Acceleration of ? 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 ? cells resemble those preceding the development of diabetes, the contribution of ? cell aging and senescence remains unclear. We generated a ? cell senescence signature and found that insulin resistance accelerates ? 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 ? 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 ? cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of ? cells as a preventive and alleviating strategy for T2D.

SUBMITTER: Aguayo-Mazzucato C 

PROVIDER: S-EPMC6610720 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature