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Exposure of Pancreatic ß-Cells to Excess Glucose Results in Bimodal Activation
of mTORC1 and mTOR-Dependent Metabolic Acceleration.
Authors Rumala CZ, Liu J, Locasale JW, Corkey BE, Deeney JT, Rameh LE
Submitted By Submitted Externally on 2/24/2020
Status Published
Journal iScience
Year 2020
Date Published 2/1/2020
Volume : Pages 23 : 100858
PubMed Reference 32058969
Abstract Chronic exposure of pancreatic ß-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 ß-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 ß-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
ß-cells to excess glucose.


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