@article{78dc2d1854d948e2bdac58722fb1f5de,
title = "Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes",
abstract = "Type 2 diabetes (T2D) is an age-related disease. Although changes in function and proliferation of aged β cells resemble those preceding the development of diabetes, the contribution of β cell aging and senescence remains unclear. We generated a β cell senescence signature and found that insulin resistance accelerates β cell senescence leading to loss of function and cellular identity and worsening metabolic profile. Senolysis (removal of senescent cells), using either a transgenic INK-ATTAC model or oral ABT263, improved glucose metabolism and β cell function while decreasing expression of markers of aging, senescence, and senescence-associated secretory profile (SASP). Beneficial effects of senolysis were observed in an aging model as well as with insulin resistance induced both pharmacologically (S961) and physiologically (high-fat diet). Human senescent β cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of β cells as a preventive and alleviating strategy for T2D.",
keywords = "SASP, beta cells, glucose metabolism, insulin resistance, insulin secretion, insulin secretion, senescence, senescence signature, senescence-associated secretory profile, senolytic therapies, type 2 diabetes",
author = "Cristina Aguayo-Mazzucato and Joshua Andle and Lee, {Terrence B.} and Ayush Midha and Lindsay Talemal and Vaja Chipashvili and Jennifer Hollister-Lock and {van Deursen}, Jan and Gordon Weir and Susan Bonner-Weir",
note = "Funding Information: We thank Dr. C.R. Kahn for helpful and insightful discussion. Human islets were provided by the NIDDK -funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant no. 2UC4DK098085 . Human pancreatic sections were provided by the Joslin Clinical Islet Isolation Core and the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative research project sponsored by JDRF . Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at https://www.jdrfnpod.org/for-partners/npod-partners . We are grateful to Brooke Sullivan and Aref Ebrahimi for technical and bioinformatic support. This study was supported by grants from the NIH ( R01 DK093909 and R01 DK110390 , S.B.W.), P30 DK036836 Joslin Diabetes Research Center (DRC Cores: Advanced Microscopy [Chris Cahill], Bioinformatics [Jonathan Dreyfuss and Hui Pan], Flow Cytometry [Angela Wood and Alison Marotta], and Animal Facilities [John Stockton] and P&F to C.A.M.), P30 DK057521 (BADRC P&F to C.A.M.), the Diabetes Research and Wellness Foundation , United States, and an important group of private donors. A.M. was supported through the Harvard College Research Program , Office of Undergraduate Research. Funding Information: We thank Dr. C.R. Kahn for helpful and insightful discussion. Human islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant no. 2UC4DK098085. Human pancreatic sections were provided by the Joslin Clinical Islet Isolation Core and the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative research project sponsored by JDRF. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at https://www.jdrfnpod.org/for-partners/npod-partners. We are grateful to Brooke Sullivan and Aref Ebrahimi for technical and bioinformatic support. This study was supported by grants from the NIH (R01 DK093909 and R01 DK110390, S.B.W.), P30 DK036836 Joslin Diabetes Research Center (DRC Cores: Advanced Microscopy [Chris Cahill], Bioinformatics [Jonathan Dreyfuss and Hui Pan], Flow Cytometry [Angela Wood and Alison Marotta], and Animal Facilities [John Stockton] and P&F to C.A.M.), P30 DK057521 (BADRC P&F to C.A.M.), the Diabetes Research and Wellness Foundation, United States, and an important group of private donors. A.M. was supported through the Harvard College Research Program, Office of Undergraduate Research. C.A.M. and S.B.W. conceived the project and wrote the manuscript; C.A.M. J.A. T.J.L. A.M. L.T. V.C. and J.H.L. researched data; and G.C.W. provided critical discussions and edited the manuscript. J.V.D. provided critical discussion, animal model, and important reagents. All authors reviewed the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = jul,
day = "2",
doi = "10.1016/j.cmet.2019.05.006",
language = "English (US)",
volume = "30",
pages = "129--142.e4",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}