Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis

Diabetes Obes Metab. 2007 Nov;9 Suppl 2:158-69. doi: 10.1111/j.1463-1326.2007.00781.x.

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 beta-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 beta-cells. These mutant mice displayed impaired glucose tolerance and significantly reduced insulin secretion. In contrast, transgenic mice overexpressing M(3) receptors in pancreatic beta-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 beta-cell M(3) muscarinic receptors are essential for maintaining proper insulin secretion and glucose homeostasis. Moreover, our data suggest that enhancing signalling through beta-cell M(3) muscarinic receptors may represent a new avenue in the treatment of glucose intolerance and type 2 diabetes.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetylcholine
  • Animals
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism
  • Glucose / administration & dosage
  • Glucose Intolerance / metabolism
  • Homeostasis
  • Insulin
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism
  • Mice
  • Mice, Knockout
  • Muscarinic Agonists / pharmacology
  • Receptor, Muscarinic M3 / deficiency
  • Receptor, Muscarinic M3 / metabolism
  • Receptor, Muscarinic M3 / physiology*

Substances

  • Blood Glucose
  • Insulin
  • Muscarinic Agonists
  • Receptor, Muscarinic M3
  • Glucose
  • Acetylcholine