期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-15935-0
关键词
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资金
- National Natural Sciences Foundation of China [81870527, 81670700]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20172006]
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.
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