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. Epub 2020 Dec 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Citric Acid Cycle / physiology*
  • Glucose / metabolism
  • Glucose / pharmacology*
  • Glutamine / metabolism
  • Glutamine / pharmacology*
  • Insulin Secretion / drug effects*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism
  • Isocitrate Dehydrogenase / antagonists & inhibitors
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Lipogenesis / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidation-Reduction
  • Phenylurea Compounds / pharmacology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Wistar
  • Sulfonamides / pharmacology
  • Sumoylation / drug effects

Substances

  • AGI-6780
  • Phenylurea Compounds
  • Protein Isoforms
  • RNA, Small Interfering
  • Sulfonamides
  • Glutamine
  • Idh2 protein, rat
  • Isocitrate Dehydrogenase
  • Glucose