Insulin signaling in the heart is impaired by growth hormone: a direct and early event.
Insulin signaling in the heart is impaired by growth hormone: a direct and early event.
复制标题
DOI：
10.1530/jme-21-0242
复制
发表时间：
2022-08-01
影响因子：
3.5
通讯作者：
Miquet, Johanna G.
中科院分区：
文献类型：
--
作者：
Munoz, Marina C.;Piazza, Veronica G.;Burghi, Valeria;Giani, Jorge F.;Martinez, Carolina S.;Cicconi, Nadia S.;Muia, Nadia, V;Fang, Yimin;Lavandero, Sergio;Sotelo, Ana, I;Bartke, Andrzej;Pennisi, Patricia A.;Dominici, Fernando P.;Miquet, Johanna G.
生长激素（GH）在心脏的生长和代谢中发挥重要作用。考虑到胰岛素在心脏中的重要作用和GH的公认抗胰岛素作用，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。由于长期暴露于GH的条件与循环GH、IGF-1和胰岛素水平的伴随增加相关，为了分析GH的直接影响，在本研究中，我们使用四种不同的模型评估了心脏中胰岛素信号传导的激活：1）过度表达GH的转基因小鼠，具有长期升高的GH、IGF-1和胰岛素循环水平，2）肝脏IGF-1缺陷小鼠，GH和胰岛素长期升高，但IGF-1循环水平降低，3）用GH短时间处理的小鼠，和4）用GH孵育的大鼠心肌细胞的原代培养物。尽管分析的三种实验小鼠模型在心脏肥大的发展和代谢改变方面存在差异，但GH暴露始终与心脏在受体水平和通过PI 3 K/Akt途径对急性胰岛素刺激的反应降低相关。此外，在培养的新生大鼠心肌细胞与GH孵育，这一信号通路的胰岛素刺激的钝化反应也被观察到。因此，这项工作的关键新发现是，心脏中胰岛素信号传导的损伤是暴露于GH的结果，这可能在心脏病理学的发展中发挥重要作用。
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, IGF-1 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: 1) transgenic mice overexpressing GH, with chronically elevated GH, IGF-1 and insulin circulating levels, 2) liver IGF-1-deficient mice, with chronically elevated GH and insulin but decreased IGF-1 circulating levels, 3) mice treated with GH for a short period of time, and 4) 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 analysed, 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.