Deficiency of GluT1 leads to neurological problems while excess is involved in cancers

By Jamshed Arslan, Pharm. D., PhD.

What Are GluTs?

Mammalian cell metabolism is incomplete without glucose. Glucose is a monosaccharide that is transported to the cells through facilitative diffusion, a process governed by membrane proteins like glucose transporters (GluTs).¹ GluTs belong to a large family of membrane transporters, called Major Facilitator Superfamily (MFS), found in virtually all forms of life.^1,2 Specifically, GluTs belong to the subfamily Sugar Porters whose members take part in the uptake of monosaccharides and disaccharides.¹ Human glucose transporter GluT1 shuttles glucose to the organs with limited access to small molecules like glucose via passive diffusion.³

GluT1 in health and disease

GluT1 mediates glucose uptake into red blood cells (RBCs) and endothelial cells of the blood-brain barrier (BBB).¹ Although GluT1 is famous for glucose transport, it can also transport other small molecules like galactose, glucosamine, mannose and dehydro-L-ascorbic acid.^1,4 Both higher and lower expressions of GluT1 are dangerous: many tumors overexpress GluT1 whereas GluT1 deficiency has been reported in several diseases of the central nervous system like psychomotor retardation and epilepsy.^3,5

More than 250 cases of GluT1-deficiency syndrome (GDS) have been reported since the year 1991 when the GDS was first described.³ GDS occurs as a result of mutations in SLC2A1    gene that exhibits autosomal dominant inheritance.⁵ The lack of glucose transport in GDS, evidenced partly by glucose levels below 40 mg/dl in cerebrospinal fluid, is typically treated with ketogenic (high-fat) diet. Ketone bodies produced as a product of this diet can cross BBB to serve as an alternative fuel for the brain.^3,5

Highlights from current research on GluT1:

GluT1 is an intensively studied membrane transport protein. Its role in various cancers has been the focus of many research groups around the world.

• GluT1 as a drug target in glioblastoma multiforme: GluT1 and one of its binding partners, Tubulin 4, have been discovered as druggable targets in this deadliest brain tumor.⁶ Using human glioblastoma patient samples, the researchers in US and Canada found that GluT1 overexpression is linked to poor prognosis and inhibiting GluT1/Tubulin 4 significantly reduces cancer proliferation.⁶
• miRNA‑10a promotes oral cancer by upregulating GluT1: Scientists in China found that miRNA‑10a and GluT1 are overexpressed in oral squamous cell carcinoma (OSCC) patient samples relative to the adjacent healthy tissues.⁷ By knocking down GluT1 in OSCC cells, they showed that miRNA‑10a-mediated cell proliferation requires GluT1.⁷
• Overexpression of ChREBP with GluT1 is associated with liver cancer: A team of investigators in China and Netherlands studied the expression patterns of carbohydrate response element binding protein (ChREBP) and various GluTs in multiple stages of human hepatocellular carcinoma.⁸ They found that overexpression of ChREBP and GluT1, but a reduced expression of GluT2, was positively correlated with malignancy.⁸

Note:
Chen et al. (2019)   used Total Protein Extraction Kit (NBP2-37853)
Guda et al. (2019)   used MTT Reagent    and Human Pluripotent Stem Cell Antibody Array