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Decreased IGF1R Attenuates Senescence and Improves Function in Pancreatic beta-Cells

ABSTRACT: We previously reported that 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. In this study, we explored the direct role of IGF1R in beta-cell function and senescence using inducible beta-cell specific IGF1R knockdown (betaIgf1rKD) mice. Adult betaIgf1rKD mice showed improved glucose clearance and glucose-induced insulin secretion, accompanied by decreased p21Cip1 protein expression in beta-cells. RNASeq of islets isolated from these betaIgf1rKD mice revealed restoration of 3 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. These results suggest that IGF1R signaling plays a causal role in aging-induced beta-cell dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE229709 | GEO | 2023/06/19

REPOSITORIES: GEO

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