Decreased IGF1R attenuates senescence and improves function in pancreatic ß-cells.

Introduction: The enhanced ß-cell senescence that accompanies insulin resistance and aging contributes to cellular dysfunction and loss of transcriptional identity leading to type 2 diabetes (T2D). While senescence is among the 12 recognized hallmarks of aging, its relation to other hallmarks including altered nutrient sensing (insulin/IGF1 pathway) in ß-cells is not fully understood. We previously reported that an increased expression of IGF1R in mouse and human ß-cells is a marker of older ß-cells; however, its contribution to age-related dysfunction and cellular senescence remains to be determined. Methods: In this study, we explored the direct role of IGF1R in ß-cell function and senescence using two independent mouse models with decreased IGF1/IGF1R signaling: a) Ames Dwarf mice (Dwarf +/+), which lack growth hormone and therefore have reduced circulating levels of IGF1, and b) inducible ß-cell-specific IGF1R knockdown (ßIgf1rKD) mice. Results: Compared to Dwarf+/- mice, Dwarf+/+ mice had lower body and pancreas weight, lower circulating IGF1 and insulin levels, and lower IGF1R and p21Cip1 protein expression in ß-cells, suggesting the suppression of senescence. Adult ßIgf1rKD mice showed improved glucose clearance and glucose-induced insulin secretion, accompanied by decreased p21Cip1 protein expression in ß-cells. RNA-Seq of islets isolated from these ßIgf1rKD mice revealed the restoration of three signaling pathways known to be downregulated by aging: sulfide oxidation, autophagy, and mTOR signaling. Additionally, deletion of IGF1R in mouse ß-cells increased transcription of genes important for maintaining ß-cell identity and function, such as Mafa, Nkx6.1, and Kcnj11, while decreasing senescence-related genes, such as Cdkn2a, Il1b, and Serpine 1. Decreased senescence and improved insulin-secretory function of ß-cells were also evident when the ßIgf1rKD mice were fed a high-fat diet (HFD; 60% kcal from fat, for 5 weeks). Discussion: These results suggest that IGF1R signaling plays a causal role in aging-induced ß-cell dysfunction. Our data also demonstrate a relationship between decreased IGF1R signaling and suppressed cellular senescence in pancreatic ß-cells. Future studies can further our understanding of the interaction between senescence and aging, developing interventions that restore ß-cell function and identity, therefore preventing the progression to T2D.

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

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.

Clearance of p16Ink4a-positive cells in a mouse transgenic model does not change ß-cell mass and has limited effects on their proliferative capacity.

Type 2 diabetes is partly characterized by decreased ß-cell mass and function which have been linked to cellular senescence. Despite a low basal proliferative rate of adult ß-cells, they can respond to growth stimuli, but this proliferative capacity decreases with age and correlates with increased expression of senescence effector, p16Ink4a. We hypothesized that selective deletion of p16Ink4a-positive cells would enhance the proliferative capacity of the remaining ß-cells due to the elimination of the local senescence-associated secretory phenotype (SASP). We aimed to investigate the effects of p16Ink4a-positive cell removal on the mass and proliferative capacity of remaining ß-cells using INK-ATTAC mice as a transgenic model of senolysis. Clearance of p16Ink4a positive subpopulation was tested in mice of different ages, males and females, and with two different insulin resistance models: high-fat diet (HFD) and insulin receptor antagonist (S961). Clearance of p16Ink4a-positive cells did not affect the overall ß-cell mass. ß-cell proliferative capacity negatively correlated with cellular senescence load and clearance of p16Ink4a positive cells in 1-year-old HFD mice improved ß-cell function and increased proliferative capacity in a subset of animals. Single-cell sequencing revealed that the targeted p16Ink4a subpopulation of ß-cells is non-proliferative and non-SASP producing whereas additional senescent subpopulations remained contributing to continued local SASP secretion. In conclusion, deletion of p16Ink4a cells did not negatively impact beta-cell mass and blood glucose under basal and HFD conditions and proliferation was restored in a subset of HFD mice opening further therapeutic targets in the treatment of diabetes.

Unique Human and Mouse ß-Cell Senescence-Associated Secretory Phenotype (SASP) Reveal Conserved Signaling Pathways and Heterogeneous Factors.

The aging of pancreatic ß-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging ß-cells acquire markers of cellular senescence and develop a senescence-associated secretory phenotype (SASP) that can lead to senescence and dysfunction of neighboring cells through paracrine actions, contributing to ß-cell failure. In this study, we defined the ß-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from mouse and human senescent ß-cells and a chemically induced mouse model of DNA damage capable of inducing SASP. These experiments revealed that the ß-cell SASP is enriched for factors associated with inflammation, cellular stress response, and extracellular matrix remodeling across species. Multiple SASP factors were transcriptionally upregulated in models of ß-cell senescence, aging, insulin resistance, and T2D. Single-cell transcriptomic analysis of islets from an in vivo mouse model of reversible insulin resistance indicated unique and partly reversible changes in ß-cell subpopulations associated with senescence. Collectively, these results demonstrate the unique secretory profile of senescent ß-cells and its potential implication in health and disease.