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)- 3 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.
| Original language | English |
|---|---|
| Pages (from-to) | 412-420 |
| Number of pages | 9 |
| Journal | Nature Medicine |
| Volume | 22 |
| Issue number | 4 |
| DOIs | |
| State | Published - 1 Apr 2016 |
Bibliographical note
Funding Information:Acknowledgments We thank M. Barbacid for CDK4lsl-R24C mice, L. Philipson for MIP-CreER mice, R. Scharfmann for the EndoC-βH2 cells; S. Efrat for the pTRIPΔU3-CMV-nlsCre vector and C. Wright for the Pdx1-specific antibody. We thank N.E. Kidess-Bassir for histological preparation and T. Szoke for experimental assistance. This research was supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation (A.H.) and by grants from Israel Science Foundation (grant no. 1009/13; I.B.-P.), the Jacob and Lena Joels Memorial Foundation Senior Lectureship for Excellence in the Life and Medical Sciences (I.B.-P.), Diabetes Onderzoek Nederland (Y.D. and I.B.-P.), the Alex U. Soyka program (Y.D. and I.B.-P.), the Juvenile Diabetes Research Foundation (Y.D. and A.C.P.), the US National Institutes of Health (NIH) Beta Cell Biology Consortium (Y.D.), the Leona M. and Harry B. Helmsley Charitable Trust (Y.D.), the Israeli Centers Of Research Excellence Program of the Planning and Budgeting Committee and the Israel Science Foundation (grant no. 41.11; Y.D.), the United States Agency for International Development's American Schools and Hospitals Abroad Program (Y.D. and I.B.-P.), the Network for Pancreatic Organ Donors with Diabetes (nPOD) (Y.D.), the US Department of Veterans Affairs (A.C.P.), the National Institute of Diabetes and Digestive and Kidney DiseasesNIH (grant no. DK089572 (A.C.P.), DK72473 (A.C.P.) and DK104211 (A.C.P.)), and the Vanderbilt Diabetes Research and Training Center (grant no. DK20593; A.C.P.). Organ procurement organizations partnering with nPOD are listed at http://www.jdrfnpod.org/our-partners.php.
