期刊
NATURE MEDICINE
卷 22, 期 4, 页码 412-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4054
关键词
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资金
- Juvenile Diabetes Research Foundation
- Israel Science Foundation [1009/13, 41.11]
- Jacob and Lena Joels Memorial Foundation Senior Lectureship for Excellence in the Life and Medical Sciences
- Diabetes Onderzoek Nederland
- Alex U. Soyka program
- US National Institutes of Health (NIH) Beta Cell Biology Consortium
- Leona M. and Harry B. Helmsley Charitable Trust
- Israeli Centers Of Research Excellence Program of the Planning and Budgeting Committee
- United States Agency for International Development's American Schools and Hospitals Abroad Program
- Network for Pancreatic Organ Donors with Diabetes (nPOD)
- US Department of Veterans Affairs
- National Institute of Diabetes and Digestive and Kidney Diseases-NIH [DK089572, DK72473, DK104211]
- Vanderbilt Diabetes Research and Training Center [DK20593]
- Alberta Innovates [201201154] Funding Source: researchfish
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.
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