title: A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.
abstract: One of the hallmarks of type 2 diabetes is that pancreatic beta cells fail to release sufficient amounts of insulin in the presence of elevated blood glucose levels. Insulin secretion is modulated by many hormones and neurotransmitters including acetylcholine, the major neurotransmitter of the peripheral parasympathetic nervous system. The physiological role of muscarinic acetylcholine receptors expressed by pancreatic beta cells remains unclear at present. Here, we demonstrate that mutant mice selectively lacking the M3 muscarinic acetylcholine receptor subtype in pancreatic beta cells display impaired glucose tolerance and greatly reduced insulin release. In contrast, transgenic mice selectively overexpressing M3 receptors in pancreatic beta cells show a profound increase in glucose tolerance and insulin release. Moreover, these mutant mice are resistant to diet-induced glucose intolerance and hyperglycemia. These findings indicate that beta cell M3 muscarinic receptors play a key role in maintaining proper insulin release and glucose homeostasis.
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Gautam
authors.forename: Sung-Jun
authors.initials: SJ
authors.lastname: Han
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Jongrye
authors.initials: J
authors.lastname: Jeon
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Li
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Cui
authors.forename: David
authors.initials: D
authors.lastname: Mears
authors.forename: Huiyan
authors.initials: H
authors.lastname: Lu
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: Thomas
authors.initials: T
authors.lastname: Heard
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004032:Diet; D005947:Glucose / Q000008:administration & dosage; D018149:Glucose Intolerance / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D006706:Homeostasis; D006946:Hyperinsulinism / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism; D007295:Inositol Phosphates / Q000096:biosynthesis; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D010641:Phenotype; D043587:Receptor, Muscarinic M3 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D007295:Inositol Phosphates; D007328:Insulin; D018721:Muscarinic Agonists; D043587:Receptor, Muscarinic M3; D005947:Glucose