Age-Related Impairment in Insulin Release

The Essential Role of β2-Adrenergic Receptor

  1. Guido Iaccarino5
  1. 1Department of Clinical Medicine, Cardiovascular & Immunologic Sciences, “Federico II” University of Naples, Naples, Italy
  2. 2Columbia-Presbyterian Medical Center, College of Physicians & Surgeons, Columbia University, New York, New York
  3. 3Columbia University Medical Center, Columbia University, New York, New York
  4. 4Department of Cellular and Molecular Biology and Pathology and Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore,” “Federico II” University of Naples, Naples, Italy
  5. 5School of Medicine, University of Salerno, Salerno, Italy
  1. Corresponding authors: Guido Iaccarino, giaccarino{at}unisa.it, and Claudia Miele, c.miele{at}ieos.cnr.it.
  1. G.S. and A.L. contributed equally to this work.

Abstract

In this study, we investigated the significance of β2-adrenergic receptor (β2AR) in age-related impaired insulin secretion and glucose homeostasis. We characterized the metabolic phenotype of β2AR-null C57Bl/6N mice (β2AR−/−) by performing in vivo and ex vivo experiments. In vitro assays in cultured INS-1E β-cells were carried out in order to clarify the mechanism by which β2AR deficiency affects glucose metabolism. Adult β2AR−/− mice featured glucose intolerance, and pancreatic islets isolated from these animals displayed impaired glucose-induced insulin release, accompanied by reduced expression of peroxisome proliferator–activated receptor (PPAR)γ, pancreatic duodenal homeobox-1 (PDX-1), and GLUT2. Adenovirus-mediated gene transfer of human β2AR rescued these defects. Consistent effects were evoked in vitro both upon β2AR knockdown and pharmacologic treatment. Interestingly, with aging, wild-type (β2AR+/+) littermates developed impaired insulin secretion and glucose tolerance. Moreover, islets from 20-month-old β2AR+/+ mice exhibited reduced density of β2AR compared with those from younger animals, paralleled by decreased levels of PPARγ, PDX-1, and GLUT2. Overexpression of β2AR in aged mice rescued glucose intolerance and insulin release both in vivo and ex vivo, restoring PPARγ/PDX-1/GLUT2 levels. Our data indicate that reduced β2AR expression contributes to the age-related decline of glucose tolerance in mice.

Footnotes

  • Received July 21, 2011.
  • Accepted December 3, 2011.

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  1. Diabetes vol. 61 no. 3 692-701
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