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

Background: Diabetes-associated cognition decline is one of central nervous system complications in diabetic mellitus, while its pathogenic mechanism remains unclear. In this study, H-1 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.-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.