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Age-related impairment in insulin release: the essential role of ϐ(2)-adrenergic receptor.

Santulli, Gaetano; Lombardi, Angela; Sorriento, Daniela; Anastasio, Antonio; del Giudice, Carmine; Formisano, Pietro; Béguinot, Francesco; Trimarco, Bruno; Miele, Claudia; Iaccarino, Guido

In this study, we investigated the significance of ϐ (2)-adrenergic receptor (ϐ (2)AR) in age-related impaired insulin secretion and glucose homeostasis. We characterized the metabolic phenotype of ϐ (2)AR-null C57Bl/6N mice (ϐ (2)AR(-/-)) 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 ϐ (2)AR deficiency affects glucose metabolism. Adult ϐ (2)AR(-/-) 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 ϐ (2)AR rescued these defects. Consistent effects were evoked in vitro both upon ϐ (2)AR knockdown and pharmacologic treatment. Interestingly, with aging, wild-type (ϐ (2)AR(+/+)) littermates developed impaired insulin secretion and glucose tolerance. Moreover, islets from 20-month-old ϐ (2)AR(+/+) mice exhibited reduced density of ϐ (2)AR compared with those from younger animals, paralleled by decreased levels of PPARγ, PDX-1, and GLUT2. Overexpression of ϐ (2)AR 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 ϐ (2)AR expression contributes to the age-related decline of glucose tolerance in mice.



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Academic Units
Physiology and Cellular Biophysics
Published Here
December 9, 2014
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