Age-Related Impairment in Insulin Release The Essential Role of β2-Adrenergic Receptor

In this study, we investigated the significance of beta(2)-adrenergic receptor (beta(2)AR) in age-related impaired insulin secretion and glucose homeostasis. We characterized the metabolic phenotype of beta(2)AR-null C57B1/6N mice (beta(2)AR(-/-)) by performing in vivo and ex vivo experiments. In vitro assays in cultured INS-1E beta-cells were carried out in order to clarify the mechanism by which beta(2)AR deficiency affects glucose metabolism. Adult (beta(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)gamma, pancreatic duodenal homeobox-1 (PDX-1), and GLUT2. Adenovirus-mediated gene transfer of human beta(2)AR rescued these defects. Consistent effects were evoked in vitro both upon beta(2)AR knockdown and pharmacologic treatment Interestingly, with aging, wild-type (beta(2)AR(+/+)) littermates developed impaired insulin secretion and glucose tolerance. Moreover, islets from 20-month-old beta(2)AR(+/+) mice exhibited reduced density of beta(2)AR compared with those from younger animals, paralleled by decreased levels of PPAR gamma, PDX-1, and GLUT2. Over-expression of beta(2)AR in aged mice rescued glucose intolerance and insulin release both in vivo and ex vivo, restoring PPAR gamma/PDX-1/GLUT2 levels. Our data indicate that reduced beta(2)AR expression contributes to the age-related decline of glucose tolerance in mice. Diabetes 61:692-701, 2012