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.
Highlights
Compromised β-cell identity is emerging as an important contributor to β-cell failure in diabetes; the precise mechanism independent of hyperglycemia is under investigation
We have reported that β-cells are dedifferentiated in type 2 diabetes (T2D) patients with adequate glucose control and non-diabetic chronic pancreatitis, suggesting dedifferentiation can be a cause of β-cell failure, not merely as a consequence of hyperglycemia[14]
MTOR is an evolutionarily conserved, nutrient-sensing serine–threonine protein kinase, functioning in the form of at least two large protein complexes, mTOR complex 1 and mTOR complex 215,16. mTORC1 consists of RAPTOR, mLST8, PRAS40, DEPTOR, and mTOR, which is sensitive to Rapamycin[17,18]
Summary
Compromised β-cell identity is emerging as an important contributor to β-cell failure in diabetes; the precise mechanism independent of hyperglycemia is under investigation. Deletion of Raptor directly impairs β-cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to β-cell failure. We have reported that β-cells are dedifferentiated in T2D patients with adequate glucose control and non-diabetic chronic pancreatitis, suggesting dedifferentiation can be a cause of β-cell failure, not merely as a consequence of hyperglycemia[14]. It still remains unclear whether certain signal pathway controls compromised β-cell identity, independent of hyperglycemia. Our results demonstrate that mTORC1 directly regulates adult β-cell identity, mitochondrial metabolic coupling, and protein synthetic activity to maintain mature β-cell differentiated phenotype. Our data highlight mTORC1 signaling as an underlying mechanism implicated in promoting the terminal differentiation of β-cells and repressing β-cell default
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