Glucose Uptake

Glucose functions diversely within the cellular microenvironment. It is a primary energy source for many cells, is an important substrate for numerous biochemical reactions, and can play dynamic roles in signaling . A ready supply of glucose is essential for tissues with a high metabolic rate, such as brain neurons and red blood cells. For some cells glucose uptake may be facultative where other metabolic fuels, such as fatty acids, supply the bulk of local energy requirements. The facilitation of glucose, done by glucose transporters, is a highly regulated process that varies considerably from one cell type to another.

Mammalian glucose transporters fall in two main categories; sodium-glucose linked transporters (SGLTs) and facilitated diffusion glucose transporters (GLUT). Though most cell surfaces contain at least one type of transporter, these transporters can differ drastically in terms of substrate specificity, distribution, and regulatory mechanisms. Due to the essential role they play in glucose uptake as well as their distribution amongst almost many types of cells, glucose transporters may hold great potential as therapeutic targets for several diseases.

Glucose Transporters

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Facilitated Glucose Transporters

GLUTs are ubiquitously distributed through tissues and primarily function to catalyze the facilitated diffusion of glucose through its concentration gradient. By using this gradient across the cell plasma membrane, GLUTs effectively equilibrate glucose levels within and outside of cellular compartments.

Knowledge of GLUTs are still expanding, though there currently exist 14 isoforms that each fall into one of three classes based on sequence homology: class I includes GLUT 1-4 and 14; class II includes GLUT 5, 7, 9, and 11; and class III includes GLUT 6, 8, 10, 12, and HMIT. Though the physiological roles of class I GLUTs have been more extensively studied than classes II or III, understanding of these transporters continues to grow. The table below provides key features of certain GLUT isoforms.

Isoform	Key Features
GLUT 1
	Found ubiquitously, but mainly in the brain. Maintains glucose transport across the BBB.
	High affinity for glucose. Insulin independent. Downregulated by high glucose concentrations and upregulated by low glucose concentrations.
	Transports glucose in hepatocytes which is controlled by thyroid hormones.
GLUT 2
	Expressed in beta cells of the pancreas, liver, kidney.
	On the hepatocyte membrane, regulates entry/exit of glucose which controls metabolism.
GLUT 3	Present in the brain, testes, and kidney. High affinity for glucose.
GLUT 4
	Found in skeletal muscle, adipose tissue, brain, and heart.
	Found in the intracellular cytoplasm of vesicles. Translocate to the plasma membrane under the influence of insulin.
GLUT 5	Primarily a fructose transporter located in the small intestine, testes, kidney.
GLUT 6
	Expressed in the brain, spleen, and in peripheral leukocytes.
	Very low affinity to glucose. Not insulin sensitive.
GLUT 7	Located in the small intestine, colon, testis, prostate. High affinity for glucose/ fructose.
GLUT 8
	Distributed brain and testis cells. Translocation is hormonally regulated.
	Facilitate glucose transport through mitochondrial, endoplasmic reticulum and lysosomal membranes.
	High-affinity transporter of glucose. Inhibited by fructose and galactose.
GLUT 9
	Expressed in the proximal tubule of the kidney, liver, placenta, and testes.
	Has two isoforms, which are selective to glucose/uric acid.
GLUT 10
	In skeletal muscle, heart, lung, brain, placenta, kidney, liver, and pancreas.
	Selective to glucose and galactose. Not sensitive to insulin.
GLUT 11
	Facilitates transport of glucose and fructose. Similar homology to GLUT 5.
	Three isoforms present in varying tissues: heart, skeletal muscle, kidney, placenta, adipose, pancreas.
GLUT 12
	Expressed in adipose tissue, small intestine, skeletal muscle, and placenta.
	Insulin sensitive. Similar homology to GLUT 10.
HMIT/GLUT 13
	Expressed in adipose, kidney, hippocampus, hypothalamus, cerebellum and brainstem.
	Associated with transport of inositol-3-phosphate. In the brain, myo-inositol is the precursor to an important regulator of various signaling pathways.
GLUT 14	Found in the testis.

Datasets:

Glucose transporter Inhibitors (IC50, Ki)

Sodium-Glucose Linked Transporters

SGLTs rely on the sodium concentration gradient generated by the influence of ATPase as a source of chemical potential. SGLTs harness the energy released from the downhill flow of sodium ions (Na+) to drive the translocation of glucose against its concentration gradient through the membrane. SGLTs are present on the luminal surfaces of cells in the kidney cortex and the small intestine lining, where they absorb glucose from dietary sources. Though a handful of SGLTs have been identified, the physiological functions of SGLT 1 and SGLT 2 have been most extensively studied. The table below provides some key features of identified SGLT isoforms.

Isoform	Key Features
SGLT 1
	Expression primarily localized in the small intestine and the late proximal tubules.
	Detected in human's salivary gland, liver, lung, skeletal muscle, heart, pancreatic α-cells.
	Intestinal activity and expression are regulated by dietary carbohydrate content. High-affinity transporter for glucose and galactose.
SGLT 2
	Responsible for glucose reabsorption in the kidney.
	Predominantly expressed in the kidneys, with lower expressions detected in the mammary glands, testis, liver, lung, intestine, skeletal muscle, spleen, cerebellum.
SGLT 3	Present in intestine, testes, uterus, lung, brain, thyroid. Function as glucose sensors for controlling levels in gut and brain.
SGLT 4	Present in intestine, kidney, liver, brain, lung, uterus, pancreas. Selective substrate for fructose, glucose, mannose, and 1-5, AG.
SGLT 5	Present in the kidney cortex. Transport glucose and galactose.
SGLT 6	Present in the brain, kidney, intestine. Substrates are myo-inositol, chiro-inositol, and xylose.

Datasets:

Sodium/glucose cotransporter 2 Inhibitors (IC50, Ki)

Glucose Transporter Regulation and Relation to Disease

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Glucose transport and uptake is regulated by a variety of factors, but specifically those that are associated with cellular stress. This includes a relation to stress hormones (e.g., glucocorticoids and epinephrine) or metabolic stresses that are associated with energy demand, inflammation, kinase signaling, endoplasmic reticulum stress, or even chronic disease. Such stress-related factors can impact glucose transporter expression, distribution, synthesis, as well as longevity. Ultimately, the regulation of glucose transport occurs in response to altered energy requirements of tissues; in this way, glucose is always distributed appropriately and with priority for tissues and organs in need.

As stress hormones have differing effects on the expression of GLUTs, SGLTs, and their subsequent transport activity, glucose regulation may likely be specific to not just the isoform in question, but also to their associated tissues.

In general, membrane proteins can be notoriously challenging to study due to the technical difficulties involved with expression, purification, and crystallization. Investigating the activity and functionality of transporters often poses another level of complexity as these molecules are highly dynamic and have lower levels of endogenous expression within the body. Further elucidating the structure and mechanism of GLUT and SGLT isoforms may help provide novel biomarkers for research, drug development, or even clinical diagnosis.

Currently, a number of diseases have been linked to specific GLUT and SGLT isoforms and genes, as shown by the table below. Interestingly, overexpression of GLUT transporters has shown clinical relevance to some diseases, specifically cancers, while under expression of GLUT transporters may be an indicator of others, like osteonecrosis. Regardless, associating glucose transporter isoforms and genes to particular diseases may not only demonstrate their potential as diagnostic biomarkers, but it may shed light to whether GLUT/SGLT inhibition or knockdown could be a potential therapy for recovery.

Isoform	Associated Diseases
GLUT 1	Cognitive decline, epilepsy, gastric cancer, osteonecrosis
GLUT 2	Type-2 diabetes
GLUT 3/ GLUT 12	Breast Cancer
GLUT 4	Gastric Cancer
GLUT 5	Colon Cancer, Chron's disease
GLUT 6	Endometrial cancer
GLUT 8	Hepatic steatosis
GLUT 10	Arterial tortuosity syndrome (ATS), leukemia
Gene	Associated Disease
SGLT1	Glucose-galactose malabsorption
SGLT2	Impaired glucose reabsorption, ATS, altered growth factor β-1 activity
GLUT2	Fanconi-Bickel Syndrome

Tools:

Glucose Standard Curve Calculator

Product Ordering Information

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References

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Glucose Uptake
Glucose transporters: physiological and pathological roles
Chapter 34 - Developmental Physiology of Carbohydrate Metabolism and the Pancreas
Chapter 22 - Glucose Transport
Importance of GLUT Transporters in Disease Diagnosis and Treatment
Sodium-glucose cotransporters: Functional properties and pharmaceutical potential
GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters