Insulin acutely increases agonist-induced airway smooth muscle contraction in humans and rats

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 5wk and treated with insulin (Lantus, 3 units/rat sc) 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). M-2 and M-3 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 mu M 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 M-2, 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 hyper-reactivity and give insights into future targets for asthma treatment.

Automated summary

This study found that hyperinsulinemia increases bronchoconstriction induced by the vagus nerve in obese rats, as well as significantly increases methacholine-induced airway smooth muscle contraction. Insulin enhances intracellular calcium and smooth muscle contraction, providing insights into potential asthma treatment targets.