PMID- 34800480
OWN - NLM
STAT- MEDLINE
DCOM- 20211227
LR  - 20211227
IS  - 1096-0007 (Electronic)
IS  - 0014-4835 (Linking)
VI  - 213
DP  - 2021 Dec
TI  - Glyceraldehyde-3-phosphate dehydrogenase and glutamine synthetase inhibition in 
      the presence of pro-inflammatory cytokines contribute to the metabolic imbalance 
      of diabetic retinopathy.
PG  - 108845
LID - S0014-4835(21)00411-5 [pii]
LID - 10.1016/j.exer.2021.108845 [doi]
AB  - Diabetic retinopathy (DR) is the leading cause of vision impairment in working 
      age adults. In addition to hyperglycemia, retinal inflammation is an important 
      driving factor for DR development. Although DR is clinically described as 
      diabetes-induced damage to the retinal blood vessels, several studies have 
      reported that metabolic dysregulation occurs in the retina prior to the 
      development of microvascular damage. The two most commonly affected metabolic 
      pathways in diabetic conditions are glycolysis and the glutamate pathway. We 
      investigated the role of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 
      glutamine synthetase (GS) in an in-vitro model of DR incorporating high glucose 
      and pro-inflammatory cytokines. We found that GAPDH and GS enzyme activity were 
      not significantly affected in hyperglycemic conditions or after exposure to 
      cytokines alone, but were significantly decreased in the DR model. This confirmed 
      that pro-inflammatory cytokines IL-1beta and TNFalpha enhance the hyperglycemic 
      metabolic deficit. We further investigated metabolite and amino acid levels after 
      specific pharmacological inhibition of GAPDH or GS in the absence/presence of 
      pro-inflammatory cytokines. The results indicate that GAPDH inhibition increased 
      glucose and addition of cytokines increased lactate and ATP levels and reduced 
      glutamate levels. GS inhibition did not alter retinal metabolite levels but the 
      addition of cytokines increased ATP levels and caused glutamate accumulation in 
      Muller cells. We conclude that it is the action of pro-inflammatory cytokines 
      concomitantly with the inhibition of the glycolytic or GS mediated glutamate 
      recycling that contribute to metabolic dysregulation in DR. Therefore, in the 
      absence of good glycemic control, therapeutic interventions aimed at regulating 
      inflammation may prevent the onset of early metabolic imbalance in DR.
CI  - Copyright (c) 2021 Elsevier Ltd. All rights reserved.
FAU - Shivashankar, Gaganashree
AU  - Shivashankar G
AD  - School of Optometry and Vision Science and the New Zealand National Eye Centre, 
      University of Auckland, Auckland, New Zealand.
FAU - Lim, Julie C
AU  - Lim JC
AD  - Department of Physiology, School of Medical and Health Sciences and the New 
      Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
FAU - Acosta, Monica L
AU  - Acosta ML
AD  - School of Optometry and Vision Science and the New Zealand National Eye Centre, 
      University of Auckland, Auckland, New Zealand. Electronic address: 
      m.acosta@auckland.ac.nz.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211117
PL  - England
TA  - Exp Eye Res
JT  - Experimental eye research
JID - 0370707
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 1982-67-8 (Methionine Sulfoximine)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 1.2.1.- (Glyceraldehyde-3-Phosphate Dehydrogenases)
RN  - EC 6.3.1.2 (Glutamate-Ammonia Ligase)
RN  - IY9XDZ35W2 (Glucose)
RN  - WF5188V710 (Iodoacetic Acid)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Diabetic Retinopathy/*enzymology/pathology
MH  - Enzyme Inhibitors/*pharmacology
MH  - Female
MH  - Glucose/pharmacology
MH  - Glutamate-Ammonia Ligase/*antagonists & inhibitors
MH  - Glyceraldehyde-3-Phosphate Dehydrogenases/*antagonists & inhibitors
MH  - Hyperglycemia/metabolism
MH  - Interleukin-1beta/*pharmacology
MH  - Iodoacetic Acid/pharmacology
MH  - L-Lactate Dehydrogenase/metabolism
MH  - Methionine Sulfoximine/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Retina/*drug effects/enzymology/pathology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
OTO - NOTNLM
OT  - Diabetic retinopathy
OT  - Glutamate recycling
OT  - Glutamine synthetase
OT  - Glyceraldehyde 3-phosphate dehydrogenase
OT  - Glycolysis
OT  - Inflammation
OT  - Metabolic dysregulation
OT  - Retina
EDAT- 2021/11/21 06:00
MHDA- 2021/12/28 06:00
CRDT- 2021/11/20 20:10
PHST- 2021/07/15 00:00 [received]
PHST- 2021/10/12 00:00 [revised]
PHST- 2021/11/12 00:00 [accepted]
PHST- 2021/11/21 06:00 [pubmed]
PHST- 2021/12/28 06:00 [medline]
PHST- 2021/11/20 20:10 [entrez]
AID - S0014-4835(21)00411-5 [pii]
AID - 10.1016/j.exer.2021.108845 [doi]
PST - ppublish
SO  - Exp Eye Res. 2021 Dec;213:108845. doi: 10.1016/j.exer.2021.108845. Epub 2021 Nov 
      17.