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

Abstract

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 H 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.

Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model—Part I: Astrocyte

“…Since capillaries comprise ≥60% of the cerebral microvasculature [31], our initial aim was to characterize the capillary NVUs in obese, insulin-resistant, type 2 diabetic female db/db DBC mouse models, and our observational findings demonstrated abnormal, multi-cellular maladaptive ultrastructural remodeling changes in the NVUs of the mid cortical gray matter regions of the brain. These ultrastructure remodeling changes were not previously described in db/db models to the best of our knowledge; however, they may contribute to impaired cognition in the DBC as described in various papers regarding behavioral testing [34][35][36][37][38][39]. These cognitive impairments include behavioral testing abnormalities of the db/db models (DBC) in the Morris water maze tests, forced swim test, tail suspension test, light/dark box test, olfactory testing, Y-maze, and open-field tests to evaluate learning and memory plus anxiety and/or depression-associated cognitive impairment/deficits.…”

S100A2 promotes glycolysis and proliferation via GLUT1 regulation in colorectal cancer

“…All NMR spectra were preprocessed using Topspin software (v2.1 pl4, Bruker Biospin, Germany), referenced to the TSP peak (δ 0.0). 15 The spectral region from 0.5 to 10.0 ppm excluding residual water signal (4.8-5.1 ppm) was subdivided with a size of 0.01 ppm for multivariate pattern recognition analysis and 0.0015 ppm for quantitative using MATLAB software (R2012a, The Mathworks Inc, Natick, MA, USA). 16 Subsequently, the level of cellular metabolites was calculated according to its peak area by reference to the internal TSP concentration and expressed as relative units (r.u.…”

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

“…High levels of HbA1c were found to be associated with high white matter hyperintensity, which suggest a possible role of HbA1c behind the decline in memory in elderly patients with diabetes (Tamura et al, 2017). This was further supported by the data which revealed memory decline when the HbA1c levels were higher than normal (Marden, Mayeda, Tchetgen, Kawachi, & Glymour, 2017 Apart from the role of insulin, HbA1c and GSK-3β, several metabolic changes like disturbed alanine, lactate, glutamine, glutamate, and glycine levels were suggested as a link to cognitive dysfunction in diabetic mice brain (Zheng et al, 2017). Also, islet amyloid polypeptide (IAPP) was found to interact with Aβ and accelerate its pathology.…”

“…Apart from the role of insulin, HbA1c and GSK‐3β, several metabolic changes like disturbed alanine, lactate, glutamine, glutamate, and glycine levels were suggested as a link to cognitive dysfunction in diabetic mice brain (Zheng et al, ). Also, islet amyloid polypeptide (IAPP) was found to interact with Aβ and accelerate its pathology.…”