A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion

Sarah M. Ronnebaum, Olga Ilkayeva, Shawn C. Burgess, Jamie W. Joseph, Danhong Lu, Robert D. Stevens, Thomas C. Becker, A. Dean Sherry, Christopher B. Newgard, Mette V. Jensen

Research output: Contribution to journalArticle

148 Scopus citations


Glucose-stimulated insulin secretion (GSIS) from pancreatic islet β-cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K+ (K ATP) channels, but multiple lines of evidence suggest participation of other signals. Here we investigated the role of cytosolic NADP-dependent isocitrate dehydrogenase (ICDc) in control of GSIS in β-cells. Delivery of small interfering RNAs specific for ICDc caused impairment of GSIS in two independent robustly glucose-responsive rat insulinoma (INS-1-derived) cell lines and in primary rat islets. Suppression of ICDc also attenuated the glucose-induced increments in pyruvate cycling activity and in NADPH levels, a predicted by-product of pyruvate cycling pathways, as well as the total cellular NADP(H) content. Metabolic profiling of eight organic acids in cell extracts revealed that suppression of ICDc caused increases in lactate production in both INS-1-derived cell lines and primary islets, consistent with the attenuation of pyruvate cycling, with no significant changes in other intermediates. Based on these studies, we propose that a pyruvate cycling pathway involving ICDc plays an important role in control of GSIS.

Original languageEnglish (US)
Pages (from-to)30593-30602
Number of pages10
JournalJournal of Biological Chemistry
Issue number41
StatePublished - Oct 13 2006


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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