Cellular Senescence in Type 2 Diabetes
It has been a few years since researchers suggested a role for senescent cells in mediating the damage done by excess fat tissue in the context of type 2 diabetes. Senescent cells accumulate with age, but accumulate significantly faster in people who are meaningfully overweight or obese. The inflammatory signaling produced by lingering senescent cells is disruptive of tissue structure and function throughout the body, and that includes problems in the insulin-generating regions of the pancreas that take place in diabetes patients. Interestingly, senescent cells may also be important in type 1 diabetes, a completely different path to pathology, but perhaps all roads involve cellular senescence in this condition.
Over the past decade, clinical trials have reported the efficacy of drugs that target cellular senescence and their potential use in the treatment of age-related chronic diseases, such as type 2 diabetes mellitus (T2DM). When normal cells are subjected to severe DNA damage, they either die by apoptosis or undergo irreversible cell proliferation arrest by induction of cellular senescence. These biological defense mechanisms prevent the proliferation of abnormal cells that have suffered DNA damage. Cellular senescence is the state in which cells irreversibly stop proliferating while retaining their metabolic activity and can be induced by external stressors such as aging, obesity, and radiation due to DNA damage, telomere shortening, and mitochondrial dysfunction.
A unique characteristic of senescent cells is the secretion of senescence-associated secretory phenotype (SASP), which induces chronic inflammation through the secretion of inflammatory proteins. The SASP has been involved in the pathogenesis of several age-related diseases, including cancer. Chronic insulin exposure, which occurs in T2DM, has been shown to cause senescence in hepatocytes, pancreatic β-cells, and adipose tissue. Hyperglycemia, pathognomonic of T2DM, can also contribute to senescence through several pathways, and animal studies have shown that removal of senescent cells improves blood glucose levels and decreases diabetic complications.
However, at least two barriers need to be overcome before these therapies can be translated to the clinic: (1) differences between senescent cells in different tissues are unknown, and (2) the specific effects of removing senescent cells in each organ remain to be determined. Therefore, this review focuses on the mechanisms of cellular senescence and its SASP in four key organs for the regulation of blood glucose levels: pancreas, liver, skeletal muscle, and adipocytes, and summarizes ongoing efforts to therapeutically target cellular senescence in them.