Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis.
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.
Gautam
D
D
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892-0810, USA.
Han
S-J
SJ
Duttaroy
A
A
Mears
D
D
Hamdan
F F
FF
Li
J H
JH
Cui
Y
Y
Jeon
J
J
Wess
J
J
D000109:Acetylcholine; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage; D018149:Glucose Intolerance / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D043587:Receptor, Muscarinic M3 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
D001786:Blood Glucose; D007328:Insulin; D018721:Muscarinic Agonists; D043587:Receptor, Muscarinic M3; D005947:Glucose; D000109:Acetylcholine