Glucose is essential for life. It is the major energy source for mammalian cells and its transport into cells is crucial for survival of both the cell and the individual. Most cells use facilitated transport for uptake of glucose by uniport since a concentration gradient often exists for glucose between extracellular fluids and the cytoplasm. A family of glucose transport proteins catalyzes facilitated transport of glucose. Distinct members of this family are expressed in most cell types. In other cells, such as intestinal epithelial cells, glucose must be transported against its concentration gradient. There, an active form of glucose transport is necessary and another family of transport proteins participates in this process (see also LIR Biochemistry, pp. 96–97).
FACILITATED TRANSPORT OF GLUCOSE
The family of glucose transporters (GLUTs) that functions in facilitated transport of glucose includes at least 14 members, 11 of which are involved in glucose transport. GLUTs 1 to 5 are the most commonly expressed. GLUTs have specific tissue locations with an affinity for glucose that permits their function within a particular tissue environment (Figure 15.1). GLUTs 1, 3, and 4 are primarily involved in glucose uptake from the blood.
GLUT 1 and GLUT 3 are found in most tissues. GLUT 4 is found in skeletal muscle and adipose (fat) cells. GLUT 2 transports glucose into liver and kidney cells when blood glucose levels are high and transports glucose out of cells into the blood when blood glucose levels are low. GLUT 2 is also found in pancreatic ? cells. GLUT 5 is unusual in that it is the primary transporter for fructose (instead of glucose) in the small intestine and testes.
FIGURE 15.1.Tissue distribution of glucose transporters.
Mechanism of glucose transport
GLUT family members transport glucose from an area of higher concentration to an area of lower concentration. In order to be transported, the sugar molecule binds to the GLUT protein (state 1) and then the membrane direction of the sugar-GLUT complex is reversed (state 2) so that the sugar is released to the other side of the membrane (Figure 15.2). After the sugar has dissociated, the GLUT flips orientation and is readied for another cycle of transport.
FIGURE 15.2.Facilitated transport of glucose through a plasma membrane.
Glucose transport depends upon the concentration of glucose and on the number of GLUT proteins present on the plasma membrane. GLUT family members have the capacity to transport glucose in both directions across membranes. However, in most cells, the cytoplasmic glucose concentration is lower than the extracellular concentration of glucose. Its transport can proceed only along (down or with) its concentration gradient, from the exterior environment into the cell. In liver and kidney cells that synthesize glucose (via gluconeogenesis), the intracellular concentration of glucose can be greater than the blood glucose concentration surrounding the cell (see also LIR BiochemistryChapter 10 for discussion of gluconeogenesis). Then, transport of glucose out of liver and kidney cells occurs. GLUT 2 proteins export glucose from these cell types.
Role of insulin
Insulin is a regulatory hormone secreted by ? cells of the islets of Langerhans in the pancreas in response to glucose (and other carbohydrates) and proteins (amino acids) (Figure 15.3). Epinephrine, a hormone released in response to stress, inhibits insulin release (see also LIR Biochemistry, Chapter 23). Insulin coordinates the use of fuel by tissues and is required for normal metabolism. The importance of insulin to health is illustrated by type 1 diabetes mellitus in which ? cells of affected individuals are destroyed and no insulin is produced (Figure 15.4).
They must receive exogenous insulin in order to survive. Insulin’s metabolic effects are anabolic, favoring the building of stores of carbohydrates, fats, and proteins. Failure of cells to respond properly to insulin, known as insulin resistance, is characteristic of type 2 diabetes mellitus. Insulin therapy may or may not be required by individuals with type 2 diabetes. Therapies for type 2 diabetes include agents designed to decrease blood glucose (hypoglycemic agents) as well as diet and exercise. (Weight loss often improves insulin resistance.) One important normal response to insulin is to initiate transport of glucose into certain cell types.
FIGURE 15.3.Regulation of insulin release from pancreatic ? cells.
FIGURE 15.4.Comparison of type 1 and type 2 diabetes mellitus.
Glucose transport and insulin secretion
GLUT 2 glucose transporters are found in pancreatic ? cells. These cells must have the capability to sense a higher concentration of glucose in order to release insulin when appropriate. GLUT 2 transporters are low affinity glucose transporters (with high Km) and only transport glucose when the concentration of circulating glucose is greater than 5 mM, the normal concentration of glucose in blood. In this manner, glucose is only transported into the ? cells when glucose levels increase from basal levels after consumption of carbohydrates.
1. Insulin-insensitive glucose transport: Most cell types do not require insulin in order to transport glucose along its concentration gradient into cells (Figure 15.5). Glucose transport into erythrocytes, leukocytes, liver, and brain cells requires only a concentration gradient for glucose since sufficient GLUT proteins are expressed on the surface of these cells. GLUT 1, GLUT 2, GLUT 3, and GLUT 5 are insulin-independent transporters.
FIGURE 15.5.Characteristics of glucose transport in various tissues.
2. Insulin-sensitive glucose transport: In skeletal muscle and fat cells (adipocytes), GLUT 4 proteins reside within intracellular vesicles, inactive and bound to the Golgi complex (Figure 15.6). Expression of GLUT 4 on the membrane surface plays a rate-limiting role in glucose utilization by skeletal muscle and adipose cells where glucose transport is stimulated by a series of events. Consumption of carbohydrates stimulates insulin release from ? cells of the pancreas. Insulin circulates throughout the blood and binds to insulin receptors on many cell types. Intracellular signaling pathways initiated by insulin binding then stimulate movement of GLUT 4 from intracellular vesicles to the membrane surface through multiple, highly organized membrane trafficking events. Actin remodeling beneath the plasma membrane must occur so that GLUT 4–containing vesicles can fuse with the plasma membrane. Once GLUT 4 is expressed on the surface of the cell, then glucose transport occurs while the glucose concentration gradient exists. GLUT 4 proteins are removed from the plasma membrane by endocytosis and recycled back to their intracellular storage compartment when insulin stimulation is withdrawn.
FIGURE 15.6.Insulin causes some cells to recruit transporters from intracellular stores.
Glucose transport in diabetes mellitus
Individuals with type 1 diabetes mellitus do not produce insulin. Approximately 10% of individuals with diabetes mellitus in the United States have the type 1 form. Their pancreatic ? cells have been destroyed and insulin production is no longer possible. Insulin must be supplied exogenously to control hyperglycemia (high blood levels of glucose) and to prevent diabetic ketoacidosis (breakdown of fats that occurs in the absence of insulin with the potentially life-threatening consequence of acidifying the blood).
In order for glucose transport to occur into the insulin-dependent skeletal muscle and fat cells, exogenous insulin must be administered. Otherwise, glucose cannot enter those cells and excessive glucose concentrations result in the blood. In persons with type 2 diabetes mellitus, peripheral tissues have become resistant to the effects of insulin. Insulin secretion may be impaired but persons with type 2 diabetes mellitus do not require insulin to sustain life. In this group that constitutes approximately 90% of persons with diabetes mellitus in the United States, insulin signaling is ineffective in tissues such as skeletal muscle and adipose.
While insulin is present, the cells do not respond to it. Insulin-dependent glucose transport does not occur efficiently and glucose remains in the blood at too high a concentration. Drug therapies for type 2 diabetes include agents that improve insulin signaling (see also LIR Biochemistry, Chapter 25 for a discussion of diabetes mellitus and Chapter 18 for a discussion of insulin signaling). Long-standing elevation of blood glucose in both types of diabetes mellitus causes chronic complications including premature atherosclerosis (including cardiovascular disease and stroke), retinopathy, nephropathy, and neuropathy.
ACTIVE TRANSPORT OF GLUCOSE
There are three main locations where glucose is found at a higher concentration inside cells than out and glucose must be transported against its gradient to enter those cells. The first is the choroid plexus, the second is the proximal convoluted tubules of the kidney, and the third is the epithelial cell brush border of the small intestine. The epithelial cells lining the small intestine are a barrier between the lumen of the small intestine and the bloodstream (Figure 15.7). Dietary glucose must be absorbed by the epithelial cells and then transferred to the underlying connective tissue so that it can enter into the blood circulation.
GLUT proteins cannot be used to transport glucose into these cells because glucose is at a higher concentration inside the cells than outside the cells. (Note that the volume of the small intestine is much greater than the volume of an epithelial cell and that concentration is dependent on volume.) The apical membranes (facing the lumen) of the epithelial cells contain sodium-glucose transport proteins (SGLT) that catalyze transport of glucose against its concentration gradient. Six members of the SGLT family have been reported but only SGLT 1 and SGLT 2 are well characterized.
FIGURE 15.7.Glucose transport from the intestinal lumen to the bloodstream.
This process of glucose transport against its concentration gradient is an example of secondary active transport (see also Chapter 13). Glucose transport by SGLTs can only occur when sodium is present and is cotransported with glucose (Figure 15.8). Since both glucose and sodium are transported in the same direction (both into the cell), this is symport process. The energy required to power the transport of glucose against its gradient is derived from the electrochemical gradient of sodium that is created and maintained by the sodium-potassium ATPase, a primary active transport system (see also Chapter 14).
Since sodium has such a strong concentration gradient from outside to inside the cell, its tendency to move down its gradient is great. On the apical membrane of intestinal epithelial cells, the only transporter for sodium is a sodium-glucose transporter. Sodium is transported only when glucose is cotransported. Glucose effectively gains a free ride into the cell owing to the strong concentration gradient of sodium. Once inside the cell, the glucose can then be transported out of the cell and into the blood by a GLUT protein on the basolateral (opposite to apical) membrane.
FIGURE 15.8.Sodium-glucose transporters cotransport sodium and glucose in a symport process.
Glucose-sodium cotransport in the kidney, implications in diabetes treatment
Under normal circumstances, the kidney filters glucose in the glomerulus and into Bowman’s space and the renal tubules. The amount filtered is related to the glucose concentration in blood. All this glucose is normally reabsorbed in the proximal tubule (by transport into the epithelial cells lining the proximal tubule) with none appearing in urine. Blood glucose concentration is normally approximately 5 mM and epithelial cells within the proximal tubule have a glucose concentration of 0.05 mM. The glucose must cross through these epithelial cells into the interstitial fluid (5 mM glucose) and back into blood.
The gradient up which glucose must be pumped is 0.05 mM to 5 mM. As this process continues, more and more glucose is removed from the tubular fluid and the concentration drops as low as 0.005 mM, increasing the concentration gradient tenfold. Secondary active transport is used to move glucose up this gradient. A sodium-glucose symport protein is used. SGLT 2 is responsible for 90% of the glucose transported (reabsorbed) in the first segment of the proximal tubules, with one sodium ion transported per glucose molecule.
SGLT 1 transports the remaining 10% of glucose in the distal segments of the proximal tubules, transporting 2 sodium ions with every glucose molecule. The sodium gradient is generated by the sodium-potassium ATPase pump so that the concentration of sodium outside the cells is approximately 140 mM and the concentration inside is approximately 10 mM.
In individuals with diabetes, elevated blood glucose levels cause a greater amount of glucose to be filtered by the kidney. The ability of the kidney to reabsorb all of the glucose is often exceeded and glucose appears in the urine. The amount of glucose appearing in the urine is the amount that exceeds the reabsorption capacity of the kidney. It has been suggested that inhibition of SGLT 2 in individuals with type 2 diabetes would lead to decreased reabsorption of glucose and increased excretion of glucose into urine.
Increased glucose excretion in urine would result in decreased plasma glucose levels. It would also result in excretion of calories (from glucose) in the urine, with the potential for weight loss. Weight loss often improves the insulin resistance seen in type 2 diabetes. Several SGLT 2 inhibitors are in clinical development now for possible use in treating individuals with type 2 diabetes.
- Most cells use facilitated transport of glucose mediated by GLUT proteins.
- In most cases, glucose is moved from higher concentration outside the cell toward the lower concentration inside the cell.
- Most cells have insulin-independent glucose transport.
- Skeletal muscle and adipose cells require insulin to stimulate movement of GLUT proteins from intracellular vesicles to the plasma membrane where they can function to take up glucose.
- If insulin is absent (type 1 diabetes) or does not signal properly (type 2 diabetes), then insulin-dependent glucose transport will cease or be impaired.
- Secondary active transport of glucose occurs via symport with sodium, using SGLT proteins, in the choroid plexus, proximal tubules of kidneys, and the intestine.