Age-Related Impairment in Insulin Release

Abstract

In this study, we investigated the significance of β2-adrenergic receptor (β2AR) in age-related impaired insulin secretion and glucose homeostasis. We characterized the metabolic phenotype of β2AR-null C57Bl/6N mice (β2AR−/−) 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 β2AR deficiency affects glucose metabolism. Adult β2AR−/− 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 β2AR rescued these defects. Consistent effects were evoked in vitro both upon β2AR knockdown and pharmacologic treatment. Interestingly, with aging, wild-type (β2AR+/+) littermates developed impaired insulin secretion and glucose tolerance. Moreover, islets from 20-month-old β2AR+/+ mice exhibited reduced density of β2AR compared with those from younger animals, paralleled by decreased levels of PPARγ, PDX-1, and GLUT2. Overexpression of β2AR 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 β2AR expression contributes to the age-related decline of glucose tolerance in mice.

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

“…β 2 ARs promote aging and reduced lifespan mostly due to adverse effects on cardiac and pulmonary functions and its age-related impairment to regulate insulin secretion (Gao et al 2003;Santulli et al 2012;Santulli and Iaccarino 2013). However, it could also be due to polymorphisms in the receptor.…”

Non-steroidal anti-inflammatory drugs attenuate the vascular responses in aging metabolic syndrome rats

“…This result is consistent with experimental data from different species showing that aging per se is associated with a continuous decrease in basal insulin release. The magnitude of this effect is enough to develop abnormalities in glucose metabolism [36][37][38] . Body weight increased in the Control and MS rats; nevertheless, the difference between the groups was not significant even though the diet of the sucrose-fed rats was hypercaloric ( Table 1).…”

“…Glucose was increased in the MS and Control rats at 18 months and is therefore a consequence of aging. Impaired glucose metabolism with age represents a major determinant of the epidemic of type 2 diabetes within the elderly population [36] . Insulin was increased at 6 months, and IR was present (indicated by HOMA-IR) in the MS rats.…”

Adrenal Signaling in Heart Failure

“…Supporting a potential role for β-arrestin-1 in the regulation of these activities, β 2 AR has been shown recently to partake in all the above-mentioned processes. 6,8,9 Equally important, growing evidence indicates that loss or dysfunction of β-arrestin-2 results in profound disturbance of insulin …”