| Beneficial metabolic effects caused by persistent activation of beta-cell M3 muscarinic acetylcholine receptors in transgenic mice. | |
| | |
MedLine Citation:
|
PMID: 20843999 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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:
|
Dinesh Gautam; Inigo Ruiz de Azua; Jian Hua Li; Jean-Marc Guettier; Thomas Heard; Yinghong Cui; Huiyan Lu; William Jou; Oksana Gavrilova; Walter S Zawalich; Jürgen Wess |
Related Documents
:
|
12239279 - Effect of rosiglitazone on the differential expression of diabetes-associated proteins ... 20807839 - A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasin... 20800279 - Modulating notch signaling to enhance neovascularization and reperfusion in diabetic mice. 19765579 - Inhibition of dpp-4 with sitagliptin improves glycemic control and restores islet cell ... 14599559 - Hepatic expression of cytochrome p450s in hepatocyte nuclear factor 1-alpha (hnf1alpha)... 2645089 - Influence of the beta 2-adrenergic agonist clenbuterol on insulin-stimulated lipogenesi... 12239279 - Effect of rosiglitazone on the differential expression of diabetes-associated proteins ... 6283579 - Absence of naloxone sensitivity in obese humans. 12380889 - Alcoholism and diabetes mellitus: case report. |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2010-09-15 |
Journal Detail:
|
Title: Endocrinology Volume: 151 ISSN: 1945-7170 ISO Abbreviation: Endocrinology Publication Date: 2010 Nov |
Date Detail:
|
Created Date: 2010-10-21 Completed Date: 2010-11-04 Revised Date: 2013-02-27 |
Medline Journal Info:
|
Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: United States |
Other Details:
|
Languages: eng Pagination: 5185-94 Citation Subset: AIM; IM |
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. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Analysis of Variance Animals Atropine / pharmacology Blood Glucose / drug effects, metabolism* Genotype Homeostasis / drug effects Insulin / blood, secretion Insulin-Secreting Cells / drug effects, metabolism*, secretion Mice Mice, Transgenic Muscarinic Antagonists / pharmacology Phenotype Receptor, Muscarinic M3 / genetics, metabolism* Reverse Transcriptase Polymerase Chain Reaction |
| Chemical | |
Reg. No./Substance:
|
0/Blood Glucose; 0/Insulin; 0/Muscarinic Antagonists; 0/Receptor, Muscarinic M3; 51-55-8/Atropine |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Development and Hormonal Regulation of the Ovarian Lymphatic Vasculature.
Next Document: Phenotypic Plasticity of the Ovarian Surface Epithelium: TGF-{beta}1 Induction of Epithelial to Mese...