title: Increased dosage of Ink4/Arf protects against glucose intolerance and insulin resistance associated with aging.
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 (18)F-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.
authors.affiliation: Institute of Health Research-INCLIVA, Valencia, 46010, Spain. gonzaleh@uv.es
authors.forename: Herminia
authors.initials: H
authors.lastname: González-Navarro
authors.forename: Ángela
authors.initials: Á
authors.lastname: Vinué
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Sanz
authors.forename: Mercedes
authors.initials: M
authors.lastname: Delgado
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Pozo
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Burks
authors.forename: Vicente
authors.initials: V
authors.lastname: Andrés
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics* / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D055106:Genome-Wide Association Study; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D007328:Insulin; D020727:ADP-Ribosylation Factors; D005947:Glucose