Glucose transport in brain – effect of inflammation

Abstract

Glucose is transported across the cell membrane by specific saturable transport system, which includes two types of glucose transporters: 1) sodium dependent glucose transporters (SGLTs) which transport glucose against its concentration gradient and 2) sodium independent glucose transporters (GLUTs), which transport glucose by facilitative diffusion in its concentration gradient. In the brain, both types of transporters are present with different function, affinity, capacity, and tissue distribution. GLUT1 occurs in brain in two isoforms. The more glycosylated GLUT1 is produced in brain microvasculature and ensures glucose transport across the blood brain barrier (BBB). The less glycosylated form is localized in astrocytic end-feet and cell bodies and is not present in axons, neuronal synapses or microglia. Glucose transported to astrocytes by GLUT1 is metabolized to lactate serving to neurons as energy source. Proinflammatory cytokine interleukin (IL)-1β upregulates GLUT1 in endothelial cells and astrocytes, whereas it induces neuronal death in neuronal cell culture. GLUT2 is present in hypothalamic neurons and serves as a glucose sensor in regulation of food intake. In neurons of the hippocampus, GLUT2 is supposed to regulate synaptic activity and neurotransmitter release. GLUT3 is the most abundant glucose transporter in the brain having five times higher transport capacity than GLUT1. It is present in neuropil, mostly in axons and dendrites. Its density and distribution correlate well with the local cerebral glucose demands. GLUT5 is predominantly fructose transporter. In brain, GLUT5 is the only hexose transporter in microglia, whose regulation is not yet clear. It is not present in neurons. GLUT4 and GLUT8 are insulin-regulated glucose transporters in neuronal cell bodies in the cortex and cerebellum, but mainly in the hippocampus and amygdala, where they maintain hippocampus-dependent cognitive functions. Insulin translocates GLUT4 from cytosol to plasma membrane to transport glucose into cells, and GLUT8 from cytosol to rough endoplasmic reticulum to recover redundant glucose to cytosol after protein glycosylation. In autoimmune diseases, the enhanced glucose uptake was found in inflamed peripheral tissue, mainly due to proliferating fibroblasts and activated macrophages. In our experimental model of rheumatoid arthritis (adjuvant arthritis), enhanced 2-deoxy-2[F-18]fluoro-D-glucose was found in the hippocampus and amygdala two days after the induction of the disease which, similarly as in the peripheral joints, can be ascribed to the activated macrophages. The knowledge on the glucose transport and the role of glucose transporters in the brain during systemic autoimmune inflammation is still incomplete and needs further investigations.

Cognitive impairment and gene expression alterations in a rodent model of binge eating disorder

“…Supporting these findings, high energy diets have been previously shown to influence GLUT2 [83] as well as IR expression in the brain [84]. A positive effect of GLUT2 on hippocampal synaptic activity, neurotransmitter release, and cognition has been previously reported [85, 86], while others have suggested involvement of insulin receptors in hippocampal dependent spatial learning and memory [87–89] as well as recognition memory [90–92]. In another series of studies, intracerebroventricular injection of streptozotocin, a drug specific to GLUT2 dependent transport [93], was shown to decrease IR expression only in the CA3 region of the rat’s hippocampus [94], and was found to be associated with memory impairments [95].…”

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

“…The insulin-independent glucose transporter GLUT3 is the major glucose transporter in neurons and is present in very few other cell types in the body. The density and distribution of GLUT3 in axons, dendrites and neuronal soma correlates with local cerebral energy demands 74 . Insulin is not required for GLUT3-mediated glucose transport; instead, NMDA receptor-mediated depolarization stimulates consumption of glucose, which prompts glucose uptake and utilization via GLUT3 73,75 .…”

Anoxia-induced changes in optimal substrate for peripheral nerve

“…Glucose transporters GLUT1 and GLUT3 are responsible for glucose transport into the Schwann cell while GLUT3 is the primary transporter in axons (Magnani et al, 1996). Fructose uses a different transporter GLUT5 at least in microglia (Jurcovicova, 2014). Increased expression of GLUT5 as has been demonstrated with GLUT1 and GLUT3 due to anoxia (Zovein et al, 2004;Li et al, 2013) would increase fructose flux into the cell and contribute to the observed results.…”