Beta Cell Senescence in Multiple Forms of Diabetes
The growing focus on cellular senescence as a contributing cause of aging has identified senescent cells as important agents in a range of conditions, age-related and otherwise. Interestingly, the pathology of both type 1 and type 2 diabetes appears to be mediated by senescent beta cells in the pancreas. Clearing senescent cells has been shown to be beneficial in animal models of these conditions, but it remains to be seen as to whether human patients will benefit. There are many conditions that might be treated with senolytic therapies to selectively destroy senescent cells, and only so many research groups and companies working in the space. Only a small number of age-related conditions are presently targeted by trials and programs of development, and forms of diabetes are not even close to the top of the much longer list awaiting attention.
Cellular senescence is a response to a wide variety of stressors, including DNA damage, oncogene activation and physiologic aging, and pathologically accelerated senescence contributes to human disease, including diabetes mellitus. Indeed, recent work in this field has demonstrated a role for pancreatic β-cell senescence in the pathogenesis of Type 1 Diabetes, Type 2 Diabetes and monogenic diabetes.
Small molecule or genetic targeting of senescent β-cells has shown promise as a novel therapeutic approach for preventing and treating diabetes. Despite these advances, major questions remain around the molecular mechanisms driving senescence in the β-cell, identification of molecular markers that distinguish senescent from non-senescent β-cell subpopulations, and translation of proof-of-concept therapies into novel treatments for diabetes in humans.
Here, we summarize the current state of the field of β-cell senescence, highlighting insights from mouse models as well as studies on human islets and β-cells. We identify markers that have been used to detect β-cell senescence to unify future research efforts in this field. We discuss emerging concepts of the natural history of senescence in β-cells, heterogeneity of senescent β-cells subpopulations, role of sex differences in senescent responses, and the consequences of senescence on integrated islet function and microenvironment. As a young and developing field, there remain many open research questions which need to be addressed to move senescence-targeted approaches towards clinical investigation.