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

ABSTRACT: Compromised ?-cell identity is emerging as an important contributor to ?-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 ?-cells. In the present study, we find that diabetic ?-cell specific Raptor-deficient mice (?RapKO^GFP) show reduced ?-cell mass, loss of ?-cell identity and acquisition of ?-cell features; which are not reversible upon glucose normalization. Deletion of Raptor directly impairs ?-cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to ?-cell failure. Moreover, loss of Raptor activates ?-cell transcription factor MafB (via modulating C/EBP? isoform ratio) and several ?-cell enriched genes i.e. Etv1 and Tspan12, thus initiates ?- to ?-cell reprograming. The present findings highlight mTORC1 as a metabolic rheostat for stabilizing ?-cell identity and repressing ?-cell program at normoglycemic level, which might present therapeutic opportunities for treatment of diabetes.

SUBMITTER: Yin Q 

PROVIDER: S-EPMC7242325 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature