Role of acetylcholine receptors in cholinergic pathway-mediated protection against autoimmune diabetes

Abstract

Abstract Type I diabetes (T1D) is a T cell-driven autoimmune disease that results in the killing of pancreatic β-cells and, consequently, loss of insulin production. Using the multiple low-dose streptozotocin (MLD-STZ) model of experimental autoimmune diabetes, we previously reported that pretreatment with a specific acetylcholinesterase inhibitor (AChEI), paraoxon, prevented the development of hyperglycemia in C57BL/6 mice. This correlated with an inhibition of T cell infiltration into the pancreatic islets and a reduction in proinflammatory cytokines. The cholinergic anti-inflammatory pathway utilizes nicotinic and muscarinic acetycholine receptors (AChR) expressed on a variety of cell types. In this study, we carried out a comparative analysis on the effect of specific antagonists of the nicotinic- or muscarinic-AChR on the development of autoimmune diabetes. Co-administration of nicotinic-AChR antagonist (mecamylamine) maintained the protective effect of AChEI on the development of hyperglycemia. In contrast, co-administration with muscarinic-AChR antagonist (atropine) mitigated AChEI-mediated protection. Mice pretreated with mecamylamine had an improved response in glucose tolerance test than mice pretreated with atropine. These findings correlated with the extent of islet cell infiltration and with the structure and functionality of the β-cells. Taken together, our data suggest that muscarinic receptors are essential for the protective effect of cholinergic stimulation on autoimmune diabetes.