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Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration. - Jan 2020

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration. - Jan 2020
https://www.ncbi.nlm.nih.gov/pubmed/32058969 ; https://linkinghub.elsevier.com/retrieve/pii/S2589004220300419
Rumala CZ1, Liu J2, Locasale JW2, Corkey BE1, Deeney JT1, Rameh LE3.


  • •Acute glucose stimulates mTORC1 in β-cells through a glycolysis-dependent mechanism
  • •Chronic excess glucose promotes mTOR-dependent metabolic acceleration of β-cells
  • •Metabolic acceleration activates a positive feedback loop for mTORC1 hyperactivation
  • •mTOR hyperactivation disturbs the metabolism and insulin secretion patterns of β-cells


Chronic exposure of pancreatic β-cells to excess glucose can lead to metabolic acceleration and loss of stimulus-secretion coupling. Here, we examined how exposure to excess glucose (defined here as concentrations above 5 mM) affects mTORC1 signaling and the metabolism of β-cells. Acute exposure to excess glucose stimulated glycolysis-dependent mTORC1 signaling, without changes in the PI3K or AMPK pathways. Prolonged exposure to excess glucose led to hyperactivation of mTORC1 and metabolic acceleration, characterized by higher basal respiration and maximal respiratory capacity, increased energy demand, and enhanced flux through mitochondrial pyruvate metabolism. Inhibition of pyruvate transport to the mitochondria decelerated the metabolism of β-cells chronically exposed to excess glucose and re-established glucose-dependent mTORC1 signaling, disrupting a positive feedback loop for mTORC1 hyperactivation. mTOR inhibition had positive and negative impacts on various metabolic pathways and insulin secretion, demonstrating a role for mTOR signaling in the long-term metabolic adaptation of β-cells to excess glucose.

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