Role of the M₃ muscarinic acetylcholine receptor in β‐cell function and glucose homeostasis

Abstract

The release of insufficient amounts of insulin in the presence of elevated blood glucose levels is one of the key features of type 2 diabetes. Various lines of evidence indicate that acetylcholine (ACh), the major neurotransmitter of the parasympathetic nervous system, can enhance glucose-stimulated insulin secretion from pancreatic b-cells. Studies with isolated islets prepared from whole body M 3 muscarinic ACh receptor knockout mice showed that cholinergic amplification of glucose-dependent insulin secretion is exclusively mediated by the M 3 muscarinic receptor subtype. To investigate the physiological relevance of this muscarinic pathway, we used Cre/loxP technology to generate mutant mice that lack M 3 receptors only in pancreatic b-cells. These mutant mice displayed impaired glucose tolerance and significantly reduced insulin secretion. In contrast, transgenic mice overexpressing M 3 receptors in pancreatic b-cells showed a pronounced increase in glucose tolerance and insulin secretion and were resistant to diet-induced glucose intolerance and hyperglycaemia. These findings indicate that b-cell M 3 muscarinic receptors are essential for maintaining proper insulin secretion and glucose homeostasis. Moreover, our data suggest that enhancing signalling through b-cell M 3 muscarinic receptors may represent a new avenue in the treatment of glucose intolerance and type 2 diabetes.

M 3 -muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1

“…Using this mouse model, we have recently demonstrated an important role for receptor phosphorylation and β-arrestin signaling in muscarinic receptor-mediated hippocampal memory and learning (14). In the present study we focus on the role of M 3 -muscarinic receptor phosphorylation in the regulation of glucose-dependent insulin release from pancreatic islets, a response that is known to be augmented by parasympathetic pathways acting on M 3 -muscarinic receptors expressed on pancreatic β-cells (15)(16)(17). Our results demonstrate that the M 3 -muscarinic receptor-stimulated increase in insulin release is mediated, at least in part, by receptor phosphorylation/arrestin signaling.…”

Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis

“…This nervous activity may also mediate the induction of β cell proliferation in response to development of insulin resistance in the liver (12). These effects are mediated by acetylcholine activating β cell muscarinic acetylcholine receptor-3 (m3AChR) (13)(14)(15), and inactivation of the m3AChR gene in β cells reduces insulin secretion and glucose tolerance (16). However, parasympathetic nerve terminals also contain vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), and gastrin-releasing peptide (GRP) acting as neurotransmitters binding to specific G protein-coupled receptors present on the β cell surface (17).…”

Assay Development and Multivariate Scoring for High-Content Discovery of Chemoprotectants of Endoplasmic-Reticulum-Stress-Mediated Amylin-Induced Cytotoxicity in Pancreatic Beta Cells

“…24 This result demonstrates a potential connection between muscarinic receptor modulation and b-cell survival, which has been previously described and is potentially related to muscarinic receptor inhibition of cytokine (IL-1b and IFNg)-mediated pancreatic b-cell apoptosis. [25][26][27] In conclusion, this high-content HTS assay platform is a viable approach for phenotypic drug discovery for identifying chemoprotectants against a clinically relevant amylin-induced b-cell death. High-content automated imaging in conjunction with automated feature extraction yields a data-rich phenotypic fingerprint for compound effects that can ultimately lead to new molecular targets, pathways, and compounds with therapeutic effects.…”