Role of AMP-activated protein kinase in the regulation by glucose of islet beta cell gene expression

Gabriela Da Silva Xavier, Isabelle Leclerc, Ian P. Salt, Bruno Doiron, D. Grahame Hardie, Axel Kahn, Guy A. Rutter

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179 Scopus citations

Abstract

Elevated glucose concentrations stimulate the transcription of the pre- proinsulin (PPI), L-type pyruvate kinase (L-PK), and other genes in islet beta cells. In liver cells, pharmacological activation by 5-amino-4- imidazolecarboxamide riboside (AlCAR) of AMP-activated protein kinase (AMPK), the mammalian homologue of the yeast SNF1 kinase complex, inhibits the effects of glucose, suggesting a key signaling role for this kinase. Here, we demonstrate that AMPK activity is inhibited by elevated glucose concentrations in MlN6 beta cells and that activation of the enzyme with AlCAR prevents the activation of the L-PK gene by elevated glucose. Furthermore, microinjection of antibodies to the α2(catalytic) or β2- subunits of AMPK complex, but not to the α1-subunit or extracellular stimulus-regulated kinase, mimics the effects of elevated glucose on the L-PK and PPI promoter activities as assessed by single-cell imaging of promoter luciferase constructs. In each case, injection of antibodies into the nucleus and cytosol, but not the nucleus alone, was necessary, indicating the importance of either a cytosolic phosphorylation event or the subcellular localization of the α2-subunits. Incubation with AlCAR diminished, but did not abolish, the effect of glucose on PPI transcription. These data suggest that glucose-induced changes in AMPK activity are necessary and sufficient for the regulation of the L-PK gene by the sugar and also play an important role in the regulation of the PPI promoter.

Original languageEnglish (US)
Pages (from-to)4023-4028
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number8
DOIs
StatePublished - Apr 11 2000

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Keywords

  • Insulin
  • L-type pyruvate kinase
  • Promoter

ASJC Scopus subject areas

  • General

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