• Open Access

Increased dosage of Ink4/Arf protects against glucose intolerance and insulin resistance associated with aging

Authors

  • Herminia González-Navarro,

    Corresponding author
    • Institute of Health Research-INCLIVA, Valencia, Spain
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    • These authors contributed equally to this work.
  • Ángela Vinué,

    1. Vascular Biology Unit, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia (IBV), Spanish Council for Scientific Research (CSIC), Valencia, Spain
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    • These authors contributed equally to this work.
  • María Jesús Sanz,

    1. Institute of Health Research-INCLIVA, Valencia, Spain
    2. Departamento de Farmacología, Universidad de Valencia-INCLIVA, Valencia, Spain
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  • Mercedes Delgado,

    1. CAI Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Madrid, Spain
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  • Miguel Angel Pozo,

    1. CAI Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Madrid, Spain
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  • Manuel Serrano,

    1. Spanish National Cancer Research Center (CNIO), Madrid, Spain
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  • Deborah J. Burks,

    1. CIBER de Diabetes y Enfermedades Metabolicas (CIBERDEM), Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
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  • Vicente Andrés

    Corresponding author
    1. Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
    • Institute of Health Research-INCLIVA, Valencia, Spain
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Correspondence

Vicente Andrés, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain. Tel.: +34-914531200; fax: +34-914531265, e-mail: vandres@cnic.es

Herminia González-Navarro, Fundación Investigación Hospital Clínico de Valencia-INCLIVA, Av. Blasco Ibáñez, 17, 46010, Valencia, Spain. Tel.: +34-96 386 28 94, fax: +34-96 398 78 60; e-mail: gonzaleh@uv.es

Summary

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 (= 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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