In animal studies, two mechanisms of hyperinsulinemia-induced BHR have been identified: (1) insulin inhibition of neuronal M2 muscarinic receptors causing increased release of acetylcholine (ACh) from airway parasympathetic nerves [31, 32]; and (2) insulin stimulation of brain stem signaling pathways leading to increased airway reactivity [33]. Here, INS is linked to hyperinsulinism.