Alteration of Interaction Between Astrocytes and Neurons in Different Stages of Diabetes: a Nuclear Magnetic Resonance Study Using [1-13C]Glucose and [2-13C]Acetate

Abstract

Increasing evidence has shown that the brain is a site of diabetic end-organ damage. This study investigates cerebral metabolism and the interactions between astrocytes and neurons at different stages of diabetes to identify the potential pathogenesis of diabetic encephalopathy. [1-13 C]glucose or [2-13 C]acetate is infused into 1-and 15-week diabetic rats, the brain extracts of which are analyzed by using 1 H and 13 C magnetic resonance spectroscopy. The 13 C-labeling pattern and enrichment of cerebral metabolites are also investigated. The increased 13 C incorporation in the glutamine, glutamate, and γ-aminobutyric acid carbons from [2-13 C]acetate suggests that the astrocytic mitochondrial metabolism is enhanced in 1-week diabetic rats. By contrast, the decreased labeling from [1-13 C]glucose reflected that the neuronal mitochondrial metabolism is impaired. As diabetes developed to 15 weeks, glutamine and glutamate concentrations significantly decreased. The increased labeling of glutamine C4 but unchanged labeling of glutamate C4 from [2-13 C]acetate suggests decreased astrocyte supply to the neurons. In addition, the enhanced pyruvate recycling pathway manifested by the increased lactate C2 enrichment in 1-week diabetic rats is weakened in 15-week diabetic rats. Our study demonstrates the overall metabolism disturbances, changes in specific metabolic pathways, and interaction between astrocytes and neurons during the onset and development of diabetes. These results contribute to the mechanistic understanding of diabetes pathogenesis and evolution.

Region-Specific Cerebral Metabolic Alterations in Streptozotocin-Induced Type 1 Diabetic Rats: An in vivo Proton Magnetic Resonance Spectroscopy Study

“…Early Metabolic Alterations at 4 Days Although there are a few previous in vivo 1 H-MRS studies that have investigated cerebral metabolic abnormalities in animal models of STZ-induced T1DM, [8][9][10]12 few of them measured metabolic changes in brain regions other than the hippocampus, nor at the time points earlier than 2 weeks after induction. In this study, we found that, under the hyperglycemia state, the STZtreated animals had significantly reduced tNAA/NAA levels in the striatum and hippocampus already at 4 days after induction.…”

“…While Wang et al 9 found NAA and tNAA levels unchanged in a voxel containing hippocampus and parts of cortex, the observations in this study are consistent with the results of a previous ex vivo 1 H-MRS study showing that the average NAA level across the whole brain is significantly reduced in the STZ-treated rats at 7 days after induction. 12 NAA constitutes~3-4% of total brain osmolarity, and may serve osmoregulatory roles under certain circumstances. 13 However, it is unlikely that the early reduction of NAA/tNAA levels is an osmoregulatory response of the brain to hyperglycemia, given that such metabolic changes persisted after insulin injection.…”

Metabolomic Analysis Identifies Lactate as an Important Pathogenic Factor in Diabetes-associated Cognitive Decline Rats

“…Control rats were injected with the same volume of vehicle (citrate buffer). Two days after STZ administration, blood glucose concentrations were measured and the rats that had glucose concentrations higher than 16.70 mmol/l were defined as diabetic (21). Diabetic rats were analyzed two weeks, eight weeks, 12 weeks, and 15 weeks after STZ administration, while age-matched rats without STZ administration were used as control rats.…”

“…Furthermore, by employing 13 C NMR with labeled glucose and acetate as substrates, we observed an altered rate of particular metabolic pathways (i.e. increased glycolysis) in the diabetic animals (20,21). By direct analysis of the metabolic features of purified astrocytes cultured in a high-glucose environment, time-dependent lactate production and the utilization of specific amino acids were identified (22,23).…”

Analysis of neuron–astrocyte metabolic cooperation in the brain of db/db mice with cognitive decline using 13C NMR spectroscopy

“…21 For instance, [2-13 C]-acetate infusion in 15-week-old rats with T1D resulted in increased labeling of Gln C4 but unchanged Glu C4, which may be attributed to a decreased Gln transfer from astrocytes to neurons. 21 However, in the present study, the 13 C-enrichments of the C2, C3, and C4 of Gln and the C2 and C3 of Glu were decreased in db/db mice with cognitive decline after [2-13 C]-acetate infusion, which may be due to an inhibition of astrocytic TCA cycle. On the contrary, increased enrichments of the C2 and C3 of Suc, the C2, C3, and C4 of Gln, and the C2, C3, and C4 of Glu after [3][4][5][6][7][8][9][10][11][12][13] C]-lactate infusion may indicate activated neuronal activity in db/db mice with cognitive decline, relative to WT mice.…”