PMID- 10760274
OWN - NLM
STAT- MEDLINE
DCOM- 20000517
LR  - 20230331
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 97
IP  - 8
DP  - 2000 Apr 11
TI  - Role of AMP-activated protein kinase in the regulation by glucose of islet beta 
      cell gene expression.
PG  - 4023-8
AB  - 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 (AICAR) 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 MIN6 beta cells and that 
      activation of the enzyme with AICAR prevents the activation of the L-PK gene by 
      elevated glucose. Furthermore, microinjection of antibodies to the alpha2- 
      (catalytic) or beta2-subunits of AMPK complex, but not to the alpha1-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 alpha2-subunits. Incubation with AICAR 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.
FAU - da Silva Xavier, G
AU  - da Silva Xavier G
AD  - Department of Biochemistry, School of Medical Sciences, University Walk, 
      University of Bristol, Bristol BS8 1TD, England, United Kingdom.
FAU - Leclerc, I
AU  - Leclerc I
FAU - Salt, I P
AU  - Salt IP
FAU - Doiron, B
AU  - Doiron B
FAU - Hardie, D G
AU  - Hardie DG
FAU - Kahn, A
AU  - Kahn A
FAU - Rutter, G A
AU  - Rutter GA
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - 13/0004672/DUK_/Diabetes UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antibodies)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Ribonucleotides)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - EC 2.7.1.40 (Pyruvate Kinase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - F0X88YW0YK (AICA ribonucleotide)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - AMP-Activated Protein Kinases
MH  - Amino Acid Sequence
MH  - Aminoimidazole Carboxamide/analogs & derivatives/pharmacology
MH  - Antibodies/immunology
MH  - Cell Line
MH  - Gene Expression Regulation, Enzymologic/*drug effects
MH  - Glucose/*pharmacology
MH  - Hypoglycemic Agents/pharmacology
MH  - Insulin/genetics
MH  - Islets of Langerhans/cytology/enzymology/*metabolism
MH  - Molecular Sequence Data
MH  - Multienzyme Complexes/immunology/*metabolism
MH  - Protein Serine-Threonine Kinases/immunology/*metabolism
MH  - Pyruvate Kinase/*genetics
MH  - Ribonucleotides/pharmacology
MH  - Subcellular Fractions/enzymology
PMC - PMC18135
EDAT- 2000/04/13 09:00
MHDA- 2000/05/20 09:00
PMCR- 2000/10/11
CRDT- 2000/04/13 09:00
PHST- 2000/04/13 09:00 [pubmed]
PHST- 2000/05/20 09:00 [medline]
PHST- 2000/04/13 09:00 [entrez]
PHST- 2000/10/11 00:00 [pmc-release]
AID - 97/8/4023 [pii]
AID - 5073 [pii]
AID - 10.1073/pnas.97.8.4023 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4023-8. doi: 10.1073/pnas.97.8.4023.