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Metabonomic profiles delineate potential role of glutamate-glutamine cycle in db/db mice with diabetes-associated cognitive decline.

Zheng Y, Yang Y, Dong B, Zheng H, Lin X, Du Y, Li X, Zhao L, Gao H - Mol Brain (2016)

Bottom Line: Diabetes-associated cognition decline is one of central nervous system complications in diabetic mellitus, while its pathogenic mechanism remains unclear.Moreover, an increase in glutamine level and a decrease in glutamate and γ-aminobutyric acid levels were observed in db/db mice.Our results suggest that the development of diabetes-associated cognition decline in db/db mice is most likely implicated in a reduction in energy metabolism and a disturbance of glutamate-glutamine shuttling between neurons and astrocytes in hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Radiology Department of the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.

ABSTRACT

Background: Diabetes-associated cognition decline is one of central nervous system complications in diabetic mellitus, while its pathogenic mechanism remains unclear. In this study, (1)H nuclear magnetic resonance-based metabonomics and immunohistochemistry was used to explore key metabolic alterations in hippocampus of type 2 diabetic db/db mice with cognition decline in order to advance understanding of mechanisms underlying the pathogenesis of the disease.

Results: Metabonomics reveals that lactate level was significantly increased in hippocampus of db/db mice with cognition decline compared with age-matched wild-type mice. Several tricarboxylic acid cycle intermediates including succinate and citrate were reduced in hippocampus of db/db mice with cognition decline. Moreover, an increase in glutamine level and a decrease in glutamate and γ-aminobutyric acid levels were observed in db/db mice. Results from immunohistochemistry analysis show that glutamine synthetase was increased and glutaminase and glutamate decarboxylase were decreased in db/db mice.

Conclusions: Our results suggest that the development of diabetes-associated cognition decline in db/db mice is most likely implicated in a reduction in energy metabolism and a disturbance of glutamate-glutamine shuttling between neurons and astrocytes in hippocampus.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemistry of glutamic acid decarboxylase (GAD), glutaminase (GLS) and glutamine synthetase (GS) in the hippocampus of WT mice and db/db mice with cognitive decline
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Fig6: Immunohistochemistry of glutamic acid decarboxylase (GAD), glutaminase (GLS) and glutamine synthetase (GS) in the hippocampus of WT mice and db/db mice with cognitive decline

Mentions: To further explore the reasons that glutamate-glutamine cycle influenced in db/db mice with DACD, we used immunohistochemistry and immunofluorescence to determine the alterations in some key enzymes involved in this cycle, such as glutamine synthetase (GS), glutaminase (GLS) and glutamate decarboxylase (GAD). GS, an ubiquitous enzyme present in the astroglial cytoplasm and involved in formation of glutamine from glutamate [22], was shown to be raised in hippocampus of db/db mice with DACD, which indicates an enhanced reaction from glutamate to glutamine (Fig. 6). Our data also show that immnuohistochemical labeling of GAD neurons [23] with a monoclonal GAD67 antibody revealed a decreased density of stained neurons, indicating that the pathway from glutamate to GABA was inhibited. In addition, a similar result was also shown in labeling with the anti-GLS antibody [24], which was consistent with the reduced trend from glutamine into glutamate. Figure 7 illustrates the metabolic changes in hippocampus of db/db mice with DACD relative to WT mice.Fig. 6


Metabonomic profiles delineate potential role of glutamate-glutamine cycle in db/db mice with diabetes-associated cognitive decline.

Zheng Y, Yang Y, Dong B, Zheng H, Lin X, Du Y, Li X, Zhao L, Gao H - Mol Brain (2016)

Immunohistochemistry of glutamic acid decarboxylase (GAD), glutaminase (GLS) and glutamine synthetase (GS) in the hippocampus of WT mice and db/db mice with cognitive decline
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835835&req=5

Fig6: Immunohistochemistry of glutamic acid decarboxylase (GAD), glutaminase (GLS) and glutamine synthetase (GS) in the hippocampus of WT mice and db/db mice with cognitive decline
Mentions: To further explore the reasons that glutamate-glutamine cycle influenced in db/db mice with DACD, we used immunohistochemistry and immunofluorescence to determine the alterations in some key enzymes involved in this cycle, such as glutamine synthetase (GS), glutaminase (GLS) and glutamate decarboxylase (GAD). GS, an ubiquitous enzyme present in the astroglial cytoplasm and involved in formation of glutamine from glutamate [22], was shown to be raised in hippocampus of db/db mice with DACD, which indicates an enhanced reaction from glutamate to glutamine (Fig. 6). Our data also show that immnuohistochemical labeling of GAD neurons [23] with a monoclonal GAD67 antibody revealed a decreased density of stained neurons, indicating that the pathway from glutamate to GABA was inhibited. In addition, a similar result was also shown in labeling with the anti-GLS antibody [24], which was consistent with the reduced trend from glutamine into glutamate. Figure 7 illustrates the metabolic changes in hippocampus of db/db mice with DACD relative to WT mice.Fig. 6

Bottom Line: Diabetes-associated cognition decline is one of central nervous system complications in diabetic mellitus, while its pathogenic mechanism remains unclear.Moreover, an increase in glutamine level and a decrease in glutamate and γ-aminobutyric acid levels were observed in db/db mice.Our results suggest that the development of diabetes-associated cognition decline in db/db mice is most likely implicated in a reduction in energy metabolism and a disturbance of glutamate-glutamine shuttling between neurons and astrocytes in hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Radiology Department of the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.

ABSTRACT

Background: Diabetes-associated cognition decline is one of central nervous system complications in diabetic mellitus, while its pathogenic mechanism remains unclear. In this study, (1)H nuclear magnetic resonance-based metabonomics and immunohistochemistry was used to explore key metabolic alterations in hippocampus of type 2 diabetic db/db mice with cognition decline in order to advance understanding of mechanisms underlying the pathogenesis of the disease.

Results: Metabonomics reveals that lactate level was significantly increased in hippocampus of db/db mice with cognition decline compared with age-matched wild-type mice. Several tricarboxylic acid cycle intermediates including succinate and citrate were reduced in hippocampus of db/db mice with cognition decline. Moreover, an increase in glutamine level and a decrease in glutamate and γ-aminobutyric acid levels were observed in db/db mice. Results from immunohistochemistry analysis show that glutamine synthetase was increased and glutaminase and glutamate decarboxylase were decreased in db/db mice.

Conclusions: Our results suggest that the development of diabetes-associated cognition decline in db/db mice is most likely implicated in a reduction in energy metabolism and a disturbance of glutamate-glutamine shuttling between neurons and astrocytes in hippocampus.

No MeSH data available.


Related in: MedlinePlus