PMID- 18493739
OWN - NLM
STAT- MEDLINE
DCOM- 20081020
LR  - 20211020
IS  - 0012-186X (Print)
IS  - 0012-186X (Linking)
VI  - 51
IP  - 7
DP  - 2008 Jul
TI  - Glibenclamide activates translation in rat pancreatic beta cells through 
      calcium-dependent mTOR, PKA and MEK signalling pathways.
PG  - 1202-12
LID - 10.1007/s00125-008-1026-8 [doi]
AB  - AIMS/HYPOTHESIS: Prolonged exposure of rat beta cells to the insulin secretagogue 
      glibenclamide has been found to induce a sustained increase in basal insulin 
      synthesis. This effect was calcium-dependent and localised in cells that had been 
      degranulated by the drug. Since it was blocked by the translation inhibitor 
      cycloheximide, we examined whether sustained exposure to glibenclamide activates 
      translational factors by calcium-dependent signalling pathways. METHODS: Purified 
      rat beta cells were cultured with and without glibenclamide in the presence or 
      absence of inhibitors of calcium-dependent signalling pathways before measurement 
      of basal and stimulated protein and insulin synthesis, and assessment of 
      abundance of (phosphorylated) translation factors. RESULTS: A 24 h exposure to 
      glibenclamide induced activation of four translation factors, i.e. 
      phosphorylation of eukaryotic initiation factor (eIF) 4e binding protein 1 and 
      ribosomal protein S6 (rpS6), and dephosphorylation of eIF-2alpha and eukaryotic 
      elongation factor 2. The rise in phospho-rpS6 intensity was localised to a 
      subpopulation of beta cells with low insulin content. This activation of 
      translational factors and the associated elevation of insulin synthesis were 
      completely blocked by the calcium channel blocker verapamil and partially blocked 
      by the mammalian target of rapamycin (mTOR) inhibitor rapamycin, the protein 
      kinase A (PKA) inhibitor Rp-8-Br-cAMPs and the mitogen-activated protein kinase/ 
      extracellular signal-regulated kinase kinase (MEK) inhibitor U0126; a combination 
      of inhibitors exhibited additive effects. CONCLUSIONS/INTERPRETATION: Prolonged 
      exposure to glibenclamide activates protein translation in pancreatic beta cells 
      through the calcium-regulated mTOR, PKA and MEK signalling pathways. The observed 
      intercellular differences in translation activation are proposed as underlying 
      mechanism for functional heterogeneity in the pancreatic beta cell population.
FAU - Wang, Q
AU  - Wang Q
AD  - Diabetes Research Center, Brussels Free University, Laarbeeklaan 103, 1090, 
      Brussels, Belgium.
FAU - Heimberg, H
AU  - Heimberg H
FAU - Pipeleers, D
AU  - Pipeleers D
FAU - Ling, Z
AU  - Ling Z
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080521
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Calcium Channel Blockers)
RN  - 0 (Crtc1 protein, rat)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Transcription Factors)
RN  - CJ0O37KU29 (Verapamil)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - SX6K58TVWC (Glyburide)
RN  - SY7Q814VUP (Calcium)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Calcium Channel Blockers/pharmacology
MH  - Calcium Signaling/*drug effects/physiology
MH  - Cells, Cultured
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Glyburide/*pharmacology
MH  - Hypoglycemic Agents/*pharmacology
MH  - Immunosuppressive Agents/pharmacology
MH  - Insulin-Secreting Cells/cytology/*drug effects/physiology
MH  - Male
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Protein Biosynthesis/*drug effects/physiology
MH  - Rats
MH  - Rats, Wistar
MH  - Sirolimus/pharmacology
MH  - Transcription Factors/metabolism
MH  - Verapamil/pharmacology
EDAT- 2008/05/22 09:00
MHDA- 2008/10/22 09:00
CRDT- 2008/05/22 09:00
PHST- 2008/01/11 00:00 [received]
PHST- 2008/04/04 00:00 [accepted]
PHST- 2008/05/22 09:00 [pubmed]
PHST- 2008/10/22 09:00 [medline]
PHST- 2008/05/22 09:00 [entrez]
AID - 10.1007/s00125-008-1026-8 [doi]
PST - ppublish
SO  - Diabetologia. 2008 Jul;51(7):1202-12. doi: 10.1007/s00125-008-1026-8. Epub 2008 
      May 21.