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Cell Metab ; 30(1): 129-142.e4, 2019 07 02.
Article in English | MEDLINE | ID: mdl-31155496

ABSTRACT

Type 2 diabetes (T2D) is an age-related disease. Although changes in function and proliferation of aged ß cells resemble those preceding the development of diabetes, the contribution of ß cell aging and senescence remains unclear. We generated a ß cell senescence signature and found that insulin resistance accelerates ß 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 ß 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 ß cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of ß cells as a preventive and alleviating strategy for T2D.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Insulin-Secreting Cells/metabolism , Aniline Compounds/therapeutic use , Animals , Body Weight/physiology , Cells, Cultured , Cellular Senescence/physiology , Flow Cytometry , Humans , In Vitro Techniques , Insulin Resistance/physiology , Insulin-Secreting Cells/drug effects , Mice , Mice, Inbred C57BL , Sulfonamides/therapeutic use
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