Insulin Regulates Neuronal M₂Muscarinic Receptor Function in the Ileum of Diabetic Rats

Abstract

Acetylcholine release from cholinergic nerves in the gastrointestinal tract is limited by neuronal M 2 muscarinic receptors. In diabetic animals, M 2 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 M 2 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 M 2 muscarinic receptor function in the gastrointestinal tract of diabetic rats. M 2 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 M 2 muscarinic receptor function and restored normal contractions to EFS. Insulin had no effect on the function of postjunctional M 3 muscarinic receptors, determined by measuring contractile responses to acetylcholine. These data suggest that insulin tonically inhibits neuronal M 2 muscarinic receptors. Thus, loss of insulin removes this inhibition and increases M 2 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 M 2 muscarinic receptor function, suggesting a bell-shaped concentration-response relationship for insulin. In conclusion, lack of insulin or excess insulin increases M 2 muscarinic receptor function in rat ileum. This mechanism may contribute to decreased acetylcholine release in the gastrointestinal tract of diabetics, resulting in dysmotility.

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

“…Our data that insulin can inhibit M 2 receptors and that STZ reverses this effect are consistent with our previous studies showing that insulin depletion increases M 2 muscarinic receptor function and expression (30,40). In these previous studies, done in nonselected Sprague Dawley rats on a noncontrolled diet, increased function of M 2 receptor on airway nerves decreased the bronchoconstriction response to vagal stimulation, an effect we did not see in obese-resistant rats on a controlled diet.…”

“…To test the direct effect of insulin on parasympathetic nerve-mediated airway smooth muscle contraction and M 3 muscarinic receptor function, human tracheal smooth muscle strips were suspended in organ baths in the absence and presence of insulin. Contractions were induced by electrical field stimulation (EFS) or by increasing concentrations of methacholine (MCh) as previously described (30). Neuronal M 2 muscarinic receptor function was tested in human tracheal smooth muscle by measuring the ability of gallamine, a selective antagonist, to potentiate EFSinduced contractions (19).…”

Diabetes and the enteric nervous system

“…Altered signalling through the protein kinase C pathway in gastric myocytes may also contribute to diabetic gastroparesis 60 . Insulin can regulate the altered neuronal M2 muscarinic receptor function seen in the ileum of diabetic rats 61 . Recent studies have demonstrated that myopathy may play a role in diabetic gastroparesis.…”

“…58,59 Altered signalling through the protein kinase C pathway in gastric myocytes may also contribute to diabetic gastroparesis. 60 Insulin can regulate the altered neuronal M2 muscarinic receptor 61 Recent studies have demonstrated that myopathy may play a role in diabetic gastroparesis. A reduction in insulin/ IGF-I signalling in diabetes causes ICC depletion, subsequent stem cell factor depletion and resultant smooth-muscle atrophy.…”

Gastric emptying in diabetic patients by the 13C-octanoic acid breath test: role of insulin in gastric motility

“…6 In diabetic rats, insulin regulates neuronal M 2 muscarinic receptor function in the ileum, suggesting that lack of insulin may lead to gastrointestinal dysmotility. 7 Differences in gastric emptying between non-insulindependent diabetes mellitus (NIDDM) and insulindependent diabetes mellitus (IDDM) have been reported, but the exact mechanism is not well evaluated. Cross-sectional studies of patients with long-standing (>∼3 years' duration) diabetes mellitus indicate that gastric emptying of solid or liquid meals is delayed in about 50% of cases and that the prevalence of delayed emptying in IDDM 1,8,9 and NIDDM 10,11 is similar.…”