NMR-based metabolomics reveals brain region-specific metabolic alterations in streptozotocin-induced diabetic rats with cognitive dysfunction

Abstract

Diabetes mellitus (DM) can result in cognitive dysfunction, but its potential metabolic mechanisms remain unclear. In the present study, we analyzed the metabolite profiling in eight different brain regions of the normal rats and the streptozotocin (STZ)-induced diabetic rats accompanied by cognitive dysfunction using a H NMR-based metabolomic approach. A mixed linear model analysis was performed to assess the effects of DM, brain region and their interaction on metabolic changes. We found that different brain regions in rats displayed significant metabolic differences. In addition, the hippocampus was more susceptible to DM compared with other brain regions in rats. More interestingly, significant interaction effects of DM and brain region were observed on alanine, creatine/creatine-phosphate, lactate, succinate, aspartate, glutamate, glutamine, γ-aminobutyric acid, glycine, choline, N-acetylaspartate, myo-inositol and taurine. Based on metabolic pathway analysis, we speculate that cognitive dysfunction in the STZ-induced diabetic rats may be associated with brain region-specific metabolic alterations involving energy metabolism, neurotransmitters, membrane metabolism and osmoregulation.

Characteristic Metabolic Alterations Identified in Primary Neurons Under High Glucose Exposure

“…Lactate was considered a signaling molecule that coordinates astrocyte and neuron function (Chih et al, 2001 ; Medina and Tabernero, 2005 ). The present data contribute to our understanding of the effects of elevated lactate levels in hippocampal extracts that we identified previously (Zheng et al, 2017a ). We also found that acetate, which exhibits a similar transport process to lactate, was also transferred from astrocyte (Wang et al, 2018 ).…”

“…By which we found an increase in glycolytic activity, inhibition of the tricarboxylic acid cycle (TCA cycle) and dysfunction in glutamate-glutamine shuttling between neurons and astrocytes in different brain regions (Zheng et al, 2016 , 2017c ). 13 C NMR technology with [1- 13 C]-glucose and [2- 13 C]-acetate substrates also revealed impaired neuronal activity, enhanced astrocytic activity and lower levels of 13 C labeling in TCA intermediates in neurons in the diabetic rats (Wang et al, 2015 ; Zheng et al, 2017a ). These results demonstrated differences between neurons and astrocytes, especially under hyperglycemic conditions.…”

High Glucose-Induced Cardiomyocyte Death May Be Linked to Unbalanced Branched-Chain Amino Acids and Energy Metabolism

“…Nuclear magnetic resonance (NMR) spectroscopy is an attractive analytical platform for metabolomics research due to its advantages, such as simple sample preparation, fast analysis and high reproducibility. In our previous study, we have successfully applied an NMR-based metabolomic approach to elucidate metabolic mechanisms underlying diabetic complications related to kidney [ 27 ] and brain [ 28 , 29 ]. In the present study, we found that cardiomyocyte death was induced by high glucose both in vitro and in vivo studies.…”

Sex-specific metabolic alterations in the type 1 diabetic brain of mice revealed by an integrated method of metabolomics and mixed-model

“…In earlier years, brain metabolic disorders have been detected in untreated T1D patients using magnetic resonance spectroscopy [17] , [18] . For animal studies, using NMR-based metabolomics, our previous findings revealed that brain region-specific metabolic changes might be implicated in cognitive impairment in rats at the 8th week after streptozotocin (STZ) treatment [19] , 17-week-old db/db mice [20] and 10-month-old APP/PS1 transgenic AD mice [21] . These results indicate that brain metabolic disorders also play a key role in diabetic brain diseases in an advanced stage.…”