Abstract
BackgroundDiabetes-associated cognition decline is one of central nervous system complications in diabetic mellitus, while its pathogenic mechanism remains unclear. In this study, 1H 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.ResultsMetabonomics 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0223-5) contains supplementary material, which is available to authorized users.
Highlights
Diabetes-associated cognition decline is one of central nervous system complications in diabetic mellitus, while its pathogenic mechanism remains unclear
By using ex vivo 13C Nuclear magnetic resonance (NMR) approach with glucose and acetate as substrate, we found enhanced pyruvate recycling pathway in earlier stage of type 1 diabetic rats induced by streptozotocin, and disordered metabolic trafficking between the astrocyte and neuron in later stage, which may be a regulated mechanism against metabolic impairments [17]
It can be seen that number of TUNELpositive cells were significantly increased in hippocampus of db/db mice with Diabetes-associated cognitive decline (DACD) compared to WT mice (Fig. 2a-c, P < 0.01), which suggests that there was more neuronal apoptosis in hippocampus of db/ db mice
Summary
Diabetes-associated cognition decline is one of central nervous system complications in diabetic mellitus, while its pathogenic mechanism remains unclear. 1H 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. Diabetes-associated cognitive decline (DACD) as a central nervous systems complication in type 2 diabetes has already been attracted considerable attention, for its negative effect on the brain and its association with other neurodegenerative diseases [3,4,5]. Hyperglycemia can affect morphology of the neuron in the hippocampus and in turn impair learning and memory [8, 9]. Hippocampal neurons have been shown to undergo apoptotic cell death under
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