PMID- 22210321
OWN - NLM
STAT- MEDLINE
DCOM- 20120313
LR  - 20211203
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 61
IP  - 2
DP  - 2012 Feb
TI  - L-leucine alters pancreatic beta-cell differentiation and function via the mTor 
      signaling pathway.
PG  - 409-17
LID - 10.2337/db11-0765 [doi]
AB  - Leucine (Leu) is an essential branched-chain amino acid, which activates the 
      mammalian target of rapamycin (mTOR) signaling pathway. The effect of Leu on cell 
      differentiation during embryonic development is unknown. Here, we show that Leu 
      supplementation during pregnancy significantly increased fetal body weight, 
      caused fetal hyperglycemia and hypoinsulinemia, and decreased the relative islet 
      area. We also used rat embryonic pancreatic explant culture for elucidating the 
      mechanism of Leu action on beta-cell development. We found that in the presence of 
      Leu, differentiation of pancreatic duodenal homeobox-1-positive progenitor cells 
      into neurogenin3-positive endocrine progenitor cells was inefficient and resulted 
      in decreased beta-cell formation. Mechanistically, Leu increases the intracellular 
      levels of hypoxia-inducible factor 1-alpha, a repressor of endocrine fate in the 
      pancreas, by activating the mTOR complex 1 signaling pathway. Collectively, our 
      findings indicate that Leu supplementation during pregnancy could potentially 
      increase the risk of type 2 diabetes mellitus by inhibiting the differentiation 
      of pancreatic endocrine progenitor cells during a susceptible period of fetal 
      life.
FAU - Rachdi, Latif
AU  - Rachdi L
AD  - INSERM U845, Research Center Growth and Signaling, Paris Descartes University, 
      Sorbonne Paris Cite, Necker Hospital, Paris, France. latif.rachdi@inserm.fr
FAU - Aiello, Virginie
AU  - Aiello V
FAU - Duvillie, Bertrand
AU  - Duvillie B
FAU - Scharfmann, Raphael
AU  - Scharfmann R
LA  - eng
GR  - U19 DK072495/DK/NIDDK NIH HHS/United States
GR  - U19-DK-072495/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111230
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (CRTC2 protein, rat)
RN  - 0 (Crtc1 protein, rat)
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Neurog3 protein, rat)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - GMW67QNF9C (Leucine)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/analysis
MH  - Cell Differentiation/*drug effects
MH  - Dietary Supplements
MH  - Female
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis
MH  - Insulin-Secreting Cells/cytology/*drug effects/physiology
MH  - Leucine/*administration & dosage
MH  - Nerve Tissue Proteins/analysis
MH  - Pregnancy
MH  - Rats
MH  - Rats, Wistar
MH  - Signal Transduction/*physiology
MH  - Sirolimus/pharmacology
MH  - Stem Cells/drug effects
MH  - TOR Serine-Threonine Kinases/*physiology
MH  - Trans-Activators
MH  - Transcription Factors/physiology
PMC - PMC3266409
EDAT- 2012/01/03 06:00
MHDA- 2012/03/14 06:00
PMCR- 2013/02/01
CRDT- 2012/01/03 06:00
PHST- 2012/01/03 06:00 [entrez]
PHST- 2012/01/03 06:00 [pubmed]
PHST- 2012/03/14 06:00 [medline]
PHST- 2013/02/01 00:00 [pmc-release]
AID - db11-0765 [pii]
AID - 0765 [pii]
AID - 10.2337/db11-0765 [doi]
PST - ppublish
SO  - Diabetes. 2012 Feb;61(2):409-17. doi: 10.2337/db11-0765. Epub 2011 Dec 30.