Age-Related Impairment in Insulin Release
The Essential Role of β2-Adrenergic Receptor
- Gaetano Santulli1,2,
- Angela Lombardi3,4,
- Daniela Sorriento1,
- Antonio Anastasio1,
- Carmine Del Giudice1,
- Pietro Formisano4,
- Francesco Béguinot4,
- Bruno Trimarco1,
- Claudia Miele4⇓ and
- Guido Iaccarino5⇓
- 1Department of Clinical Medicine, Cardiovascular & Immunologic Sciences, “Federico II” University of Naples, Naples, Italy
- 2Columbia-Presbyterian Medical Center, College of Physicians & Surgeons, Columbia University, New York, New York
- 3Columbia University Medical Center, Columbia University, New York, New York
- 4Department of Cellular and Molecular Biology and Pathology and Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore,” “Federico II” University of Naples, Naples, Italy
- 5School of Medicine, University of Salerno, Salerno, Italy
- Corresponding authors: Guido Iaccarino, , and Claudia Miele, .
G.S. and A.L. contributed equally to this work.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1027/-/DC1.
- Received July 21, 2011.
- Accepted December 3, 2011.
- © 2012 by the American Diabetes Association.
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