Cognitive decline in type 2 diabetic db/db mice may be associated with brain region-specific metabolic disorders.
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 a1H 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.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Hong
H
Zheng
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Yongquan
Y
Zheng
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Liangcai
L
Zhao
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Minjiang
M
Chen
Radiology Department of the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325027, China.
Guanghui
G
Bai
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Yongsheng
Y
Hu
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Wenyi
W
Hu
Radiology Department of the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: zhihanyan@hotmail.com.
Zhihan
Z
Yan
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: gaohc27@wmu.edu.cn.
Hongchang
H
Gao
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001928:Brain Diseases, Metabolic / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D060825:Cognitive Dysfunction / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D008810:Mice, Inbred C57BL
Brain; Cognition; Diabetes; Metabolomics; Mixed model; Region-specific