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

Compromised beta -cell identity is emerging as an important contributor to beta -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 beta -cells. In the present study, we find that diabetic beta -cell specific Raptor-deficient mice (beta RapKO(GFP)) show reduced beta -cell mass, loss of beta -cell identity and acquisition of alpha -cell features; which are not reversible upon glucose normalization. Deletion of Raptor directly impairs beta -cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to beta -cell failure. Moreover, loss of Raptor activates alpha -cell transcription factor MafB (via modulating C/EBP beta isoform ratio) and several alpha -cell enriched genes i.e. Etv1 and Tspan12, thus initiates beta- to alpha -cell reprograming. The present findings highlight mTORC1 as a metabolic rheostat for stabilizing beta -cell identity and repressing alpha -cell program at normoglycemic level, which might present therapeutic opportunities for treatment of diabetes. During the progression of type 2 diabetes, insulin-producing beta -cells can lose their identity and become reprogrammed into other cell types. Here the authors show that murine diabetic beta -cells require the protein Raptor for maintaining beta -cell health and preventing them from turning into alpha -cells, independent of Raptor's involvement in regulating blood sugar levels.