Age-Related Impairment in Insulin Release The Essential Role of β_2-Adrenergic Receptor

摘要

In this study, we investigated the significance of β_2-adrenergic receptor (β_2AR) in age-related impaired insulin secretion and glucose homeostasis. We characterized the metabolic phenotype of β_2AR-null C57B1/6N mice (β_2AR~(-/-)) by performing in vivo and ex vivo experiments. In vitro assays in cultured INS-IE β-cells were carried out in order to clarify the mechanism by which β_2AR deficiency affects glucose metabolism. Adult β_2AR~(-/-) 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_2AR rescued these defects. Consistent effects were evoked in vitro both upon β_2AR knockdown and pharmacologic treatment. Interestingly, with aging, wild-type (β_2AR~(+/+)) littermates developed impaired insulin secretion and glucose tolerance. Moreover, islets from 20-month-old β_2AR~(+/+) mice exhibited reduced density of β_2AR compared with those from younger animals, paralleled by decreased levels of PPAR_γ, PDX-1, and GLUT2. Over-expression of β_2AR in aged mice rescued glucose intolerance and insulin release both in vivo and ex vivo, restoring PPAR7/PDX-1/ GLUT2 levels. Our data indicate that reduced β_2AR expression contributes to the age-related decline of glucose tolerance in mice.