title: Chronic activation of a designer G(q)-coupled receptor improves β cell function.
abstract: Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. Therapeutic strategies aimed at improving pancreatic β cell function are predicted to prove beneficial for the treatment of T2D. In the present study, we demonstrate that drug-mediated, chronic, and selective activation of β cell G(q) signaling greatly improve β cell function and glucose homeostasis in mice. These beneficial metabolic effects were accompanied by the enhanced expression of many genes critical for β cell function, maintenance, and differentiation. By employing a combination of in vivo and in vitro approaches, we identified a novel β cell pathway through which receptor-activated G(q) leads to the sequential activation of ERK1/2 and IRS2 signaling, thus triggering a series of events that greatly improve β cell function. Importantly, we found that chronic stimulation of a designer G(q)-coupled receptor selectively expressed in β cells prevented both streptozotocin-induced diabetes and the metabolic deficits associated with the consumption of a high-fat diet in mice. Since β cells are endowed with numerous receptors that mediate their cellular effects via activation of G(q)-type G proteins, our findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors.
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jain
authors.forename: Inigo
authors.initials: I
authors.lastname: Ruiz de Azua
authors.forename: Huiyan
authors.initials: H
authors.lastname: Lu
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Guettier
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D018721:Muscarinic Agonists / Q000494:pharmacology; D015202:Protein Engineering; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D018721:Muscarinic Agonists; D043587:Receptor, Muscarinic M3; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D003024:Clozapine; C079149:clozapine N-oxide