Pancreatic β-cell senescence in diabetes: mechanisms, markers and therapies

Abstract

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.

Keywords: cellular senescence; monogenic diabetes; pancreatic beta cells; type 1 diabetes; type 2 diabetes.

Figure 1

Common molecular features of senescent β-cells characterized in mouse models of diabetes. In response to metabolic stress, aging, direct DNA damage or the MafA ^S64F/+ gene variant, β-cells can develop senescence defined by several common features. These include (1) increased DNA damage and upregulation of Cdk inhibitors p21^Cip1 and/or p16^Ink4a; (2) increased activity of lysosomal enzyme GLB1, also referred to as senescence-associated βgalactosidase (SA-βgal); (3) increased expression of anti-apoptotic BCL-2 family proteins which mediate a prosurvival state; and (4) development of a Senescence-Associated Secretory Phenotype (SASP).