Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 200137, Shanghai, China.
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 (βRapKO) 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.
β 细胞功能障碍被认为是糖尿病中β 细胞衰竭的一个重要因素；然而，独立于高血糖的精确机制仍在研究中。我们之前曾报道过 mTORC1/Raptor 调节β 细胞的功能成熟。在本研究中，我们发现糖尿病β 细胞特异性 Raptor 缺失小鼠（βRapKO）β 细胞数量减少，β 细胞特征丧失，获得α 细胞特征；这些特征在血糖正常化后无法逆转。Raptor 的缺失直接损害β 细胞的特征、线粒体代谢偶联和蛋白质合成活性，导致β 细胞衰竭。此外，Raptor 的缺失激活了α 细胞转录因子 MafB（通过调节 C/EBPβ 异构体比例）和几个α 细胞高表达基因，如 Etv1 和 Tspan12，从而启动β 细胞向α 细胞的重编程。这些发现强调了 mTORC1 作为一种代谢变阻器，在正常血糖水平下稳定β 细胞特征并抑制α 细胞程序，这可能为糖尿病的治疗提供新的治疗机会。
