Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice

Qinglei Yin, Qicheng Ni, Yichen Wang, Hongli Zhang, Wenyi Li, Aifang Nie, Shu Wang, Yanyun Gu, Qidi Wang () and Guang Ning ()
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Qinglei Yin: Shanghai Jiao Tong University School of Medicine
Qicheng Ni: Shanghai Jiao Tong University School of Medicine
Yichen Wang: Shanghai Jiao Tong University School of Medicine
Hongli Zhang: Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine
Wenyi Li: Shanghai Jiao Tong University School of Medicine
Aifang Nie: Shanghai Jiao Tong University School of Medicine
Shu Wang: Shanghai Jiao Tong University School of Medicine
Yanyun Gu: Shanghai Jiao Tong University School of Medicine
Qidi Wang: Shanghai Jiao Tong University School of Medicine
Guang Ning: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Compromised β-cell identity is emerging as an important contributor to β-cell failure in diabetes; however, the precise mechanism independent of hyperglycemia is under investigation. We have previously reported that mTORC1/Raptor regulates functional maturation in β-cells. In the present study, we find that diabetic β-cell specific Raptor-deficient mice (βRapKOGFP) show reduced β-cell mass, loss of β-cell identity and acquisition of α-cell features; which are not reversible upon glucose normalization. Deletion of Raptor directly impairs β-cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to β-cell failure. Moreover, loss of Raptor activates α-cell transcription factor MafB (via modulating C/EBPβ isoform ratio) and several α-cell enriched genes i.e. Etv1 and Tspan12, thus initiates β- to α-cell reprograming. The present findings highlight mTORC1 as a metabolic rheostat for stabilizing β-cell identity and repressing α-cell program at normoglycemic level, which might present therapeutic opportunities for treatment of diabetes.

Date: 2020
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DOI: 10.1038/s41467-020-15935-0

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