Hyperinsulinemia potentiates airway responsiveness to parasympathetic nerve stimulation in obese rats.
Obesity is a substantial risk factor for developing asthma, but the molecular mechanisms underlying this relationship are unclear. We tested the role of insulin in airway responsiveness to nerve stimulation using rats genetically prone or resistant to diet-induced obesity. Airway response to vagus nerve stimulation and airway M2 and M3 muscarinic receptor function were measured in obese-prone and -resistant rats with high or low circulating insulin. The effects of insulin on nerve-mediated human airway smooth muscle contraction and human M2 muscarinic receptor function were tested in vitro. Our data show that increased vagally mediated bronchoconstriction in obesity is associated with hyperinsulinemia and loss of inhibitory M2 muscarinic receptor function on parasympathetic nerves. Obesity did not induce airway inflammation or increase airway wall thickness. Smooth muscle contraction to acetylcholine was not increased, indicating that hyperresponsiveness is mediated at the level of airway nerves. Reducing serum insulin with streptozotocin protected neuronal M2 receptor function and prevented airway hyperresponsiveness to vagus nerve stimulation in obese rats. Replacing insulin restored dysfunction of neuronal M2 receptors and airway hyperresponsiveness to vagus nerve stimulation in streptozotocin-treated obese rats. Treatment with insulin caused loss of M2 receptor function, resulting in airway hyperresponsiveness to vagus nerve stimulation in obese-resistant rats, and inhibited human neuronal M2 receptor function in vitro. This study shows that it is not obesity per se but hyperinsulinemia accompanying obesity that potentiates vagally induced bronchoconstriction by inhibiting neuronal M2 muscarinic receptors and increasing acetylcholine release from airway parasympathetic nerves.
['Nie|Zhenying|Z|', 'Jacoby|David B|DB|', 'Fryer|Allison D|AD|']
D000109:Acetylcholine D000818:Animals D001249:Asthma D016535:Bronchial Hyperreactivity D016084:Bronchoconstriction D016085:Bronchoconstrictor Agents D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D004558:Electric Stimulation D006801:Humans D006946:Hyperinsulinism D007004:Hypoglycemic Agents D007328:Insulin D008168:Lung D018721:Muscarinic Agonists D009433:Neural Inhibition D009765:Obesity D051381:Rats D043585:Receptor, Muscarinic M2 D043587:Receptor, Muscarinic M3 D013311:Streptozocin D013997:Time Factors D014630:Vagus Nerve
hyperinsulinemia airway responsiveness obesity asthma neural M2 muscarinic receptor