Journal
CELL METABOLISM
Volume 30, Issue 1, Pages 129-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2019.05.006
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Funding
- NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH [2UC4DK098085]
- JDRF
- NIH [R01 DK093909, R01 DK110390]
- Joslin Diabetes Research Center [P30 DK036836]
- (BADRC PF) [P30 DK057521]
- Diabetes Research and Wellness Foundation, United States
- Harvard College Research Program, Office of Undergraduate Research
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Type 2 diabetes (T2D) is an age-related disease. Although changes in function and proliferation of aged beta cells resemble those preceding the development of diabetes, the contribution of beta cell aging and senescence remains unclear. We generated a beta cell senescence signature and found that insulin resistance accelerates beta 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 beta 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 beta cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of beta cells as a preventive and alleviating strategy for T2D.
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