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Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion.

Publication ,  Journal Article
Jensen, MV; Joseph, JW; Ilkayeva, O; Burgess, S; Lu, D; Ronnebaum, SM; Odegaard, M; Becker, TC; Sherry, AD; Newgard, CB
Published in: J Biol Chem
August 4, 2006

We have previously reported that glucose-stimulated insulin secretion (GSIS) is tightly correlated with pyruvate carboxylase (PC)-catalyzed anaplerotic flux into the tricarboxylic acid cycle and stimulation of pyruvate cycling activity. To further evaluate the role of PC in beta-cell function, we constructed a recombinant adenovirus containing a small interfering RNA (siRNA) specific to PC (Ad-siPC). Ad-siPC reduced PC mRNA levels by 83 and 64% and PC protein by 56 and 35% in INS-1-derived 832/13 cells and primary rat islets, respectively. Surprisingly, this manipulation did not impair GSIS in rat islets. In Ad-siPC-treated 832/13 cells, GSIS was slightly increased, whereas glycolytic rate and glucose oxidation were unaffected. Flux through PC at high glucose was decreased by only 20%, suggesting an increase in PC-specific activity. Acetyl carnitine, a surrogate for acetyl-CoA, an allosteric activator of PC, was increased by 36% in Ad-siPC-treated cells, suggesting a mechanism by which PC enzymatic activity is maintained with suppressed PC protein levels. In addition, the NADPH:NADP ratio, a proposed coupling factor for GSIS, was unaffected in Ad-siPC-treated cells. We conclude that beta-cells activate compensatory mechanisms in response to suppression of PC expression that prevent impairment of anaplerosis, pyruvate cycling, NAPDH production, and GSIS.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 4, 2006

Volume

281

Issue

31

Start / End Page

22342 / 22351

Location

United States

Related Subject Headings

  • Rats
  • RNA, Small Interfering
  • Pyruvate Carboxylase
  • NADP
  • Islets of Langerhans
  • Insulin-Secreting Cells
  • Insulin Secretion
  • Insulin
  • Glucose
  • Cell Line
 

Citation

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Jensen, M. V., Joseph, J. W., Ilkayeva, O., Burgess, S., Lu, D., Ronnebaum, S. M., … Newgard, C. B. (2006). Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion. J Biol Chem, 281(31), 22342–22351. https://doi.org/10.1074/jbc.M604350200
Jensen, Mette V., Jamie W. Joseph, Olga Ilkayeva, Shawn Burgess, Danhong Lu, Sarah M. Ronnebaum, Matthew Odegaard, Thomas C. Becker, A Dean Sherry, and Christopher B. Newgard. “Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion.J Biol Chem 281, no. 31 (August 4, 2006): 22342–51. https://doi.org/10.1074/jbc.M604350200.
Jensen MV, Joseph JW, Ilkayeva O, Burgess S, Lu D, Ronnebaum SM, et al. Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion. J Biol Chem. 2006 Aug 4;281(31):22342–51.
Jensen, Mette V., et al. “Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion.J Biol Chem, vol. 281, no. 31, Aug. 2006, pp. 22342–51. Pubmed, doi:10.1074/jbc.M604350200.
Jensen MV, Joseph JW, Ilkayeva O, Burgess S, Lu D, Ronnebaum SM, Odegaard M, Becker TC, Sherry AD, Newgard CB. Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion. J Biol Chem. 2006 Aug 4;281(31):22342–22351.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 4, 2006

Volume

281

Issue

31

Start / End Page

22342 / 22351

Location

United States

Related Subject Headings

  • Rats
  • RNA, Small Interfering
  • Pyruvate Carboxylase
  • NADP
  • Islets of Langerhans
  • Insulin-Secreting Cells
  • Insulin Secretion
  • Insulin
  • Glucose
  • Cell Line