Age-related impairment in insulin release: The essential role of ? 2-adrenergic receptor

In this study, we investigated the significance of ?(2)-adrenergic receptor (?(2)AR) in age-related impaired insulin secretion and glucose homeostasis. We characterized the metabolic phenotype of ?(2)AR-null C57Bl/6N mice (?(2)AR(-/-)) by performing in vivo and ex vivo experiments. In vitro assays in cultured INS-1E ?-cells were carried out in order to clarify the mechanism by which ?(2)AR deficiency affects glucose metabolism. Adult ?(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)?, pancreatic duodenal homeobox-1 (PDX-1), and GLUT2. Adenovirus-mediated gene transfer of human ?(2)AR rescued these defects. Consistent effects were evoked in vitro both upon ?(2)AR knockdown and pharmacologic treatment. Interestingly, with aging, wild-type (?(2)AR(+/+)) littermates developed impaired insulin secretion and glucose tolerance. Moreover, islets from 20-month-old ?(2)AR(+/+) mice exhibited reduced density of ?(2)AR compared with those from younger animals, paralleled by decreased levels of PPAR?, PDX-1, and GLUT2. Overexpression of ?(2)AR in aged mice rescued glucose intolerance and insulin release both in vivo and ex vivo, restoring PPAR?/PDX-1/GLUT2 levels. Our data indicate that reduced ?(2)AR expression contributes to the age-related decline of glucose tolerance in mice.