PMID- 24759959
OWN - NLM
STAT- MEDLINE
DCOM- 20150129
LR  - 20211021
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 57
IP  - 7
DP  - 2014 Jul
TI  - Methylglyoxal impairs endothelial insulin sensitivity both in vitro and in vivo.
PG  - 1485-94
LID - 10.1007/s00125-014-3243-7 [doi]
AB  - AIMS/HYPOTHESIS: Insulin exerts a direct action on vascular cells, thereby 
      affecting the outcome and progression of diabetic vascular complications. 
      However, the mechanism through which insulin signalling is impaired in the 
      endothelium of diabetic individuals remains unclear. In this work, we have 
      evaluated the role of the AGE precursor methylglyoxal (MGO) in generating 
      endothelial insulin resistance both in cells and in animal models. METHODS: Time 
      course experiments were performed on mouse aortic endothelial cells (MAECs) 
      incubated with 500 mumol/l MGO. The glyoxalase-1 inhibitor 
      S-p-bromobenzylglutathione-cyclopentyl-diester (SpBrBzGSHCp2) was used to 
      increase the endogenous levels of MGO. For the in vivo study, an MGO solution was 
      administrated i.p. to C57BL/6 mice for 7 weeks. RESULTS: MGO prevented the 
      insulin-dependent activation of the IRS1/protein kinase Akt/endothelial nitric 
      oxide synthase (eNOS) pathway, thereby blunting nitric oxide (NO) production, 
      while extracellular signal-regulated kinase (ERK1/2) activation and endothelin-1 
      (ET-1) release were increased by MGO in MAECs. Similar results were obtained in 
      MAECs treated with SpBrBzGSHCp2. In MGO- and SpBrBzGSHCp2-exposed cells, 
      inhibition of ERK1/2 decreased IRS1 phosphorylation on S616 and rescued 
      insulin-dependent Akt activation and NO generation, indicating that MGO 
      inhibition of the IRS1/Akt/eNOS pathway is mediated, at least in part, by ERK1/2. 
      Chronic administration of MGO to C57BL/6 mice impaired whole-body insulin 
      sensitivity and induced endothelial insulin resistance. 
      CONCLUSIONS/INTERPRETATION: MGO impairs the action of insulin on the endothelium 
      both in vitro and in vivo, at least in part through an ERK1/2-mediated mechanism. 
      These findings may be instrumental in developing novel strategies for preserving 
      endothelial function in diabetes.
FAU - Nigro, Cecilia
AU  - Nigro C
AD  - Institute of Experimental Endocrinology and Oncology 'G. Salvatore', National 
      Council of Research, Via Pansini 5, 80131, Naples, Italy.
FAU - Raciti, Gregory A
AU  - Raciti GA
FAU - Leone, Alessia
AU  - Leone A
FAU - Fleming, Thomas H
AU  - Fleming TH
FAU - Longo, Michele
AU  - Longo M
FAU - Prevenzano, Immacolata
AU  - Prevenzano I
FAU - Fiory, Francesca
AU  - Fiory F
FAU - Mirra, Paola
AU  - Mirra P
FAU - D'Esposito, Vittoria
AU  - D'Esposito V
FAU - Ulianich, Luca
AU  - Ulianich L
FAU - Nawroth, Peter P
AU  - Nawroth PP
FAU - Formisano, Pietro
AU  - Formisano P
FAU - Beguinot, Francesco
AU  - Beguinot F
FAU - Miele, Claudia
AU  - Miele C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140424
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, mouse)
RN  - 166038-00-2 (S-4-bromobenzylglutathione cyclopentyl diester)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 722KLD7415 (Pyruvaldehyde)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Endothelial Cells/*drug effects/metabolism
MH  - Glutathione/analogs & derivatives/pharmacology
MH  - Insulin/*metabolism
MH  - Insulin Receptor Substrate Proteins/metabolism
MH  - Insulin Resistance/*physiology
MH  - Mice
MH  - Nitric Oxide/biosynthesis
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyruvaldehyde/*pharmacology
MH  - Signal Transduction/*drug effects
EDAT- 2014/04/25 06:00
MHDA- 2015/01/30 06:00
CRDT- 2014/04/25 06:00
PHST- 2014/02/10 00:00 [received]
PHST- 2014/03/27 00:00 [accepted]
PHST- 2014/04/25 06:00 [entrez]
PHST- 2014/04/25 06:00 [pubmed]
PHST- 2015/01/30 06:00 [medline]
AID - 10.1007/s00125-014-3243-7 [doi]
PST - ppublish
SO  - Diabetologia. 2014 Jul;57(7):1485-94. doi: 10.1007/s00125-014-3243-7. Epub 2014 
      Apr 24.