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Nat Med. 2016 Apr;22(4):412-20. doi: 10.1038/nm.4054. Epub 2016 Mar 7.

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

Author information

1
Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
2
Computation Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
3
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
4
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
5
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
6
Veteran Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
7
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
8
Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.
9
Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

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)-γ 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.

PMID:
26950362
PMCID:
PMC5546206
DOI:
10.1038/nm.4054
[Indexed for MEDLINE]
Free PMC Article

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