Journal
CELL METABOLISM
Volume 33, Issue 4, Pages 804-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2020.11.020
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Funding
- NIH, United States [T32 DK007012, F32 DK121420, R01 DK42583, R01 DK123075]
- American Diabetes Association, United States faculty development award [1-18-JDF-075]
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The reductive TCA cycle flux plays a crucial role in regulating insulin secretion by affecting biomass generation and NADPH levels.
Metabolic fuels regulate insulin secretion by generating second messengers that drive insulin granule exocytosis, but the biochemical pathways involved are incompletely understood. Here we demonstrate that stimulation of rat insulinoma cells or primary rat islets with glucose or glutamine + 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (Gln + BCH) induces reductive, counter-clockwise'' tricarboxylic acid (TCA) cycle flux of glutamine to citrate. Molecular or pharmacologic suppression of isocitrate dehydrogenase-2 (IDH2), which catalyzes reductive carboxylation of 2-ketoglutarate to isocitrate, results in impairment of glucose- and Gln + BCH-stimulated reductive TCA cycle flux, lowering of NADPH levels, and inhibition of insulin secretion. Pharmacologic suppression of IDH2 also inhibits insulin secretion in living mice. Reductive TCA cycle flux has been proposed as a mechanism for generation of biomass in cancer cells. Here we demonstrate that reductive TCA cycle flux also produces stimulus-secretion coupling factors that regulate insulin secretion, including in non-dividing cells.
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