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.
Original language | English (US) |
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Pages (from-to) | 129-142.e4 |
Journal | Cell Metabolism |
Volume | 30 |
Issue number | 1 |
DOIs | |
State | Published - Jul 2 2019 |
Keywords
- SASP
- beta cells
- glucose metabolism
- insulin resistance
- insulin secretion
- insulin secretion
- senescence
- senescence signature
- senescence-associated secretory profile
- senolytic therapies
- type 2 diabetes
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology