Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?

Abstract

Type 2 diabetes (T2D) is a metabolic disease with impact on brain function through mechanisms that include glucose toxicity, vascular damage and blood-brain barrier (BBB) impairments, mitochondrial dysfunction, oxidative stress, brain insulin resistance, synaptic failure, neuroinflammation, and gliosis. Rodent models have been developed for investigating T2D, and have contributed to our understanding of mechanisms involved in T2D-induced brain dysfunction. Namely, mice or rats exposed to diabetogenic diets that are rich in fat and/or sugar have been widely used since they develop memory impairment, especially in tasks that depend on hippocampal processing. Here we summarize main findings on brain energy metabolism alterations underlying dysfunction of neuronal and glial cells promoted by diet-induced metabolic syndrome that progresses to a T2D phenotype.

Keywords: brain metabolism; diet-induced obesity; glucose; high-fat; insulin resistance; sucrose.

FIGURE 1

Possible mechanisms by which insulin might regulate fueling of neurons to sustain adequate brain function.

FIGURE 2

Brain energy metabolism alterations in insulin resistant GK rats (A). Down and up arrows indicate decreased and increased rate of pathways in insulin-resistant GK rats, respectively (Girault et al., 2019; Soares et al., 2019). These alterations are supported by findings of increased astroglial markers (GFAP and vimentin) and reduced levels of synaptic proteins in the hippocampus of GK rats, relative to control Wistar rats (B). Mice exposed to 60% HFD for 6 months also show synaptic degeneration in the hippocampus, as suggested by reduced levels of synaptic proteins, versus 10% fat-fed control mice (C). MAP2 is a neuronal marker, PSD95 and gephyrin are post-synaptic density markers, SNAP25, synaptophysin, and syntaxin-1/4 are located in the presynaptic button, and vGluT1/2 and vGAT are transporters in synaptic vesicles. Data in graphs of B and C are from Duarte et al. (2019) and Lizarbe et al. (2019a), respectively, and are shown as% of controls (mean ± SD). T_glc, glucose transport; CMR_glc, cerebral metabolic rate of glucose; PC, pyruvate carboxylase; TCA, tricarboxylic acid; GLUergic NT, glutamatergic neurotransmission.