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p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion.
- Source :
-
Nature medicine [Nat Med] 2016 Apr; Vol. 22 (4), pp. 412-20. Date of Electronic Publication: 2016 Mar 07. - Publication Year :
- 2016
-
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.
- Subjects :
- Aging pathology
Animals
Cell Proliferation genetics
Cyclin-Dependent Kinase Inhibitor p16 genetics
Fibroblasts metabolism
Gene Expression Regulation
Glucose metabolism
Humans
Insulin genetics
Insulin Secretion
Insulin-Secreting Cells pathology
Mice
Mice, Transgenic
PPAR gamma genetics
TOR Serine-Threonine Kinases genetics
Aging genetics
Cellular Senescence genetics
Cyclin-Dependent Kinase Inhibitor p16 biosynthesis
Insulin metabolism
Insulin-Secreting Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 22
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 26950362
- Full Text :
- https://doi.org/10.1038/nm.4054