Previously, we have used mathematical modeling to gain mechanistic insight into insulin-stimulated glucose uptake. Phosphatidylinositol 3-kinase-dependent (PI3K) insulin signaling required for metabolic actions of insulin also regulates endothelium-dependent production of the vasodilator nitric oxide (NO). Vasodilation increases blood flow that augments direct metabolic actions of insulin in skeletal muscle. This is counterbalanced by mitogen-activated protein kinase (MAPK)-dependent insulin signaling in endothelium that promotes secretion of the vasoconstrictor endothelin-1 (ET-1). In the present study, we extended our model of metabolic insulin signaling into a dynamic model of insulin signaling in vascular endothelium that explicitly represents opposing PI3K/NO and MAPK/ET-1 pathways. Novel NO and ET-1 subsystems were developed using published and new experimental data to generate model structures/parameters. The signal-response relationships of our model with respect to insulin-stimulated NO production, ET-1 secretion, and resultant vascular tone, agree with published experimental data independent of those used for model development. Simulations of pathological stimuli directly impairing only insulin-stimulated PI3K/Akt activity predict altered dynamics of NO and ET-1 consistent with endothelial dysfunction in insulin-resistant states. Indeed, modeling pathway-selective impairment of PI3K/Akt pathways consistent with insulin resistance caused by glucotoxicity, lipotoxicity, or inflammation predict diminished NO production and increased ET-1 secretion characteristic of diabetes and endothelial dysfunction. We conclude that our mathematical model of insulin signaling in vascular endothelium supports the hypothesis that pathway-selective insulin resistance accounts, in part, for relationships between insulin resistance and endothelial dysfunction. This may be relevant for developing novel approaches for treatment of diabetes and its cardiovascular complications.

中文翻译：

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血管内皮选择性胰岛素抵抗引起的内皮功能障碍：来自机械模型的见解。

以前，我们使用数学建模来获得对胰岛素刺激葡萄糖摄取的机制洞察。胰岛素代谢作用所需的磷脂酰肌醇 3-激酶依赖性 (PI3K) 胰岛素信号也调节血管扩张剂一氧化氮 (NO) 的内皮依赖性产生。血管舒张增加血流量，从而增强骨骼肌中胰岛素的直接代谢作用。这被促血管收缩内皮素-1 (ET-1) 分泌的内皮中丝裂原活化蛋白激酶 (MAPK) 依赖性胰岛素信号所抵消。在本研究中，我们将代谢胰岛素信号传导模型扩展为血管内皮中胰岛素信号传导的动态模型，该模型明确表示对抗 PI3K/NO 和 MAPK/ET-1 通路。新型 NO 和 ET-1 子系统是使用已发布的和新的实验数据开发的，以生成模型结构/参数。我们的模型在胰岛素刺激的 NO 产生、ET-1 分泌和由此产生的血管张力方面的信号响应关系与已发表的实验数据一致，这些数据独立于模型开发所用的数据。病理刺激的模拟仅直接损害胰岛素刺激的 PI3K/Akt 活性，预测 NO 和 ET-1 的动态变化与胰岛素抵抗状态下的内皮功能障碍一致。事实上，模拟 PI3K/Akt 通路的通路选择性损伤与由糖毒性、脂毒性或炎症引起的胰岛素抵抗一致，预示着糖尿病和内皮功能障碍所特有的 NO 产生减少和 ET-1 分泌增加。我们得出结论，血管内皮中胰岛素信号传导的数学模型支持通路选择性胰岛素抵抗的假设，部分原因是胰岛素抵抗和内皮功能障碍之间的关系。这可能与开发治疗糖尿病及其心血管并发症的新方法有关。