Diabetes Metab J.  2023 Jul;47(4):441-453. 10.4093/dmj.2022.0416.

Regulation of Cellular Senescence in Type 2 Diabetes Mellitus: From Mechanisms to Clinical Applications

• Iwasaki K
• Abarca C
• Aguayo-Mazzucato C

• KMID: 2544724
• DOI: http://doi.org/10.4093/dmj.2022.0416

Abstract

Cellular senescence is accelerated by hyperglycemia through multiple pathways. Therefore, senescence is an important cellular mechanism to consider in the pathophysiology of type 2 diabetes mellitus (T2DM) and an additional therapeutic target. The use of drugs that remove senescent cells has led to improvements in blood glucose levels and diabetic complications in animal studies. Although the removal of senescent cells is a promising approach for the treatment of T2DM, two main challenges limit its clinical application: the molecular basis of cellular senescence in each organ is yet to be understood, and the specific effect of removing senescent cells in each organ has to be determined. This review aims to discuss future applications of targeting senescence as a therapeutic option in T2DM and elucidate the characteristics of cellular senescence and senescence-associated secretory phenotype in the tissues important for regulating glucose levels: pancreas, liver, adipocytes, and skeletal muscle.

Keyword

Aging; Diabetes mellitus; type 2; Insulin-secreting cells; Senotherapeutics

Figure

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  Fig. 1 Role of cellular senescence in type 2 diabetes mellitus. The upper part of the figure depicts factors known to lead to senescence in cells: mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and increased production of reactive oxygen species (ROS). Additional factors include telomere dysfunction or shortening, DNA damage, hyperglycemia, insulin resistance, and inflammatory signals. The lower part of the picture reflects some of the reported negative effects of cellular senescence: secretion of the senescence-associated secretory phenotype (SASP), which can promote the entry to senescence of neighboring cells and their dysfunction. The proliferation of cells is suppressed and they downregulate hallmark identity genes. Due to these characteristics, senescent cells can promote diabetes and metabolic diseases in multiple ways. Created in BioRender.

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  Fig. 2 Senotherapeutics used in diabetes and diabetes related diseases. Schematic representation of cellular senescence agents used and their target pathways. (1) Senescence molecules effectors, such as hyperglycemia and DNA damage, cause healthy cells to senesce; (2) Senescent cells secrete senescence-associated secretory phenotype (SASP) and lose their cell identity. (3) There are two types of senotherapeutics: senolytics, which eliminate senescent cells, and senomorphics, which inhibit SASP. The drugs in the figures have been used in mouse and human models of type 2 diabetes mellitus. Of these, dasatinib, quercetin, and fisetin have been used in clinical studies. Created in BioRender. HIF-1α, hypoxia-inducible factor 1α; PI3K, phosphoinositide 3-kinase; Bcl2, B-cell lymphoma 2; AMPK, AMP-activated protein kinase; mTOR, mammalian TORC1.

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