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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation
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Clozapine / analogs & derivatives*
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Clozapine / pharmacology
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Experimental / prevention & control
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Drug Evaluation, Preclinical
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Female
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GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
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GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
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Gene Expression / drug effects
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Hypoglycemic Agents / pharmacology*
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Insulin Receptor Substrate Proteins / genetics
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Insulin Receptor Substrate Proteins / metabolism
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Insulin Receptor Substrate Proteins / physiology
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Insulin-Secreting Cells / drug effects*
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Insulin-Secreting Cells / metabolism
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Insulin-Secreting Cells / physiology
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MAP Kinase Signaling System
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Molecular Targeted Therapy
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Muscarinic Agonists / pharmacology
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Protein Engineering
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Receptor, Muscarinic M3 / agonists
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Receptor, Muscarinic M3 / physiology
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Recombinant Proteins / agonists
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
Substances
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Hypoglycemic Agents
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Insulin Receptor Substrate Proteins
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Irs2 protein, mouse
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Muscarinic Agonists
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Receptor, Muscarinic M3
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Receptors, G-Protein-Coupled
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Recombinant Proteins
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GTP-Binding Protein alpha Subunits, Gq-G11
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Clozapine
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clozapine N-oxide