TY - JOUR T1 - Insulin Regulates Neuronal M<sub>2</sub> Muscarinic Receptor Function in the Ileum of Diabetic Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 760 LP - 766 DO - 10.1124/jpet.103.057570 VL - 308 IS - 2 AU - Fiona R. Coulson AU - David B. Jacoby AU - Allison D. Fryer Y1 - 2004/02/01 UR - http://jpet.aspetjournals.org/content/308/2/760.abstract N2 - Acetylcholine release from cholinergic nerves in the gastrointestinal tract is limited by neuronal M2 muscarinic receptors. In diabetic animals, M2 muscarinic receptor function in the ileum is increased, leading to decreased acetylcholine release and smooth muscle contraction in response to nerve stimulation. The mechanisms responsible for increased M2 muscarinic receptor function are unknown but may contribute to the gastrointestinal dysmotility that occurs frequently in diabetics. In this study, we investigated whether insulin modulates M2 muscarinic receptor function in the gastrointestinal tract of diabetic rats. M2 muscarinic receptor function was tested by measuring the ability of an agonist, pilocarpine, to inhibit and an antagonist, methoctramine, to potentiate electrical field stimulation (EFS)-induced contraction of ileum in vitro. Insulin administration (0.2, 0.6, and 2 U s.c. daily for 7 days) reversed the diabetes-induced increase in M2 muscarinic receptor function and restored normal contractions to EFS. Insulin had no effect on the function of postjunctional M3 muscarinic receptors, determined by measuring contractile responses to acetylcholine. These data suggest that insulin tonically inhibits neuronal M2 muscarinic receptors. Thus, loss of insulin removes this inhibition and increases M2 muscarinic receptor function leading to decreased acetylcholine release and contraction to EFS. In nondiabetic rats, there was a trend that higher insulin doses (0.6 and 2 U) increased M2 muscarinic receptor function, suggesting a bell-shaped concentration-response relationship for insulin. In conclusion, lack of insulin or excess insulin increases M2 muscarinic receptor function in rat ileum. This mechanism may contribute to decreased acetylcholine release in the gastrointestinal tract of diabetics, resulting in dysmotility. The American Society for Pharmacology and Experimental Therapeutics ER -