Cognitive decline in type 2 diabetic db/db mice may be associated with brain region-specific metabolic disorders

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1863; no. 1; pp. 266 - 273
• Main Authors: Zheng, Hong, Zheng, Yongquan, Zhao, Liangcai, Chen, Minjiang, Bai, Guanghui, Hu, Yongsheng, Hu, Wenyi, Yan, Zhihan, Gao, Hongchang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2017
• Subjects: Animals; Brain; Brain - metabolism; Brain - pathology; Brain Diseases, Metabolic - complications; Brain Diseases, Metabolic - metabolism; Brain Diseases, Metabolic - pathology; Cognition; Cognitive Dysfunction - complications; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Male; Metabolome; Metabolomics; Mice, Inbred C57BL; Mixed model; Region-specific; Brain; Metabolomics; Gln; Tau; Cognition; Cho; Ino; ADP; Glu; Cre/PCre; Gly; wt; Asp; Suc; FWT; Myo; AMP; T2D; IMP; Lac; NAA; NAD; Region-specific; Mixed model; Ala; GABA; Diabetes
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2016.11.003

Type 2 diabetes has been associated with cognitive decline, but its metabolic mechanism remains unclear. In the present study, we attempted to investigate brain region-specific metabolic changes in db/db mice with cognitive decline and explore the potential metabolic mechanism linking type 2 diabetes and cognitive decline. We analyzed the metabolic changes in seven brain regions of two types of mice (wild-type mice and db/db mice with cognitive decline) using a 1H NMR-based metabolomic approach. Then, a mixed-model analysis was used to evaluate the effects of mice type, brain region, and their interaction on metabolic changes. Compared with the wild-type mice, the db/db mice with cognitive decline had significant increases in lactate, glutamine (Gln) and taurine as well as significant decreases in alanine, aspartate, choline, succinate, γ-Aminobutyric acid (GABA), glutamate (Glu), glycine, N-acetylaspartate, inosine monophosphate, adenosine monophosphate, adenosine diphosphate, and nicotinamide adenine dinucleotide. Brain region-specific metabolic differences were also observed between these two mouse types. In addition, we found significant interaction effects of mice type and brain region on creatine/phosphocreatine, lactate, aspartate, GABA, N-acetylaspartate and taurine. Based on metabolic pathway analysis, the present study suggests that cognitive decline in db/db mice might be linked to a series of brain region-specific metabolic changes, involving an increase in anaerobic glycolysis, a decrease in tricarboxylic acid (TCA) and Gln-Glu/GABA cycles as well as a disturbance in lactate-alanine shuttle and membrane metabolism. •An increased brain anaerobic glycolysis is associated with cognitive decline in T2D.•TCA and Gln-Glu/GABA cycles are inhibited in T2D mice with cognitive decline.•A disturbance in lactate-alanine shuttle is responsible for cognitive decline in T2D.•Brain region-specific metabolic disorders exist in T2D mice with cognitive decline.