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

Aging Cell

Herminia González-Navarro¹  Ángela Vinué³  María Jesús Sanz¹  Mercedes Delgado⁴  Miguel Angel Pozo⁴  Manuel Serrano⁵  Deborah J. Burks² 

[1] Institute of Health Research-INCLIVA, Valencia, Spain;CIBER de Diabetes y Enfermedades Metabolicas (CIBERDEM), Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain;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;CAI Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Madrid, Spain;Spanish National Cancer Research Center (CNIO), Madrid, Spain

关键词: 18F‐fluorodeoxyglucose‐PET;    ARF;    CDKN2A;    CDKN2B;    diabetes;    insulin resistance;    insulin signaling;    p15ink4b;    p16ink4a;    pancreatic islet;   

DOI  :  10.1111/acel.12023

来源: Wiley

【 摘 要 】

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 (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.

【 授权许可】

Unknown   
© 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland