ABSTRACT
The aging of pancreatic ß-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging ß-cells acquire markers of cellular senescence and develop a senescence-associated secretory phenotype (SASP) that can lead to senescence and dysfunction of neighboring cells through paracrine actions, contributing to ß-cell failure. In this study, we defined the ß-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from mouse and human senescent ß-cells and a chemically induced mouse model of DNA damage capable of inducing SASP. These experiments revealed that the ß-cell SASP is enriched for factors associated with inflammation, cellular stress response, and extracellular matrix remodeling across species. Multiple SASP factors were transcriptionally upregulated in models of ß-cell senescence, aging, insulin resistance, and T2D. Single-cell transcriptomic analysis of islets from an in vivo mouse model of reversible insulin resistance indicated unique and partly reversible changes in ß-cell subpopulations associated with senescence. Collectively, these results demonstrate the unique secretory profile of senescent ß-cells and its potential implication in health and disease.
Subject(s)
Cellular Senescence/physiology , Diabetes Mellitus, Type 2/metabolism , Insulin-Secreting Cells/metabolism , Signal Transduction/physiology , Animals , Biomarkers/metabolism , Cellular Senescence/genetics , DNA Damage/genetics , DNA Damage/physiology , Diabetes Mellitus, Type 2/genetics , Humans , Insulin-Secreting Cells/cytology , Mice , Signal Transduction/geneticsABSTRACT
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.