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

Abstract

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.

• Authors: Gaetano Santulli, Angela Lombardi, Daniela Sorriento, Antonio Anastasio, Carmine Del Giudice, Pietro Formisano, Francesco Béguinot, Bruno Trimarco, Claudia Miele, Guido Iaccarino
• Journal: Diabetes (Diabetes) Vol. 61 Issue 3 Pg. 692-701 (Mar 2012) ISSN: 1939-327X [Electronic] United States
• PMID: 22315324 (Publication Type: Journal Article)

Chemical References

• Glucose Transporter Type 2
• Homeodomain Proteins
• Insulin
• PPAR gamma
• Receptors, Adrenergic, beta-2
• Slc2a2 protein, mouse
• Trans-Activators
• pancreatic and duodenal homeobox 1 protein

Topics

• Age Factors
• Animals
• Glucose Tolerance Test
• Glucose Transporter Type 2 (analysis, physiology)
• Homeodomain Proteins (physiology)
• Insulin (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• PPAR gamma (physiology)
• Phenotype
• Receptors, Adrenergic, beta-2 (physiology)
• Trans-Activators (physiology)