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Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
¹ Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
² Department of Medicine (Diabetes, Endocrinology, and Metabolism), Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
⁴ Center for Computational Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA

(Requests for offprints should be addressed to L E Limbird, 464A Robinson Research Building, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600, USA; Email: lee.limbird{at}vanderbilt.edu)

The present studies extend recent findings that mice null for the _2A adrenergic receptor (_2A AR KO mice) lack suppression of exogenous secretagogue-stimulated insulin secretion in response to ₂ AR agonists by evaluating the endogenous secretagogue, glucose, ex vivo, and providing in vivo data that baseline insulin levels are elevated and baseline glucose levels are decreased in _2A AR KO mice. These latter findings reveal that the _2A AR subtype regulates glucose-stimulated insulin release in response to endogenous catecholamines in vivo. The changes in _2A AR responsiveness and resultant changes in insulin/glucose homeostasis encouraged us to utilize proteomics strategies to identify possible _2A AR downstream signaling molecules or other resultant changes due to perturbation of _2A AR expression. Although agonist stimulation of islets from wild type (WT) mice did not significantly alter islet protein profiles, several proteins were enriched in islets from _2A AR KO mice when compared with those from WT mice, including an enzyme participating in insulin protein processing. The present studies document the important role of the _2A AR subtype in tonic suppression of insulin release in response to endogenous catecholamines as well as exogenous ₂ agonists and provide insights into pleiotropic changes that result from loss of _2A AR expression and tonic suppression of insulin release.