{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:46:01Z","timestamp":1789195561695,"version":"build-2803163510"},"reference-count":34,"publisher":"American Diabetes Association","issue":"12","license":[{"start":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T00:00:00Z","timestamp":1630108800000},"content-version":"vor","delay-in-days":4366,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,12,1]]},"abstract":"<jats:sec><jats:title>OBJECTIVE<\/jats:title><jats:p>An increase in the rate of hepatic glucose production is the major determinant of fasting hyperglycemia in type 2 diabetes. A better understanding of the signaling pathways and molecules that regulate hepatic glucose metabolism is therefore of great clinical importance. Recent studies suggest that an increase in vagal outflow to the liver leads to decreased hepatic glucose production and reduced blood glucose levels. Since acetylcholine (ACh) is the major neurotransmitter of the vagus nerve and exerts its parasympathetic actions via activation of muscarinic ACh receptors (mAChRs), we examined the potential metabolic relevance of hepatocyte mAChRs.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESEARCH DESIGN AND METHODS<\/jats:title><jats:p>We initially demonstrated that the M3 mAChR is the only mAChR subtype expressed by mouse liver\/hepatocytes. To assess the physiological role of this receptor subtype in regulating hepatic glucose fluxes and glucose homeostasis in vivo, we used gene targeting and transgenic techniques to generate mutant mice lacking or overexpressing M3 receptors in hepatocytes only.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Strikingly, detailed in vivo phenotyping studies failed to reveal any significant metabolic differences between the M3 receptor mutant mice and their control littermates, independent of whether the mice were fed regular or a high-fat diet. Moreover, the expression levels of genes for various key transcription factors, signaling molecules, and enzymes regulating hepatic glucose fluxes were not significantly altered in the M3 receptor mutant mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>This rather surprising finding suggests that the pronounced metabolic effects mediated by activation of hepatic vagal nerves are mediated by noncholinergic signaling pathways.<\/jats:p><\/jats:sec>","DOI":"10.2337\/db09-0522","type":"journal-article","created":{"date-parts":[[2009,9,15]],"date-time":"2009-09-15T00:45:16Z","timestamp":1252975516000},"page":"2776-2787","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":46,"title":["Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice"],"prefix":"10.2337","volume":"58","author":[{"given":"Jian H.","family":"Li","sequence":"first","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Gautam","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Jun","family":"Han","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Guettier","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghong","family":"Cui","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyan","family":"Lu","sequence":"additional","affiliation":[{"name":"Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuxia","family":"Deng","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Section, Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"O'Hare","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Neuroscience, Mount Sinai School of Medicine, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Jou","sequence":"additional","affiliation":[{"name":"Mouse Metabolic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Gavrilova","sequence":"additional","affiliation":[{"name":"Mouse Metabolic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Buettner","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Neuroscience, Mount Sinai School of Medicine, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Wess","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2009,9,14]]},"reference":[{"key":"2022031215555512800_B1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0092-8674(00)80709-6","article-title":"Deconstructing type 2 diabetes","volume":"97","author":"Taylor","year":"1999","journal-title":"Cell"},{"key":"2022031215555512800_B2","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/0301-0082(83)90016-3","article-title":"Afferent and efferent neural roles in liver function","volume":"21","author":"Lautt","year":"1983","journal-title":"Prog Neurobiol"},{"key":"2022031215555512800_B3","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1515\/bchm3.1986.367.2.559","article-title":"Control of glucose balance in the perfused rat liver by the parasympathetic innervation","volume":"367","author":"Gardemann","year":"1986","journal-title":"Biol Chem Hoppe Seyler"},{"key":"2022031215555512800_B4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0026-0495(00)90538-9","article-title":"Important role of the hepatic vagus nerve in glucose uptake and production by the liver","volume":"49","author":"Matsuhisa","year":"2000","journal-title":"Metabolism"},{"key":"2022031215555512800_B5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/0304-4165(71)90088-2","article-title":"Regulation of glycogen metabolism in liver by the autonomic nervous system: IV. Neural control of glycogen biosynthesis","volume":"252","author":"Shimazu","year":"1971","journal-title":"Biochim Biophys Acta"},{"key":"2022031215555512800_B6","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1006\/jsre.2000.5820","article-title":"Isolated hepatic cholinergic denervation impairs glucose and glycogen metabolism","volume":"90","author":"Xue","year":"2000","journal-title":"J Surg Res"},{"key":"2022031215555512800_B7","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0014-5793(97)00254-8","article-title":"Sensing by intrahepatic muscarinic nerves of a portal-arterial glucose concentration gradient as a signal for insulin-dependent glucose uptake in the perfused rat liver","volume":"406","author":"St\u00fcmpel","year":"1997","journal-title":"FEBS Lett"},{"key":"2022031215555512800_B8","doi-asserted-by":"crossref","first-page":"E544","DOI":"10.1152\/ajpendo.2000.278.3.E544","article-title":"Combined intraportal infusion of acetylcholine and adrenergic blockers augments net hepatic glucose uptake","volume":"278","author":"Shiota","year":"2000","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022031215555512800_B9","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/0006-291X(74)90556-7","article-title":"Studies on the effects of insulin and acetylcholine on activation of glycogen synthase and on glycogenesis in hepatocytes","volume":"61","author":"Akpan","year":"1974","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031215555512800_B10","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1016\/S0024-3205(02)02506-7","article-title":"Acetylcholine affects rat liver metabolism via type 3 muscarinic receptors in hepatocytes","volume":"72","author":"Vatamaniuk","year":"2003","journal-title":"Life Sci"},{"key":"2022031215555512800_B11","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.cmet.2004.11.001","article-title":"A brain-liver circuit regulates glucose homeostasis","volume":"1","author":"Pocai","year":"2005","journal-title":"Cell Metab"},{"key":"2022031215555512800_B12","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/nature03439","article-title":"Hypothalamic KATP channels control hepatic glucose production","volume":"434","author":"Pocai","year":"2005","journal-title":"Nature"},{"key":"2022031215555512800_B13","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/nm1201","article-title":"Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis","volume":"11","author":"Lam","year":"2005","journal-title":"Nat Med"},{"key":"2022031215555512800_B14","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1038\/nature06852","article-title":"Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production","volume":"452","author":"Wang","year":"2008","journal-title":"Nature"},{"key":"2022031215555512800_B15","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0031-6997(24)01362-0","article-title":"International Union of Pharmacology: XVII. classification of muscarinic acetylcholine receptors","volume":"50","author":"Caulfield","year":"1998","journal-title":"Pharmacol Rev"},{"key":"2022031215555512800_B16","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nrd2379","article-title":"Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development","volume":"6","author":"Wess","year":"2007","journal-title":"Nat Rev Drug Discov"},{"key":"2022031215555512800_B17","doi-asserted-by":"crossref","first-page":"G1044","DOI":"10.1152\/ajpgi.00184.2004","article-title":"IFN-\u03b3\/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1","volume":"287","author":"Jaruga","year":"2004","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2022031215555512800_B18","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1053\/j.gastro.2008.01.016","article-title":"Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury","volume":"134","author":"Horiguchi","year":"2008","journal-title":"Gastroenterology"},{"key":"2022031215555512800_B19","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.2337\/diabetes.53.7.1714","article-title":"Muscarinic stimulation of pancreatic insulin and glucagon release is abolished in M3 muscarinic acetylcholine receptor-deficient mice","volume":"53","author":"Duttaroy","year":"2004","journal-title":"Diabetes"},{"key":"2022031215555512800_B20","doi-asserted-by":"crossref","first-page":"26284","DOI":"10.1074\/jbc.M704875200","article-title":"Distinct structural changes in a G protein-coupled receptor caused by different classes of agonist ligands","volume":"282","author":"Li","year":"2007","journal-title":"J Biol Chem"},{"key":"2022031215555512800_B21","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1126\/science.1092341","article-title":"Regulation of fasted blood glucose by resistin","volume":"303","author":"Banerjee","year":"2004","journal-title":"Science"},{"key":"2022031215555512800_B22","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1073\/pnas.0237106100","article-title":"Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice","volume":"100","author":"Gelling","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031215555512800_B23","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1172\/JCI119711","article-title":"Peripheral but not hepatic insulin resistance in mice with one disrupted allele of the glucose transporter type 4 (GLUT4) gene","volume":"100","author":"Rossetti","year":"1997","journal-title":"J Clin Invest"},{"key":"2022031215555512800_B24","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.cmet.2006.04.009","article-title":"A critical role for \u03b2 cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo","volume":"3","author":"Gautam","year":"2006","journal-title":"Cell Metab"},{"key":"2022031215555512800_B25","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1074\/jbc.274.1.305","article-title":"Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic \u03b2 cell-specific gene knock-outs using Cre recombinase","volume":"274","author":"Postic","year":"1999","journal-title":"J Biol Chem"},{"key":"2022031215555512800_B26","doi-asserted-by":"crossref","first-page":"715","DOI":"10.2337\/diacare.18.5.715","article-title":"Glucagon and its family revisited","volume":"18","author":"Lefebvre","year":"1995","journal-title":"Diabetes Care"},{"key":"2022031215555512800_B27","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s001250051322","article-title":"Autonomic regulation of islet hormone secretion: implications for health and disease","volume":"43","author":"Ahren","year":"2000","journal-title":"Diabetologia"},{"key":"2022031215555512800_B28","first-page":"565","article-title":"Mechanisms and physiological significance of the cholinergic control of pancreatic \u03b2-cell function","volume":"22","author":"Gilon","year":"2001","journal-title":"Endocr Rev"},{"key":"2022031215555512800_B29","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1002\/hep.510250437","article-title":"Transgenic expression of hepatitis C virus structural proteins in the mouse","volume":"25","author":"Kawamura","year":"1997","journal-title":"Hepatology"},{"key":"2022031215555512800_B30","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1126\/science.1163971","article-title":"Regulation of pancreatic \u03b2 cell mass by neuronal signals from the liver","volume":"322","author":"Imai","year":"2008","journal-title":"Science"},{"key":"2022031215555512800_B31","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1042\/bj2990735","article-title":"Inhibition of hepatic gluconeogenesis by nitric oxide: a comparison with endotoxic shock","volume":"299","author":"Horton","year":"1994","journal-title":"Biochem J"},{"key":"2022031215555512800_B32","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1042\/bj2620195","article-title":"Cellular communication inside the liver: binding, conversion and metabolic effect of prostaglandin D2 on parenchymal liver cells","volume":"262","author":"Kuiper","year":"1989","journal-title":"Biochem J"},{"key":"2022031215555512800_B33","first-page":"1462","article-title":"Kupffer cell cytokines interleukin-1\u03b2 and interleukin-10 combine to inhibit phosphoenolpyruvate carboxykinase and gluconeogenesis in cultured hepatocytes","volume":"36","author":"Yerkovich","year":"2004","journal-title":"Int J Biochem Cell Biol"},{"key":"2022031215555512800_B34","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cmet.2006.02.009","article-title":"Role of hepatic STAT3 in brain-insulin action on hepatic glucose production","volume":"3","author":"Inoue","year":"2006","journal-title":"Cell Metab"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/58\/12\/2776\/394498\/zdb01209002776.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/58\/12\/2776\/394498\/zdb01209002776.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T04:34:58Z","timestamp":1739334898000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/58\/12\/2776\/24082\/Hepatic-Muscarinic-Acetylcholine-Receptors-Are-Not"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,9,14]]},"references-count":34,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2009,9,14]]},"published-print":{"date-parts":[[2009,12,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db09-0522","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,9,14]]}}}