title: Beneficial metabolic effects caused by persistent activation of beta-cell M3 muscarinic acetylcholine receptors in transgenic mice.
abstract: Previous studies have shown that β-cell M(3) muscarinic acetylcholine receptors (M3Rs) play a key role in maintaining blood glucose homeostasis by enhancing glucose-dependent insulin release. In this study, we tested the hypothesis that long-term, persistent activation of β-cell M3Rs can improve glucose tolerance and ameliorate the metabolic deficits associated with the consumption of a high-fat diet. To achieve the selective and persistent activation of β-cell M3Rs in vivo, we generated transgenic mice that expressed the Q490L mutant M3R in their pancreatic β-cells (β-M3-Q490L Tg mice). The Q490L point mutation is known to render the M3R constitutively active. The metabolic phenotypes of the transgenic mice were examined in several in vitro and in vivo metabolic tests. In the presence of 15 mm glucose and the absence of M3R ligands, isolated perifused islets prepared from β-M3-Q490L Tg mice released considerably more insulin than wild-type control islets. This effect could be completely blocked by incubation of the transgenic islets with atropine (10 μm), an inverse muscarinic agonist, indicating that the Q490L mutant M3R exhibited ligand-independent signaling (constitutive activity) in mouse β-cells. In vivo studies showed that β-M3-Q490L Tg mice displayed greatly improved glucose tolerance and increased serum insulin levels as well as resistance to diet-induced glucose intolerance and hyperglycemia. These results suggest that chronic activation of β-cell M3Rs may represent a useful approach to boost insulin output in the long-term treatment of type 2 diabetes.
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 8 Center Drive MSC 0810, Bethesda, MD 20892-0810, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Gautam
authors.forename: Inigo
authors.initials: I
authors.lastname: Ruiz de Azua
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Li
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Guettier
authors.forename: Thomas
authors.initials: T
authors.lastname: Heard
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Cui
authors.forename: Huiyan
authors.initials: H
authors.lastname: Lu
authors.forename: William
authors.initials: W
authors.lastname: Jou
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Walter S
authors.initials: WS
authors.lastname: Zawalich
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D005838:Genotype; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010641:Phenotype; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D001285:Atropine