The influence of diabetes on glutamate metabolism in retinas

Gowda, Kavitha; Zinnanti, William J.; LaNoue, Kathryn F.

doi:10.1111/j.1471-4159.2011.07206.x

Cited by 44 publications

(25 citation statements)

References 49 publications

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“…Dietary taurine ameliorates diabetic retinopathy in part via increased GLAST expression (Zeng et al, 2009). Further factors which reduce the glutamate transport in Müller cells are a reduction of the extracellular pH, as occurring in ischemia, zinc ions released from photoreceptors, and an increase in intracellular glutamate as observed after retinal detachment and in experimental diabetic retinopathy (Billups and Attwell, 1996; Marc et al, 1998b; Spiridon et al, 1998; Gowda et al, 2011). …”

Section: Glutamate Uptake and Metabolismmentioning

confidence: 99%

“…Energy substrates are formed from glutamate also by other metabolic pathways, e.g., transamination of pyruvate (Figure 3) (Poitry et al, 2000). The conversion of glutamate into α-ketoglutarate is reduced in Müller cells of diabetic rats; this results in increased intracellular glutamate which impairs the glutamate uptake by Müller cells (Gowda et al, 2011). …”

Section: Glutamate Uptake and Metabolismmentioning

confidence: 99%

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GABA and Glutamate Uptake and Metabolism in Retinal Glial (Müller) Cells

Bringmann¹,

Grosche²,

Pannicke³

et al. 2013

Front. Endocrinol.

143

123

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Müller cells, the principal glial cells of the retina, support the synaptic activity by the uptake and metabolization of extracellular neurotransmitters. Müller cells express uptake and exchange systems for various neurotransmitters including glutamate and γ-aminobutyric acid (GABA). Müller cells remove the bulk of extracellular glutamate in the inner retina and contribute to the glutamate clearance around photoreceptor terminals. By the uptake of glutamate, Müller cells are involved in the shaping and termination of the synaptic activity, particularly in the inner retina. Reactive Müller cells are neuroprotective, e.g., by the clearance of excess extracellular glutamate, but may also contribute to neuronal degeneration by a malfunctioning or even reversal of glial glutamate transporters, or by a downregulation of the key enzyme, glutamine synthetase. This review summarizes the present knowledge about the role of Müller cells in the clearance and metabolization of extracellular glutamate and GABA. Some major pathways of GABA and glutamate metabolism in Müller cells are described; these pathways are involved in the glutamate-glutamine cycle of the retina, in the defense against oxidative stress via the production of glutathione, and in the production of substrates for the neuronal energy metabolism.

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Section: Glutamate Uptake and Metabolismmentioning

confidence: 99%

Section: Glutamate Uptake and Metabolismmentioning

confidence: 99%

GABA and Glutamate Uptake and Metabolism in Retinal Glial (Müller) Cells

Bringmann¹,

Grosche²,

Pannicke³

et al. 2013

Front. Endocrinol.

143

123

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“…The underlying causes of these acquired abnormalities remain to be established but they may, in part, involve glutamate turnover. In retina of diabetic rats, glutamate levels are elevated and conversion of glutamate to glutamine is reduced (Lieth et al, 1998) due to (i) impaired glutamate oxidation, probably arising from inhibition of glutamate transamination by branched chain amino acids and (ii) decreased activity and content of glutamine synthetase, suggesting that abnormal glutamate metabolism in retinal Müller cells may contribute to retinopathy via glutamate excitotoxicity (Lieth et al, 2000; Gowda et al, 2011). The glutamate transporter GLAST is also dysfunctional in retinal Müller cells, presumably due to oxidative damage (Li and Puro, 2002), and glutamate uptake is increased in glial plasmalemmal vesicles isolated from diabetic brain regions, whereas glutamate transporter levels are not altered in various brain structures (Coleman et al, 2004; Coleman et al, 2010).…”

Section: Glutamate Is An Important Astrocytic Energy Sourcementioning

confidence: 99%

Astrocytic energetics during excitatory neurotransmission: What are contributions of glutamate oxidation and glycolysis?

Dienel

2013

Neurochemistry International

104

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Astrocytic energetics of excitatory neurotransmission is controversial due to discrepant findings in different experimental systems in vitro and in vivo. The energy requirements of glutamate uptake are believed by some researchers to be satisfied by glycolysis coupled with shuttling of lactate to neurons for oxidation. However, astrocytes increase glycogenolysis and oxidative metabolism during sensory stimulation in vivo, indicating that other sources of energy are used by astrocytes during brain activation. Furthermore, glutamate uptake into cultured astrocytes stimulates glutamate oxidation and oxygen consumption, and glutamate maintains respiration as well as glucose. The neurotransmitter pool of glutamate is associated with the faster component of total glutamate turnover in vivo, and use of neurotransmitter glutamate to fuel its own uptake by oxidation-competent perisynaptic processes has two advantages, substrate is supplied concomitant with demand, and glutamate spares glucose for use by neurons and astrocytes. Some, but not all, perisynaptic processes of astrocytes in adult rodent brain contain mitochondria, and oxidation of only a small fraction of the neurotransmitter glutamate taken up into these structures would be sufficient to supply the ATP required for sodium extrusion and conversion of glutamate to glutamine. Glycolysis would, however, be required in perisynaptic processes lacking oxidative capacity. Three lines of evidence indicate that critical cornerstones of the astrocyte-to-neuron lactate shuttle model are not established and normal brain does not need lactate as supplemental fuel: (i) rapid onset of hemodynamic responses to activation delivers oxygen and glucose in excess of demand, (ii) total glucose utilization greatly exceeds glucose oxidation in awake rodents during activation, indicating that the lactate generated is released, not locally oxidized, and (iii) glutamate-induced glycolysis is not a robust phenotype of all astrocyte cultures. Various metabolic pathways, including glutamate oxidation and glycolysis with lactate release, contribute to cellular energy demands of excitatory neurotransmission.

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“…These alterations include biochemical defects such as impaired neurotransmitter metabolism (Gowda et al . ), loss of synaptic activity and dendrites (Gastinger et al . ; VanGuilder et al .…”

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confidence: 99%

Epigenetic control of early neurodegenerative events in diabetic retinopathy by the histone deacetylase SIRT6

Zorrilla-Zubilete

Yeste

Quintana

et al. 2017

Journal of Neurochemistry

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Diabetic retinopathy (DR) is one of the common complications associated with diabetes mellitus and the leading cause of blindness worldwide. Recent research has demonstrated that DR is not only a microvascular disease but may be a result of neurodegenerative processes. Moreover, glucose-induced neuron and glial cell damage may occur shortly after the onset of diabetes which makes the disease hard to diagnose at early stages. SIRT6, a NAD-dependent sirtuin deacylase, modulates aging, energy metabolism, and neurodegeneration. In previous studies we showed that SIRT6 deficiency causes major retinal transmission defects, changes in the expression of glycolytic genes, and elevated levels of apoptosis. Given the importance of glucose availability for retinal function and the critical role of SIRT6 in modulating glycolysis, we aimed to analyze SIRT6 participation in the molecular machinery that regulates the development of experimental DR. Using non-obese diabetic mice, we determined by western blot that 2 weeks after the onset of the disease, high glucose concentrations induced retinal increase in a neovascularization promoting factor (vascular endothelial growth factor, VEGF), and the loss of a neuroprotective factor (brain-derived neurotrophic factor, BDNF) associated with reduced levels of SIRT6 and increased acetylation levels of its substrates (H3K9 and H3K56) suggesting a deregulation of key neural factors. Noteworthy, retinas from CNS conditionally deleted SIRT6 mice showed a resemblance to diabetic retinas exhibiting lower protein levels of BDNF factor and increased protein levels of VEGF. Moreover, cultured Müller glial cells subjected to high glucose concentrations exhibited decreased levels of SIRT6 and increased levels of H3K56 acetylation. In addition, the increment of VEGF levels induced by high glucose was reverted by the over-expression of SIRT6 in this cell type. Accordingly, siRNA experiments showed that, when SIRT6 was silenced, VEGF levels increased. Our findings suggest that epigenetically regulated neurodegenerative events may occur at an early diabetic stage prior to the characteristic proliferative and vascular changes observed at a later diabetic stage.

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The influence of diabetes on glutamate metabolism in retinas

Cited by 44 publications

References 49 publications

GABA and Glutamate Uptake and Metabolism in Retinal Glial (Müller) Cells

GABA and Glutamate Uptake and Metabolism in Retinal Glial (Müller) Cells

Astrocytic energetics during excitatory neurotransmission: What are contributions of glutamate oxidation and glycolysis?

Epigenetic control of early neurodegenerative events in diabetic retinopathy by the histone deacetylase SIRT6

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