PMID- 12589707
OWN - NLM
STAT- MEDLINE
DCOM- 20030528
LR  - 20220309
IS  - 0264-6021 (Print)
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 371
IP  - Pt 3
DP  - 2003 May 1
TI  - Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and 
      preproinsulin gene expression.
PG  - 761-74
AB  - AMP-activated protein kinase (AMPK) has recently been implicated in the control 
      of preproinsulin gene expression in pancreatic islet beta-cells [da Silva Xavier, 
      Leclerc, Salt, Doiron, Hardie, Kahn and Rutter (2000) Proc. Natl. Acad. Sci. 
      U.S.A. 97, 4023-4028]. Using pharmacological and molecular strategies to regulate 
      AMPK activity in rat islets and clonal MIN6 beta-cells, we show here that the 
      effects of AMPK are exerted largely upstream of insulin release. Thus forced 
      increases in AMPK activity achieved pharmacologically with 
      5-amino-4-imidazolecarboxamide riboside (AICAR), or by adenoviral overexpression 
      of a truncated, constitutively active form of the enzyme (AMPK alpha 1.T(172)D), 
      blocked glucose-stimulated insulin secretion. In MIN6 cells, activation of AMPK 
      suppressed glucose metabolism, as assessed by changes in total, cytosolic or 
      mitochondrial [ATP] and NAD(P)H, and reduced increases in intracellular [Ca(2+)] 
      caused by either glucose or tolbutamide. By contrast, inactivation of AMPK by 
      expression of a dominant-negative form of the enzyme mutated in the catalytic 
      site (AMPK alpha 1.D(157)A) did not affect glucose-stimulated increases in [ATP], 
      NAD(P)H or intracellular [Ca(2+)], but led to the unregulated release of insulin. 
      These results indicate that inhibition of AMPK by glucose is essential for the 
      activation of insulin secretion by the sugar, and may contribute to the 
      transcriptional stimulation of the preproinsulin gene. Modulation of AMPK 
      activity in the beta-cell may thus represent a novel therapeutic strategy for the 
      treatment of type 2 diabetes mellitus.
FAU - da Silva Xavier, Gabriela
AU  - da Silva Xavier G
AD  - Henry Wellcome Laboratories of Integrated Cell Signalling and Department of 
      Biochemistry, University Walk, University of Bristol, Bristol BS8 1TD, UK.
FAU - Leclerc, Isabelle
AU  - Leclerc I
FAU - Varadi, Aniko
AU  - Varadi A
FAU - Tsuboi, Takashi
AU  - Tsuboi T
FAU - Moule, S Kelly
AU  - Moule SK
FAU - Rutter, Guy A
AU  - Rutter GA
LA  - eng
GR  - 13/0004672/DUK_/Diabetes UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Insulin)
RN  - 0 (Protein Precursors)
RN  - 61116-24-3 (preproinsulin)
RN  - 9035-68-1 (Proinsulin)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - IY9XDZ35W2 (Glucose)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Apoptosis
MH  - Blotting, Western
MH  - Calcium/metabolism
MH  - Cell Line
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - *Gene Expression Regulation
MH  - Glucose/*pharmacology
MH  - Insulin/*metabolism
MH  - Insulin Secretion
MH  - Phosphorylation
MH  - Proinsulin/*genetics
MH  - Protein Precursors/*genetics
PMC - PMC1223356
EDAT- 2003/02/19 04:00
MHDA- 2003/05/29 05:00
PMCR- 2003/11/01
CRDT- 2003/02/19 04:00
PHST- 2003/02/17 00:00 [accepted]
PHST- 2003/02/10 00:00 [revised]
PHST- 2002/11/20 00:00 [received]
PHST- 2003/02/19 04:00 [pubmed]
PHST- 2003/05/29 05:00 [medline]
PHST- 2003/02/19 04:00 [entrez]
PHST- 2003/11/01 00:00 [pmc-release]
AID - BJ20021812 [pii]
AID - 10.1042/BJ20021812 [doi]
PST - ppublish
SO  - Biochem J. 2003 May 1;371(Pt 3):761-74. doi: 10.1042/BJ20021812.