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

Nat Commun. 2020 May 21;11(1):2538. doi: 10.1038/s41467-020-15935-0.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Cell Differentiation* / genetics
  • Cell Plasticity* / genetics
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology*
  • Gene Expression Regulation
  • Glucagon-Secreting Cells / metabolism
  • Glucagon-Secreting Cells / pathology
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • MafB Transcription Factor / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Knockout
  • Regulatory-Associated Protein of mTOR / genetics
  • Regulatory-Associated Protein of mTOR / metabolism*
  • Signal Transduction


  • Blood Glucose
  • Insulin
  • MafB Transcription Factor
  • Mafb protein, mouse
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • Mechanistic Target of Rapamycin Complex 1