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Defining the contribution of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) in regulation of glucose uptake by metformin in skeletal muscle cells

Defining the contribution of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) in regulation of glucose uptake by metformin in skeletal muscle cells

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Authors

  • Sophie Turban
  • Clare Stretton
  • Olivier Drouin
  • Charlotte J. Green
  • Maria L. Watson
  • Alexander Gray
  • Fiona Ross
  • Louise Lantier
  • Benoit Viollet
  • D.Grahame Hardie
  • Andre Marette
  • Harinder S. Hundal (Lead / Corresponding author)

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Original languageEnglish
Pages20088-20099
Number of pages12
JournalJournal of Biological Chemistry
Journal publication date8 Jun 2012
Journal number24
Volume287
DOIs
StatePublished

Abstract

The importance of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) as effectors of metformin (Met) action on glucose uptake (GU) in skeletal muscle cells was investigated. GUin L6 myotubes was stimulated 2-fold following 16 h of Met treatment and acutely enhanced by insulin in an additive fashion. Insulin-stimulatedGUwas sensitive to PI3K inhibition, whereas that induced by Met was not. Met and its related biguanide, phenformin, stimulated AMPK activation/phosphorylation to a level comparable with that induced by the AMPK activator, 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR). However, the increase in GU elicited by AICAR was significantly lower than that induced by either biguanide. Expression of a constitutively active AMPK mimicked the effects of AICAR on GU, whereas a dominant interferingAMPK or shRNA silencing of AMPK prevented AICAR-stimulated GU and Met-induced AMPK signaling but only repressed biguanide- stimulated GU by ~20%. Consistent with this, analysis of GU in muscle cells from a1 /a2 AMPK-deficient mice revealed a significant retention of Met-stimulated GU, being reduced by ~35% compared with that of wild type cells. Atypical PKCs (aPKCs) have been implicated in Met-stimulated GU, and in line with this, Met and phenformin induced activation/phosphorylation of aPKC in L6 myotubes. However, although cellular depletion of aPKC (>90%) led to loss in biguanide-induced aPKC phosphorylation, it had no effect on Met-stimulated GU, whereas inhibitors targeting novel/conventional PKCs caused a significant reduction in biguanide-induced GU. Our findings indicate that although Met activates AMPK, a significant component of Met-stimulated GU in muscle cells is mediated via an AMPK-independent mechanism that involves novel/conventional PKCs. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

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