期刊
AGING CELL
卷 12, 期 1, 页码 102-111出版社
WILEY-BLACKWELL
DOI: 10.1111/acel.12023
关键词
18F-fluorodeoxyglucose-PET; ARF; CDKN2A; CDKN2B; diabetes; insulin resistance; insulin signaling; p15ink4b; p16ink4a; pancreatic islet
资金
- Spanish Ministry of Economy and Competiveness (MINECO)
- European Regional Development Fund [SAF2007-62110, SAF2010-16044, SAF2008-0011, SAF2011-23777]
- Instituto de Salud Carlos III [FIS: PI-CP10/00555, RECAVA: RD06/0014/0021, EMER07-12]
- MINECO
- Pro-CNIC Foundation
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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