Role of Cellular Senescence in Type II Diabetes

Abstract

Cellular senescence is a cell fate that occurs in response to numerous types of stress and can promote tissue repair or drive inflammation and disruption of tissue homeostasis depending on the context. Aging and obesity lead to an increase in the senescent cell burden in multiple organs. Senescent cells release a myriad of senescence-associated secretory phenotype factors that directly mediate pancreatic β-cell dysfunction, adipose tissue dysfunction, and insulin resistance in peripheral tissues, which promote the onset of type II diabetes mellitus. In addition, hyperglycemia and metabolic changes seen in diabetes promote cellular senescence. Diabetes-induced cellular senescence contributes to various diabetic complications. Thus, type II diabetes is both a cause and consequence of cellular senescence. This review summarizes recent studies on the link between aging, obesity, and diabetes, focusing on the role of cellular senescence in disease processes.

Keywords: Diabetes; aging; cellular senescence; inflammation; obesity; senotherapeutics.

Figure 1.

Characteristics of senescent cells. SnCs have upregulation of the cell cycle inhibitors p16^INK4a and p21^CIP1. In addition, SnCs show telomere shortening or damage (TAF), and epigenetic changes (SAHF). SnCs have decreased levels of nuclear Lamin B1 and increased lysosomal SA-β-gal activity. Many SnCs have a SASP comprised of chemokines, inflammatory factors and interleukins, growth factors and regulators, extracellular matrix components, soluble receptors, proteases and regulators, reactive metabolites, bioactive lipids, microRNAs, and extracellular vesicles. Early in senescence, SnCs secrete HMBG1, a key DAMP (an endogenous molecule that activates the innate immune system), which amplifies the SASP. There is no senescent-specific marker and not all SnCs express the same markers, especially in terms of the SASP. ROS, reactive oxygen species; SA-β-gal, senescence-associated β-galactosidase; SAHF, senescence-associated heterochromatin foci; SASP, senescence-associated secretory phenotype; TAF, telomere-associated foci. Figure created with BioRender.com.

Figure 2.

Diabetes and cellular senescence. Aging and obesity induce inflammation and cellular senescence in pancreatic β-cells and adipocytes. Senescence of β-cells results in β-cell dysfunction and decreased insulin exocytosis. Senescence of adipocytes leads to ectopic lipid accumulation and insulin resistance. Together these contribute to progression of T2D. Hyperglycemia-induced endothelial senescence plays a major role in development of various diabetic complications such as diabetic retinopathy, diabetic nephropathy, and cardiovascular complications. Figure created with BioRender.com.