| First Author | Iwasaki K | Year | 2023 |
| Journal | Front Endocrinol (Lausanne) | Volume | 14 |
| Pages | 1203534 | PubMed ID | 37441495 |
| Mgi Jnum | J:346964 | Mgi Id | MGI:7507804 |
| Doi | 10.3389/fendo.2023.1203534 | Citation | Iwasaki K, et al. (2023) Decreased IGF1R attenuates senescence and improves function in pancreatic beta-cells. Front Endocrinol (Lausanne) 14:1203534 |
| abstractText | INTRODUCTION: The enhanced beta-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 (betaIgf1rKD) 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 betaIgf1rKD mice showed improved glucose clearance and glucose-induced insulin secretion, accompanied by decreased p21Cip1 protein expression in beta-cells. RNA-Seq of islets isolated from these betaIgf1rKD 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 beta-cells increased transcription of genes important for maintaining beta-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 beta-cells were also evident when the betaIgf1rKD 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. |
