2. Academic Validation
  3. Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion

Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion

  • Cell Metab. 2021 Apr 6;33(4):804-817.e5. doi: 10.1016/j.cmet.2020.11.020.
Guo-Fang Zhang 1,  Mette V Jensen 2,  Sarah M Gray 2,  Kimberley El 2,  You Wang 2,  Danhong Lu 2,  Thomas C Becker 1,  Jonathan E Campbell 3,  Christopher B Newgard 4
Affiliations

Affiliations

  • 1 Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA; Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, NC 27701, USA.
  • 2 Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA.
  • 3 Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA; Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27701, USA.
  • 4 Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA; Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27701, USA. Electronic address: chris.newgard@duke.edu.
PMID: 33321098 DOI: 10.1016/j.cmet.2020.11.020
Abstract

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.

Keywords

NADPH; anaplerosis; insulin secretion; isocitrate dehydrogenase-2; metabolic flux; pancreatic islet β cells; reductive TCA cycle; stable isotopes.

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