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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

PLS-DA score plot (a) and validation plot (b) based on the 1H NMR spectra of hippocampus samples obtained from db/db mice (red circle, n = 7) and WT mice (■, n = 11). The coefficient-coded loading plot (c) corresponding to PLS-DA revealing the metabolites with large intensities responsible for the discrimination of the corresponding score plot
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Fig4: PLS-DA score plot (a) and validation plot (b) based on the 1H NMR spectra of hippocampus samples obtained from db/db mice (red circle, n = 7) and WT mice (■, n = 11). The coefficient-coded loading plot (c) corresponding to PLS-DA revealing the metabolites with large intensities responsible for the discrimination of the corresponding score plot

Mentions: Representative 1H NMR-based metabolic profiling of the hippocampus extracts obtained from 17-wk db/db and WT mice was shown in Fig. 3. The spectral resonances of the metabolites assigned based on previous studies [19–21] and the 600 MHz library of the Chenomx NMR suite 7.0 (Chenomx Inc., Edmonton, Canada) were shown in Fig. 3b and Additional file 1: Table S1. Furthermore, projection to latent structure discriminant analysis (PLS-DA) was implemented to investigate the metabolic difference between db/db and WT mice (Fig. 4). As shown in Fig. 4a, clear discrimination was observed between them (R2X = 0.533, R2Y = 0.841, Q2Y = 0.585), which was validated by the permutation test (Fig. 4b). Figure 4c shows the corresponding loading plot with color-coded correlation coefficients (/r/) of PLS-DA, indicating metabolites that contributed to the separation between two groups. The results showed increased levels of lactate, glutamine and taurine, and decreased levels of glutamate, N-acetyl aspartate (NAA), citrate, glycine, choline, aspartate and succinate in hippocampus of db/db mice with DACD as compared with WT mice.Fig. 3


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)

PLS-DA score plot (a) and validation plot (b) based on the 1H NMR spectra of hippocampus samples obtained from db/db mice (red circle, n = 7) and WT mice (■, n = 11). The coefficient-coded loading plot (c) corresponding to PLS-DA revealing the metabolites with large intensities responsible for the discrimination of the corresponding score plot
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: PLS-DA score plot (a) and validation plot (b) based on the 1H NMR spectra of hippocampus samples obtained from db/db mice (red circle, n = 7) and WT mice (■, n = 11). The coefficient-coded loading plot (c) corresponding to PLS-DA revealing the metabolites with large intensities responsible for the discrimination of the corresponding score plot
Mentions: Representative 1H NMR-based metabolic profiling of the hippocampus extracts obtained from 17-wk db/db and WT mice was shown in Fig. 3. The spectral resonances of the metabolites assigned based on previous studies [19–21] and the 600 MHz library of the Chenomx NMR suite 7.0 (Chenomx Inc., Edmonton, Canada) were shown in Fig. 3b and Additional file 1: Table S1. Furthermore, projection to latent structure discriminant analysis (PLS-DA) was implemented to investigate the metabolic difference between db/db and WT mice (Fig. 4). As shown in Fig. 4a, clear discrimination was observed between them (R2X = 0.533, R2Y = 0.841, Q2Y = 0.585), which was validated by the permutation test (Fig. 4b). Figure 4c shows the corresponding loading plot with color-coded correlation coefficients (/r/) of PLS-DA, indicating metabolites that contributed to the separation between two groups. The results showed increased levels of lactate, glutamine and taurine, and decreased levels of glutamate, N-acetyl aspartate (NAA), citrate, glycine, choline, aspartate and succinate in hippocampus of db/db mice with DACD as compared with WT mice.Fig. 3

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