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.

Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview

“…Taking this into account, the most common experimental models to study the consequences of obesity are rodents fed high-fat diets (HFDs; Buettner et al, 2006 , 2007 ). Nowadays, rodents exposed to HFDs are also widely used to evaluate the impact of obesity on the brain ( Arnold et al, 2014 ; Underwood and Thompson, 2016 ; Nakandakari et al, 2019 ; Garcia-Serrano and Duarte, 2020 ).…”

“…Despite astrogliosis ( Duarte et al, 2019 ), neuroinflammatory microglia have not been yet reported in non-obese T2D models. Also, BBB leakage has not been confirmed in insulin resistance models, even though there have been reports of endothelial dysfunction (which impacts cerebral perfusion; see the discussion in Garcia-Serrano and Duarte, 2020 ).…”

Diabetes is associated with familial idiopathic normal pressure hydrocephalus: a case–control comparison with family members

“…It has been suggested that in iNPH the glymphatic system is possibly impaired through neuroinflammation, reactive astrogliosis, depolarization and reduced density of aquaporin-4 (AQP4) and sleep disturbances, which could reduce the normal clearance of CSF [ 43 – 45 ]. Interestingly in rat models, diabetes has been found to cause glymphatic system dysfunction, reduction in AQP4 density, neuroinflammation, microvascular damage, blood–brain barrier damage and cognitive decline that could be associated with glymphatic system dysfunction [ 46 – 49 ]. It seems that diabetes could also cause astrogliosis and dysregulated metabolism in astrocytes in mouse and rat models [ 49 ].…”

“…Interestingly in rat models, diabetes has been found to cause glymphatic system dysfunction, reduction in AQP4 density, neuroinflammation, microvascular damage, blood–brain barrier damage and cognitive decline that could be associated with glymphatic system dysfunction [ 46 – 49 ]. It seems that diabetes could also cause astrogliosis and dysregulated metabolism in astrocytes in mouse and rat models [ 49 ]. By affecting the astrocytes diabetes has also been found to reduce the glutamate uptake in brain in rat models [ 50 , 51 ].…”

Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease

“…In the polyol pathway, glucose is converted to sorbitol by aldose reductase and sorbitol is oxidized to fructose by SORD. Under hyperglycemic conditions, accumulations of sorbitol and fructose due to increased polyol pathway flux may contribute to tissue damage [ 111 , 112 ]. In 2020, Cortese et al reported that biallelic mutations in SORD caused inherited neuropathies including CMT and distal hereditary motor neuropathy (MIM #618912) [ 113 ].…”