Increased dosage of Ink4/Arf protects against glucose intolerance and insulin resistance associated with aging |
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Authors: | Herminia González‐Navarro Ángela Vinué María Jesús Sanz Mercedes Delgado Miguel Angel Pozo Manuel Serrano Deborah J Burks Vicente Andrés |
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Institution: | 1. Institute of Health Research‐INCLIVA, , Valencia, 46010 Spain;2. Vascular Biology Unit, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia (IBV), Spanish Council for Scientific Research (CSIC), , Valencia, 46010 Spain;3. Departamento de Farmacología, Universidad de Valencia‐INCLIVA, , Valencia, 46010 Spain;4. CAI Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, , Madrid, 28040 Spain;5. Spanish National Cancer Research Center (CNIO), , Madrid, 28029 Spain;6. CIBER de Diabetes y Enfermedades Metabolicas (CIBERDEM), Centro de Investigación Príncipe Felipe (CIPF), , Valencia, 46012 Spain;7. Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), , Madrid, 28029 Spain |
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Abstract: | Recent genome‐wide association studies have linked type‐2 diabetes mellitus to a genomic region in chromosome 9p21 near the Ink4/Arf locus, 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 Ink4/Arf locus. In the present study, we investigated the role of Ink4/Arf in age‐dependent alterations of insulin and glucose homeostasis using Super‐Ink4/Arf mice which bear an extra copy of the entire Ink4/Arf locus. We find that, in contrast to age‐matched wild‐type controls, Super‐Ink4/Arf mice do not develop glucose intolerance with aging. Insulin tolerance tests demonstrated increased insulin sensitivity in Super‐Ink4/Arf 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 Super‐Ink4/Arf mice showed a tendency toward increased 18F‐fluorodeoxyglucose uptake in skeletal muscle compared with wild‐type mice (P = 0.079). Furthermore, a positive correlation between glucose uptake and baseline glucose levels was observed in Super‐Ink4/Arf mice (P < 0.008) but not in wild‐type mice. Our studies reveal a protective role of the Ink4/Arf locus against the development of age‐dependent insulin resistance and glucose intolerance. |
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Keywords: | 18F‐fluorodeoxyglucose‐PET
ARF
CDKN2A CDKN2B diabetes insulin resistance insulin signaling p15ink4b p16ink4a pancreatic islet |
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