PMID- 23595987
OWN - NLM
STAT- MEDLINE
DCOM- 20130806
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 22
DP  - 2013 May 31
TI  - cAMP-responsive element-binding protein (CREB)-regulated transcription 
      coactivator 2 (CRTC2) promotes glucagon clearance and hepatic amino acid 
      catabolism to regulate glucose homeostasis.
PG  - 16167-76
LID - 10.1074/jbc.M113.460246 [doi]
AB  - cAMP-responsive element-binding protein (CREB)-regulated transcription 
      coactivator 2 (CRTC2) regulates transcription of gluconeogenic genes by 
      specifying targets for the transcription factor CREB in response to glucagon. We 
      used an antisense oligonucleotide directed against CRTC2 in both normal rodents 
      and in rodent models of increased gluconeogenesis to better understand the role 
      of CRTC2 in metabolic disease. In the context of severe hyperglycemia and 
      elevated hepatic glucose production, CTRC2 knockdown (KD) improved glucose 
      homeostasis by reducing endogenous glucose production. Interestingly, despite the 
      known role of CRTC2 in coordinating gluconeogenic gene expression, CRTC2 KD in a 
      rodent model of type 2 diabetes resulted in surprisingly little alteration of 
      glucose production. However, CRTC2 KD animals had elevated circulating 
      concentrations of glucagon and a  approximately 80% reduction in glucagon clearance. When this 
      phenomenon was prevented with somatostatin or a glucagon-neutralizing antibody, 
      endogenous glucose production was reduced by CRTC2 KD. Additionally, CRTC2 
      inhibition resulted in reduced expression of several glucagon-induced pyridoxal 
      5'-phosphate-dependent enzymes that convert amino acids to gluconeogenic 
      intermediates, suggesting that it may control substrate availability as well as 
      gluconeogenic gene expression. CRTC2 is an important regulator of gluconeogenesis 
      with tremendous impact in models of elevated hepatic glucose production. 
      Surprisingly, it is also part of a previously unidentified negative feedback loop 
      that degrades glucagon and regulates amino acid metabolism to coordinately 
      control glucose homeostasis in vivo.
FAU - Erion, Derek M
AU  - Erion DM
AD  - Department of Internal Medicine, Yale University School of Medicine, New Haven, 
      Connecticut 06536, USA.
FAU - Kotas, Maya E
AU  - Kotas ME
FAU - McGlashon, Jacob
AU  - McGlashon J
FAU - Yonemitsu, Shin
AU  - Yonemitsu S
FAU - Hsiao, Jennifer J
AU  - Hsiao JJ
FAU - Nagai, Yoshio
AU  - Nagai Y
FAU - Iwasaki, Takanori
AU  - Iwasaki T
FAU - Murray, Susan F
AU  - Murray SF
FAU - Bhanot, Sanjay
AU  - Bhanot S
FAU - Cline, Gary W
AU  - Cline GW
FAU - Samuel, Varman T
AU  - Samuel VT
FAU - Shulman, Gerald I
AU  - Shulman GI
FAU - Gillum, Matthew P
AU  - Gillum MP
LA  - eng
GR  - R01 DK-40936/DK/NIDDK NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - U24 DK059635/DK/NIDDK NIH HHS/United States
GR  - P30 DK-45735/DK/NIDDK NIH HHS/United States
GR  - R01 DK040936/DK/NIDDK NIH HHS/United States
GR  - P30 DK045735/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 - 20130417
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amino Acids)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (CRTC2 protein, rat)
RN  - 0 (Crtc2 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 5V5IOJ8338 (Pyridoxal Phosphate)
RN  - 9007-92-5 (Glucagon)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Amino Acids/genetics/*metabolism
MH  - Animals
MH  - Antibodies, Neutralizing/pharmacology
MH  - Diabetes Mellitus, Experimental/genetics/metabolism/pathology
MH  - Gene Knockdown Techniques
MH  - Glucagon/antagonists & inhibitors/genetics/*metabolism
MH  - Gluconeogenesis/drug effects/genetics
MH  - Glucose/genetics/*metabolism
MH  - *Homeostasis
MH  - Liver/*metabolism/pathology
MH  - Mice
MH  - Pyridoxal Phosphate/genetics/metabolism
MH  - Rats
MH  - Trans-Activators/genetics/*metabolism
MH  - Transcription Factors/genetics/*metabolism
PMC - PMC3668772
OTO - NOTNLM
OT  - Amino Acid
OT  - CRTC2
OT  - Diabetes
OT  - Glucagon
OT  - Gluconeogenesis
OT  - Liver
OT  - Physiology
EDAT- 2013/04/19 06:00
MHDA- 2013/08/07 06:00
PMCR- 2014/05/31
CRDT- 2013/04/19 06:00
PHST- 2013/04/19 06:00 [entrez]
PHST- 2013/04/19 06:00 [pubmed]
PHST- 2013/08/07 06:00 [medline]
PHST- 2014/05/31 00:00 [pmc-release]
AID - S0021-9258(20)46002-8 [pii]
AID - M113.460246 [pii]
AID - 10.1074/jbc.M113.460246 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 May 31;288(22):16167-76. doi: 10.1074/jbc.M113.460246. Epub 
      2013 Apr 17.