GSE121539
Acceleration of beta cell aging plays a key role in diabetes and senolysis improves metabolic, functional and cellular outcomes
The risk of type 2 diabetes increases with age. 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. The proportion of aged beta cells increases with animal age but even in young mice, senescent beta cells can be found. We showed that different models of insulin resistance accelerated aging and senescence marker expression in beta cells, BGal, led to loss of function and impaired glucose tolerance. Clearance of p16Ink4a+ cells, using the INK-ATTAC mouse model, ameliorated glucose metabolism, insulin secretion and decreased expression of aging, senescence and SASP genes in pancreatic islets. Senolytic drug ABT263 also improved glucose metabolism and beta cell identity when administered during insulin resistance. Human beta cells from diabetic and non-diabetic donors shared some of the same biology laying the foundation for translation into humans. These novel findings lay the framework to pursue senolysis of beta cells as a preventive and alleviating strategy for T2D. Overall design: Cells from dispersed islets of 7 month old male C57BL/6J mice were FACS sorted based on acidic beta-galactosidase activity and RNA was extracted using PicoPure Arcturus kit. Gene expression profiling was performed using HiSeq v4 SE50 250 mil reads by Hudson Alpha Institute for Biotechnology (Huntsville, AL).  Reads were aligned to the mouse genome (GRCm38) using Subread and counted with featureCounts.