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Glucose is transported into cells by a family of specialised transporter proteins called glucose transporters (GLUTs) (Figure 5.17). The process of glucose uptake is energy independent.

The best characterised GLUTs are:

 GLUT‐1: ubiquitously expressed and probably mediates basal, non‐insulin mediated glucose uptake.

 GLUT‐2: present in the islet β cell, and also in the liver, intestine, and kidney. Together with glucokinase, it forms the β cell’s glucose sensor and, because it has a high Km, allows glucose to enter the β cell at a rate proportional to the extracellular glucose level.

 GLUT‐3: together with GLUT‐1, involved in non‐insulin mediated uptake of glucose into the brain.

 GLUT‐4: responsible for insulin‐stimulated glucose uptake in muscle and adipose tissue, and thus the classic hypoglycaemic action of insulin.

 GLUT‐8: important in blastocyst development.

 GLUT‐9 and 10: unclear functional significance.

Figure 5.17 (a) The structure of a typical glucose transporter (GLUT). (b) The intramembrane domains pack together to form a central hydrophilic channel through which glucose passes.

Most of the other GLUTs are present at the cell surface, but in the basal state GLUT‐4 is sequestered within vesicles in the cytoplasm. Insulin causes these vesicles to be translocated to the cell surface, where they fuse with the plasma membrane. The inserted GLUT‐4 unit then functions as a membrane pore that allows glucose entry into the cell. The process is reversible: when insulin levels fall, the plasma membrane GLUT‐4 is removed by endocytosis and recycled back into intracellular vesicles for storage (Figure 5.18).

In normal subjects, blood glucose concentrations are maintained within relatively narrow limits at around 5 mmol/L (90 mg/dL) (Figure 5.19). This is achieved by a balance between glucose entry into the circulation from the liver and from intestinal absorption, and glucose uptake into the peripheral tissues such as muscle and adipose tissue. Insulin is secreted at a low, basal level in the non‐fed state, with increased, stimulated levels at mealtimes (Figure 5.20).

At rest in the fasting state, the brain consumes about 80% of the glucose utilised by the whole body, but brain glucose uptake is not regulated by insulin. Glucose is the main fuel for the brain, such that brain function critically depends on the maintenance of normal blood glucose levels.

Figure 5.18 Insulin regulation of glucose transport into cells.

Figure 5.19 Profiles of plasma glucose and insulin concentrations in individuals without diabetes.

Insulin lowers glucose levels partly by suppressing glucose output from the liver, both by inhibiting glycogen breakdown (glycogenolysis) and by inhibiting gluconeogenesis (i.e. the formation of ‘new’ glucose from sources such as glycerol, lactate and amino acids, like alanine). Relatively low concentrations of insulin are needed to suppress hepatic glucose output in this way, such as occur with basal insulin secretion between meals and at night. With much higher insulin levels after meals, GLUT‐4 mediated glucose uptake into the periphery is stimulated.

Figure 5.20 Overview of carbohydrate metabolism. cats, catecholamines; cort, cortisol; glcg, glucagon; ins, insulin; NIMGU, non‐insulin mediated glucose uptake.