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Published on: June 25, 2012
Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice
Qinglei Yin1, Qicheng Ni1, Yichen Wang1
1Shanghai 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.
Abstract:
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.
Insights
mTORC1/Raptor loss causes loss of pancreatic beta-cell identity and function, leading to diabetes. This reprogramming into alpha-cells occurs independently of blood glucose levels.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Diseases
Background:
- Compromised beta-cell identity contributes to beta-cell failure in diabetes.
- The precise mechanisms driving this identity loss, independent of hyperglycemia, require further investigation.
- mTORC1/Raptor signaling has been previously implicated in regulating beta-cell functional maturation.
Purpose of the Study:
- To investigate the role of mTORC1/Raptor in maintaining beta-cell identity and function.
- To elucidate the mechanisms by which Raptor deficiency leads to beta-cell failure and reprogramming.
- To explore the potential of targeting mTORC1 for diabetes therapeutics.
Main Methods:
- Utilized diabetic beta-cell specific Raptor-deficient mice (βRapKOGFP).
- Assessed beta-cell mass, identity markers, and alpha-cell features.
- Analyzed mitochondrial metabolic coupling, protein synthesis, and key transcription factors (MafB, C/EBPβ).
Main Results:
- Raptor deficiency in beta-cells resulted in reduced beta-cell mass and loss of identity, with acquisition of alpha-cell features.
- These changes were irreversible even after normalizing glucose levels.
- Raptor deletion impaired beta-cell identity, mitochondrial function, and protein synthesis, activating alpha-cell programs (MafB, Etv1, Tspan12) and initiating beta- to alpha-cell reprogramming.
Conclusions:
- mTORC1 signaling is crucial for maintaining beta-cell identity and suppressing the alpha-cell program under normoglycemic conditions.
- Loss of Raptor directly destabilizes beta-cell identity, leading to metabolic dysfunction and failure.
- These findings suggest mTORC1 as a potential therapeutic target for preserving beta-cell function in diabetes.
