Decreased IGF1R attenuates senescence and improves function in pancreatic beta-cells

Introduction: The enhanced b-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 beta-cells is not fully understood. We previously reported that an increased expression of IGF1R in mouse and human beta-cells is a marker of older beta-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 beta-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 beta-cell-specific IGF1R knockdown (bIgf1rKD) 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 beta-cells, suggesting the suppression of senescence. Adult bIgf1rKD mice showed improved glucose clearance and glucose-induced insulin secretion, accompanied by decreased p21Cip1 protein expression in bcells. RNA-Seq of islets isolated from these bIgf1rKD 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 b-cells increased transcription of genes important for maintaining bcell 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 b-cells were also evident when the bIgf1rKD 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 beta-cell dysfunction. Our data also demonstrate a relationship between decreased IGF1R signaling and suppressed cellular senescence in pancreatic beta-cells. Future studies can further our understanding of the interaction between senescence and aging, developing interventions that restore beta-cell function and identity, therefore preventing the progression to T2D.

Automated summary

The IGF1R signaling pathway plays a crucial role in age-induced dysfunction and senescence of beta-cells. Understanding the interaction between senescence and aging can provide insights into the development of interventions to restore beta-cell function and prevent progression to type 2 diabetes (T2D).