Chronic activation of a designer G(q)-coupled receptor improves β cell function

J Clin Invest. 2013 Apr;123(4):1750-62. doi: 10.1172/JCI66432. Epub 2013 Mar 8.


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

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Clozapine / analogs & derivatives*
  • Clozapine / pharmacology
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / prevention & control
  • Drug Evaluation, Preclinical
  • Female
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • Gene Expression / drug effects
  • Hypoglycemic Agents / pharmacology*
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Receptor Substrate Proteins / physiology
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Muscarinic Agonists / pharmacology
  • Protein Engineering
  • Receptor, Muscarinic M3 / agonists
  • Receptor, Muscarinic M3 / physiology
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Recombinant Proteins / agonists
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • Hypoglycemic Agents
  • Insulin Receptor Substrate Proteins
  • Irs2 protein, mouse
  • Muscarinic Agonists
  • Receptor, Muscarinic M3
  • Receptors, G-Protein-Coupled
  • Recombinant Proteins
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Clozapine
  • clozapine N-oxide