Age-related impairment in insulin release: the essential role of β(2)-adrenergic receptor.
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.
Department of Clinical Medicine, Cardiovascular & Immunologic Sciences, Federico II University of Naples, Naples, Italy.
Gaetano
G
Santulli
Angela
A
Lombardi
Daniela
D
Sorriento
Antonio
A
Anastasio
Carmine
C
Del Giudice
Pietro
P
Formisano
Francesco
F
Béguinot
Bruno
B
Trimarco
Claudia
C
Miele
Guido
G
Iaccarino
D000367:Age Factors; D000818:Animals; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2 / Q000032:analysis / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000502:physiology; D010641:Phenotype; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology
D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D047495:PPAR gamma; D018343:Receptors, Adrenergic, beta-2; C495682:Slc2a2 protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein