Obesity increases incidence and severity of asthma but the molecular mechanisms are not completely understood. Hyperinsulinemia potentiates vagally induced bronchoconstriction in obese rats. Since bronchoconstriction results from airway smooth muscle contraction, we tested whether insulin changed agonist-induced airway smooth muscle contraction. Obesity prone and resistant rats were fed a low-fat diet for 5 weeks and treated with insulin (Lantus, 3 units/rat s.c.) 16 h before vagally induced bronchoconstriction was measured. Ex vivo, contractile responses to methacholine were measured in isolated rat tracheal rings and human airway smooth muscle strips before and after incubation (0.5 - 2 h) with 100 nM insulin or 13.1 nM insulin like growth factor-1 (IGF-1). M₂ and M₃ muscarinic receptor mRNA expression was quantified by qRT-PCR and changes in intracellular calcium were measured in response to methacholine or serotonin in isolated rat tracheal smooth muscle cells treated with 1 µM insulin. Insulin, administered to animals 16 h prior, potentiated vagally induced bronchoconstriction in both obese prone and resistant rats. Insulin, not IGF-1, significantly increased methacholine-induced contraction of rat and human isolated airway smooth muscle. In cultured rat tracheal smooth muscle cells, insulin significantly increased M₂, not M_3, mRNA expression and enhanced methacholine- and serotonin-induced increase in intracellular calcium. Insulin alone did not cause an immediate increase in intracellular calcium. Thus, insulin, acutely potentiated agonist-induced increase in intracellular calcium and airway smooth muscle contraction. These findings may explain why obese individuals with hyperinsulinemia are prone to airway hyperreactivity and give insights into future targets for asthma treatment.

中文翻译：

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胰岛素急性增加激动剂诱导的人和大鼠气道平滑肌收缩

肥胖会增加哮喘的发病率和严重程度，但其分子机制尚不完全清楚。高胰岛素血症增强肥胖大鼠迷走神经诱导的支气管收缩。由于支气管收缩是由气道平滑肌收缩引起的，我们测试了胰岛素是否改变了激动剂诱导的气道平滑肌收缩。在测量迷走神经诱导的支气管收缩前 16 小时，肥胖倾向和抵抗力大鼠被喂食低脂饮食 5 周，并用胰岛素（Lantus，3 单位/大鼠 sc）治疗。离体，在用 100 nM 胰岛素或 13.1 nM 胰岛素样生长因子-1 (IGF-1) 孵育 (0.5-2 小时) 之前和之后，在分离的大鼠气管环和人气道平滑肌条中测量对乙酰甲胆碱的收缩反应。M ₂和 M ₃通过 qRT-PCR 定量毒蕈碱受体 mRNA 表达，并测量用 1 µM 胰岛素处理的离体大鼠气管平滑肌细胞中乙酰甲胆碱或血清素对细胞内钙的变化。胰岛素在 16 小时前给予动物，在肥胖易发和耐药大鼠中增强迷走神经诱导的支气管收缩。胰岛素，而不是 IGF-1，显着增加了乙酰甲胆碱诱导的大鼠和人分离气道平滑肌的收缩。在培养的大鼠气管平滑肌细胞中，胰岛素显着增加 M ₂，而不是 M _{3 ，}mRNA 表达和增强的乙酰甲胆碱和血清素诱导的细胞内钙增加。单独使用胰岛素不会立即引起细胞内钙的增加。因此，胰岛素、急性增强激动剂诱导的细胞内钙增加和气道平滑肌收缩。这些发现可以解释为什么患有高胰岛素血症的肥胖个体容易出现气道高反应性，并为哮喘治疗的未来目标提供见解。