Increased dosage of Ink4/Arf protects against glucose intolerance and insulin resistance associated with aging. Issue 1 (5th December 2012)

• Record Type: Journal Article
• Authors: González‐Navarro, Herminia; Vinué, Ángela; Sanz, María Jesús; Delgado, Mercedes; Pozo, Miguel Angel; Serrano, Manuel; Burks, Deborah J.; Andrés, Vicente
• Is Part Of: Aging cell. Volume 12:Issue 1(2013:Feb.)
• Page Start: 102
• Page End: 111
• Publication Date: 2012-12-05
• Subjects: Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.12023
• Languages: English
• ISSNs: 1474-9718

Abstract

<abstract abstract-type="main" xml:lang="en" id="acel12023-abs-0001"> <title>Summary</title> <p>Recent genome‐wide association studies have linked type‐2 diabetes mellitus to a genomic region in chromosome 9p21 near the <italic>Ink4/Arf</italic> locus<italic>, </italic> which encodes tumor suppressors that are up‐regulated in a variety of mammalian organs during aging. However, it is unclear whether the susceptibility to type‐2 diabetes is associated with altered expression of the <italic>Ink4/Arf</italic> locus. In the present study, we investigated the role of <italic>Ink4/Arf</italic> in age‐dependent alterations of insulin and glucose homeostasis using <italic>Super‐Ink4/Arf</italic> mice which bear an extra copy of the entire <italic>Ink4/Arf</italic> locus. We find that, in contrast to age‐matched wild‐type controls, <italic>Super‐Ink4/Arf</italic> mice do not develop glucose intolerance with aging. Insulin tolerance tests demonstrated increased insulin sensitivity in <italic>Super‐Ink4/Arf</italic> compared with wild‐type mice, which was accompanied by higher activation of the insulin receptor substrate (IRS)‐PI3K‐AKT pathway in liver, skeletal muscle and heart. Glucose uptake studies in <italic>Super‐Ink4/Arf</italic> mice showed a tendency toward increased <sup>18</sup>F‐fluorodeoxyglucose uptake in skeletal muscle compared with wild‐type mice (<italic>P </italic>=<italic> </italic>0.079). Furthermore, a positive correlation between glucose uptake and baseline glucose levels was observed in <italic>Super‐Ink4/Arf</italic> mice (<italic>P</italic> < 0.008) but not in wild‐type mice. Our studies reveal a protective role of the <italic>Ink4/Arf</italic> locus against the development of age‐dependent insulin resistance and glucose intolerance.</p> </abstract>