exendin-4 (EX4), a glucagon-like peptide-1 receptor (GLP-1R) agonist acutely stimulates hypothalamo-pituitary-adrenal (HPA) axis in the rat. EX4 is a potent insulinotropic agent, which is currently under clinical trial for treatment of type 2 diabetes. Since diabetes is known to affect adrenal function, we investigated the effects of the prolonged administration of EX4 and/or the GLP-1R antagonist EX4(9-39) (EX4-A) (daily subcutaneous injections of 1 nmol/kg EX4 and/or EX4-A, for 7 days) on the HPA axis of normoglycemic and streptozotocin (STZ)-induced diabetic rats. In STZ-untreated rats, chronic EX4 treatment did not change the blood level of ACTH. In contrast, it evoked a marked rise in the plasma concentrations of aldosterone and corticosterone, these effects being reversed by EX4-A. In STZ-induced diabetic rats, prolonged EX4 administration increased the plasma levels of ACTH, aldosterone and corticosterone. EX4-A did not prevent the first two effects of EX4, and annulled the latter one. These findings allow us to draw the following conclusions: i) EX4 prolonged exposure desensitizes hypothalamo-hypophyseal GLP-1R in normal rats, and exerts an ACTH-independent GLP-1R-mediated aldosterone and corticosterone secretagogue effect; and ii) experimental diabetes induces the expression of EX4 receptors other than the classic GLP-1R, whose activation mediate the ACTH and aldosterone, but not corticosterone, secretagogue effects. Our study provides evidence that metabolic dysregulations occurring in STZ-induced diabetic rats are able to profoundly affect the response of the HPA axis to GLP-1.
有证据表明，艾塞那肽-4（EX4），一种胰高血糖素样肽-1受体（GLP-1R）激动剂，可在大鼠中急性刺激下丘脑-垂体-肾上腺（HPA）轴。EX4是一种有效的促胰岛素分泌剂，目前正处于治疗2型糖尿病的临床试验阶段。由于已知糖尿病会影响肾上腺功能，我们研究了长期给予EX4和/或GLP-1R拮抗剂EX4(9-39)（EX4-A）（每日皮下注射1 nmol/kg EX4和/或EX4-A，共7天）对正常血糖和链脲佐菌素（STZ）诱导的糖尿病大鼠HPA轴的影响。在未用STZ处理的大鼠中，慢性EX4治疗并未改变促肾上腺皮质激素（ACTH）的血液水平。相反，它引起醛固酮和皮质酮血浆浓度显著升高，这些作用可被EX4-A逆转。在STZ诱导的糖尿病大鼠中，长期给予EX4可增加ACTH、醛固酮和皮质酮的血浆水平。EX4-A并未阻止EX4的前两种作用，而是消除了后一种作用。这些发现使我们能够得出以下结论：i）EX4长时间暴露会使正常大鼠下丘脑-垂体的GLP-1R脱敏，并发挥一种不依赖ACTH的GLP-IR介导的醛固酮和皮质酮促分泌作用；ii）实验性糖尿病诱导了除经典GLP-1R之外的EX4受体表达，其激活介导ACTH和醛固酮而非皮质酮的促分泌作用。我们的研究提供了证据，表明STZ诱导的糖尿病大鼠中发生的代谢失调能够深刻影响HPA轴对GLP-1的反应。
