Obesity Biology, Novo Nordisk A/S, Maalov, Denmark.
Department of Clinical Biochemistry, Glostrup Research Institute, Glostrup Hospital, Glostrup, Denmark.
Basic Clin Pharmacol Toxicol. 2018 May;122(5):460-469. doi: 10.1111/bcpt.12937. Epub 2017 Dec 15.
The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue, that only activate a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance. Here, we studied the effect of SII Ang II on insulin receptor (IR) signalling and glucose metabolism in primary rat hepatocytes. We show that long-term pre-treatment of hepatocytes with SII Ang II increased insulin-stimulated glycogen synthesis, while Ang II and the AT1R antagonist losartan had no effect. Insulin-stimulated suppression of hepatic glucose output was not affected by Ang II or SII Ang II. It is well known that insulin regulates glycogen synthesis and glucose output through Akt-mediated phosphorylation of glycogen synthase kinase α/β (GSK3α/β) and forkhead box protein O1 (FOXO1), respectively. In line with this, we show that SII Ang II potentiated insulin-stimulated phosphorylation of Akt and GSK3α/β, but not FOXO1. Furthermore, we demonstrate that the effect of SII Ang II on insulin-stimulated signalling and glycogen synthesis was dependent on Src and Gαq, as inhibitors of these proteins abolished the potentiating effect of SII Ang II. Thus, our results demonstrate that SII Ang II may have a positive effect on IR signalling and glucose metabolism in hepatocytes.
血管紧张素 II 型 1 型受体（AT1R）参与心血管功能的调节。血管紧张素 II（Ang II）对 AT1R 的过度激活导致心血管疾病，并可能与胰岛素抵抗和糖尿病的发展有关。功能选择性 Ang II 类似物，如[Sar1，Ile4，Ile8]-血管紧张素 II（SII Ang II）类似物，仅激活部分信号网络，已被证明在某些情况下对心血管功能具有有益作用，包括降低血压和提高心脏性能。在这里，我们研究了 SII Ang II 对原代大鼠肝细胞胰岛素受体（IR）信号和葡萄糖代谢的影响。我们表明，肝细胞长期预孵育 SII Ang II 增加了胰岛素刺激的糖原合成，而 Ang II 和 AT1R 拮抗剂氯沙坦则没有作用。胰岛素刺激的肝葡萄糖输出抑制不受 Ang II 或 SII Ang II 的影响。众所周知，胰岛素通过 Akt 介导的糖原合酶激酶α/β（GSK3α/β）和叉头框蛋白 O1（FOXO1）的磷酸化来调节糖原合成和葡萄糖输出。与此一致，我们表明 SII Ang II 增强了胰岛素刺激的 Akt 和 GSK3α/β磷酸化，但不影响 FOXO1。此外，我们证明 SII Ang II 对胰岛素刺激的信号和糖原合成的作用依赖于Src 和 Gαq，因为这些蛋白的抑制剂消除了 SII Ang II 的增强作用。因此，我们的结果表明 SII Ang II 可能对肝细胞中的 IR 信号和葡萄糖代谢产生积极影响。
