Analysis of Metabolic Alterations Related to Pathogenic Process of Diabetic Encephalopathy Rats

Abstract

Diabetic encephalopathy (DE) is a diabetic complication characterized by alterations in cognitive function and nervous system structure. The pathogenic transition from hyperglycemia to DE is a long-term process accompanied by multiple metabolic disorders. Exploring time-dependent metabolic changes in hippocampus will facilitate our understanding of the pathogenesis of DE. In the present study, we first performed behavioral and histopathological experiments to confirm the appearance of DE in rats with streptozotocin-induced diabetes. We then utilized nuclear magnetic resonance-based metabonomics to analyze metabolic disorders in the hippocampus at different stages of DE. After 1 week, we observed no cognitive or structural impairments in diabetic rats, although some metabolic changes were observed in local hippocampal extracts. At 5 weeks, while cognitive function was still normal, we then examined initial levels of neuronal apoptosis. The characteristic metabolic changes of this stage included elevated levels of energy metabolites (i.e., ATP, ADP, AMP, and creatine phosphate/creatine). At 9 weeks, significant cognitive decline and histopathological brain damage were observed, in conjunction with reduced levels of some amino acids. Thus, this stage was classified as the DE period. Our findings indicated that the pathogenesis of DE is associated with time-dependent alterations in metabolic features in hippocampal regions, such as glycolysis, osmoregulation, energy metabolism, choline metabolism, branched-chain amino acid metabolism, and the glutamate–glutamine cycle. Furthermore, we observed alterations in levels of lactate and its receptor in hippocampal cells, which may be involved in the pathogenesis of DE.

Conditional Knockout of Pdha1 in Mouse Hippocampus Impairs Cognitive Function: The Possible Involvement of Lactate

“…Our study found that Pdha1 knockout inhibited the cAMP/PKA/CREB signaling pathway, which may be mediated by lactate. Similar to our results, some studies have shown that lactate inhibits the HCAR1/PKA/CREB pathway in the brain of diabetes-associated cognitive decline rats (Dong et al, 2018;Zhao et al, 2018).…”

Green tea protects against hippocampal neuronal apoptosis in diabetic encephalopathy by inhibiting JNK/MLCK signaling

“…Dietary factors might serve a role in prevention of cognitive dysfunction and among these factors, beverages are considered useful because their intake does not substantially affect other dietary habits and is more acceptable (1). Green tea is one of the most common beverages consumed worldwide and serves a role in neurodegenerative diseases and improving cognitive function (21).…”

“…Diabetic encephalopathy (DE) is a serious chronic complication of diabetes (1,2) and its clinical manifestations include loss of learning and memory abilities, and cognitive dysfunction (3). At present, the pathogenesis of DE is unclear, but substantial data have shown that neuronal apoptosis is one of the key pathogenic mechanisms of DE (2,4).…”

Effects of Fibroblast Growth Factor 21 on Lactate Uptake and Usage in Mice with Diabetes-Associated Cognitive Decline

“…We have previously examined disturbances in the glutamate-glutamine cycle in the hippocampal regions of db/db mice by using NMR-based metabonomics [28]. Further, we integrated molecular biology approaches to identify the glycolytic pathway and lactate levels, which were closely related to the pathogenesis of DACD [29][30][31][32]. By applying the same strategies, we also analyzed the basic FGF-remodeled metabolic phenotypes in the db/db mice, which involved reductions in oxidative stress and apoptosis mediated by reactive oxygen species signaling [33].…”