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Keywords:

p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion

Citation:

Helman A, Klochendler A, Azazmeh N, Gabai Y, Horwitz E, Anzi S, Swisa A, Condiotti R, Granit RZ, Nevo Y, Fixler Y, Shreibman D, Zamir A, Tornovsky-Babeay S, Dai C, Glaser B, Powers AC, Shapiro AM, Magnuson MA, Dor Y, Ben-Porath I. p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion. Nat Med 2016;22:412-20.

Date Published:

Apr

Abstract:

Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-gamma proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.

Notes:

Helman, AharonKlochendler, AgnesAzazmeh, NarmenGabai, YaelHorwitz, EladAnzi, ShiraSwisa, AvitalCondiotti, RebaGranit, Roy ZNevo, YuvalFixler, YaakovShreibman, DorinZamir, AmitTornovsky-Babeay, SharonaDai, ChunhuaGlaser, BenjaminPowers, Alvin CShapiro, A M JamesMagnuson, Mark ADor, YuvalBen-Porath, IttaiengP60 DK020593/DK/NIDDK NIH HHS/UC4 DK104211/DK/NIDDK NIH HHS/DK104211/DK/NIDDK NIH HHS/U01 DK072473/DK/NIDDK NIH HHS/DK089572/DK/NIDDK NIH HHS/U01 DK089572/DK/NIDDK NIH HHS/P30 DK020593/DK/NIDDK NIH HHS/DK72473/DK/NIDDK NIH HHS/R24 DK106755/DK/NIDDK NIH HHS/DK20593/DK/NIDDK NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, Non-P.H.S.Nat Med. 2016 Apr;22(4):412-20. doi: 10.1038/nm.4054. Epub 2016 Mar 7.

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Last updated on 09/22/2022