{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:16:18Z","timestamp":1793042178850,"version":"4.5.0"},"reference-count":24,"publisher":"National Academy of Sciences","issue":"45","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,11,10]]},"abstract":"<jats:p>\n                    Impaired functioning of pancreatic \u03b2 cells is a key hallmark of type 2 diabetes. \u03b2 cell function is modulated by the actions of different classes of heterotrimeric G proteins. The functional consequences of activating specific \u03b2 cell G protein signaling pathways in vivo are not well understood at present, primarily due to the fact that \u03b2 cell G protein-coupled receptors (GPCRs) are also expressed by many other tissues. To circumvent these difficulties, we developed a chemical-genetic approach that allows for the conditional and selective activation of specific \u03b2 cell G proteins in intact animals. Specifically, we created two lines of transgenic mice each of which expressed a specific designer GPCR in \u03b2 cells only. Importantly, the two designer receptors differed in their G protein-coupling properties (G\n                    <jats:sub>q\/11<\/jats:sub>\n                    versus G\n                    <jats:sub>s<\/jats:sub>\n                    ). They were unable to bind endogenous ligand(s), but could be efficiently activated by an otherwise pharmacologically inert compound (clozapine-N-oxide), leading to the conditional activation of either \u03b2 cell G\n                    <jats:sub>q\/11<\/jats:sub>\n                    or G\n                    <jats:sub>s<\/jats:sub>\n                    G proteins. Here we report the findings that conditional and selective activation of \u03b2 cell G\n                    <jats:sub>q\/11<\/jats:sub>\n                    signaling in vivo leads to striking increases in both first- and second-phase insulin release, greatly improved glucose tolerance in obese, insulin-resistant mice, and elevated \u03b2 cell mass, associated with pathway-specific alterations in islet gene expression levels. Selective stimulation of \u03b2 cell G\n                    <jats:sub>s<\/jats:sub>\n                    triggered qualitatively similar in vivo metabolic effects. Thus, this developed chemical-genetic strategy represents a powerful approach to study G protein regulation of \u03b2 cell function in vivo.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0906593106","type":"journal-article","created":{"date-parts":[[2009,10,26]],"date-time":"2009-10-26T21:47:49Z","timestamp":1256593669000},"page":"19197-19202","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":322,"title":["A chemical-genetic approach to study G protein regulation of \u03b2 cell function in vivo"],"prefix":"10.1073","volume":"106","author":[{"given":"Jean-Marc","family":"Guettier","sequence":"first","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,"}],"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,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Scarselli","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inigo Ruiz","family":"de Azua","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Rosemond","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochao","family":"Ma","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, National Cancer Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J.","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, National Cancer Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blaine N.","family":"Armbruster","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Division of Medicinal Chemistry and Natural Products, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514"}],"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, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan L.","family":"Roth","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Division of Medicinal Chemistry and Natural Products, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514"}],"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,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,11,10]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/414782a"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2337\/diab.43.8.1066"},{"key":"e_1_3_3_3_2","first-page":"4034","article-title":"Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion","volume":"117","author":"Regard JB","year":"2007","unstructured":"JB Regard, et al., Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. 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