Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Universidad de Buenos Aires, Buenos Aires, Argentina.
Department of Internal Medicine, Geriatrics Research, Southern Illinois University School of Medicine, Springfield, Illinois, USA.
J Mol Endocrinol. 2022 Jun 23;69(2):357-376. doi: 10.1530/JME-21-0242. Print 2022 Aug 1.
Growth hormone (GH) exerts major actions in cardiac growth and metabolism. Considering the important role of insulin in the heart and the well-established anti-insulin effects of GH, cardiac insulin resistance may play a role in the cardiopathology observed in acromegalic patients. As conditions of prolonged exposure to GH are associated with a concomitant increase of circulating GH, IGF1 and insulin levels, to dissect the direct effects of GH, in this study, we evaluated the activation of insulin signaling in the heart using four different models: (i) transgenic mice overexpressing GH, with chronically elevated GH, IGF1 and insulin circulating levels; (ii) liver IGF1-deficient mice, with chronically elevated GH and insulin but decreased IGF1 circulating levels; (iii) mice treated with GH for a short period of time; (iv) primary culture of rat cardiomyocytes incubated with GH. Despite the differences in the development of cardiomegaly and in the metabolic alterations among the three experimental mouse models analyzed, exposure to GH was consistently associated with a decreased response to acute insulin stimulation in the heart at the receptor level and through the PI3K/AKT pathway. Moreover, a blunted response to insulin stimulation of this signaling pathway was also observed in cultured cardiomyocytes of neonatal rats incubated with GH. Therefore, the key novel finding of this work is that impairment of insulin signaling in the heart is a direct and early event observed as a consequence of exposure to GH, which may play a major role in the development of cardiac pathology.
生长激素（GH）在心脏生长和代谢中发挥主要作用。考虑到胰岛素在心脏中的重要作用以及 GH 对胰岛素的明确的抗作用，心脏胰岛素抵抗可能在肢端肥大症患者中观察到的心脏病理学中发挥作用。由于长时间暴露于 GH 会伴随着循环 GH、IGF1 和胰岛素水平的同时升高，为了剖析 GH 的直接作用，在这项研究中，我们使用了四种不同模型来评估心脏中胰岛素信号的激活：（i）过表达 GH 的转基因小鼠，其具有慢性升高的 GH、IGF1 和胰岛素循环水平；（ii）肝脏 IGF1 缺陷型小鼠，其具有慢性升高的 GH 和胰岛素但降低 IGF1 循环水平；（iii）短时间接受 GH 治疗的小鼠；（iv）用 GH 孵育的大鼠心肌细胞的原代培养物。尽管在分析的三种实验小鼠模型中，心脏肥大和代谢改变的发展存在差异，但暴露于 GH 始终与心脏在受体水平和通过 PI3K/AKT 途径对急性胰岛素刺激的反应降低有关。此外，在用 GH 孵育的新生大鼠心肌细胞的培养物中，也观察到该信号通路对胰岛素刺激的反应迟钝。因此，这项工作的主要新发现是，心脏中胰岛素信号的损伤是暴露于 GH 后观察到的直接和早期事件，这可能在心脏病理学的发展中起主要作用。
