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p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion

Nature Medicine volume 22, pages 412–420 (2016)Cite this article

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Abstract

Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16Ink4a 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 p16Ink4a 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 p16Ink4a 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 p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a 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 p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.

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Figure 1: p16 induces senescence of beta cells.
Figure 2: p16 expression enhances insulin secretion.
Figure 3: p16 expression increases glucose uptake and mitochondrial activity.
Figure 4: Increased insulin secretion in mature mice is driven by p16.
Figure 5: Senescent beta cells in human islets.
Figure 6: p16-induced senescence of human cells leads to enhanced GSIS.

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Acknowledgements

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 Diseases–NIH (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.

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Authors and Affiliations

  1. Department of Developmental Biology and Cancer Research, Institute for Medical Research–Israel-Canada, Hebrew University–Hadassah Medical School, Jerusalem, Israel

    Aharon Helman, Agnes Klochendler, Narmen Azazmeh, Yael Gabai, Elad Horwitz, Shira Anzi, Avital Swisa, Reba Condiotti, Roy Z Granit, Yaakov Fixler, Dorin Shreibman, Amit Zamir, Yuval Dor & Ittai Ben-Porath

  2. Computation Center, Hebrew University–Hadassah Medical School, Jerusalem, Israel

    Yuval Nevo

  3. Department of Internal Medicine, Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Sharona Tornovsky-Babeay & Benjamin Glaser

  4. Division of Diabetes, Department of Medicine, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Chunhua Dai & Alvin C Powers

  5. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Alvin C Powers & Mark A Magnuson

  6. Veteran Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA

    Alvin C Powers

  7. Department of Surgery, University of Alberta, Edmonton, Alberta, Canada

    A M James Shapiro

  8. Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada

    A M James Shapiro

  9. Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Mark A Magnuson

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  1. Aharon Helman
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Contributions

A.H., I.B.-P. and Y.D. designed experiments, analyzed data and wrote the manuscript; A.H. performed experiments; A.K., N.A., Y.G., E.H., S.A., A.S., R.C., Y.F., D.S., A.Z., S.T.-B., B.G., C.D. and A.C.P. did experiments and contributed experimental data; R.Z.G. and Y.N. performed bioinformatic analyses; A.M.J.S. contributed human islet samples; and M.A.M. assisted in generation of the tet-p16 mice.

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Correspondence to Yuval Dor or Ittai Ben-Porath.

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A.H., A.K., Y.D. and I.B.-P. are inventors of intellectual property related to this work.

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Supplementary Figures 1–8 and Supplementary Tables 2–3 (PDF 3286 kb)

Supplementary Table 1

Gene expression changes in p16-expressing beta cells (XLSX 45 kb)

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Helman, A., Klochendler, A., Azazmeh, N. et al. p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion. Nat Med 22, 412–420 (2016). https://doi.org/10.1038/nm.4054

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