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Homologous to SGLT-1; SGLT-2 in particular has high capacity and low affinity (high Km for glucose). SGLT-2 co-transports 1 mol sugarwith 1 mol Na+; SGLT-3 co-transports 1 mol sugarwith 2 mol Na +

Based on Gould & Holman 1993; Joost ei al. 2002; Thorens 1996; Wallner ei al. 2001; Wright 1993.

Based on Gould & Holman 1993; Joost ei al. 2002; Thorens 1996; Wallner ei al. 2001; Wright 1993.

glucose concentrations. This would be appropriate in, for instance, the brain, where the rate of glucose uptake needs to be constant despite cycles of feeding and fasting. With a Km for glucose entry of 20 mmol/l (e.g. GLUT2), the rate of glucose entry is almost proportional to the extracellular glucose concentration (the higher the external concentration, the greater the rate of entry). The lines are plotted assuming Michaelis-Menten kinetics. This is oversimplified because it assumes that glucose within the cells is removed as fast as it enters. Therefore, the enzyme responsible for phosphorylation of glucose (hexokinase or glucokinase) must have similar characteristics to (or a greater capacity than) the glucose transporter in order for these kinetics to be expressed. The removal of glucose 6-phosphate must also occur at approximately the same rate as glucose enters the cell; the pathways of glucose metabolism are regulated hormonally so as to coordinate all these events (see Fig. 4.2).

The terminology is that GLUT refers to the proteins. These are related and all have 12 membrane-spanning regions. The genes encoding them are called SLC2A1 (the gene for GLUT1), SLC2A2 (for GLUT2), etc.

linking glucose transport to that of sodium: i.e. sodium moves down a strong concentration gradient, carrying glucose with it up a concentration gradient. This process is illustrated in Fig. 2.4. SGLT-1 to -3 are expressed in the renal tubule and are involved in kidney function; this will be described further in Section 4.6.2.

GLUT4 has special characteristics relevant for metabolic regulation. Many years ago it was recognised that when insulin stimulates glucose uptake by muscle preparations, it appears to do so by increasing the maximal rate of uptake (the Vmax) rather than by changing the Km. There is a large cellular store of the

Typical concentrations (mmol/l) Intracellular Extracellular Na+ 12 140

Substance X Na+

Typical concentrations (mmol/l) Intracellular Extracellular Na+ 12 140

Substance X Na+

Substance X transporter

Sodium-potassium linked ATPase ('the sodium pump')

Fig. 2.4 Sodium-linked active transport. By co-transport with Na + ions, substance X may move up a concentration gradient. The Na + ions move down a gradient maintained by the activity of the Na + -K+-linked ATPase or 'sodium pump', which uses energy derived from ATP to pump Na+ ions out of, and K+ ions into the cell, both against concentration gradients. Substance X may be glucose (if the transporter belongs to the SGLT family) or an amino acid.

Fig. 2.5 GLUT4 recruitment to the cell membrane. There is an intracellular pool of GLUT4 in membranous vesicles that can translocate to the cell membrane when insulin binds to its receptor. When the insulin signal is withdrawn, the GLUT4 proteins return to their intracellular pool. Based loosely on Shepherd & Kahn (1999).

Fig. 2.5 GLUT4 recruitment to the cell membrane. There is an intracellular pool of GLUT4 in membranous vesicles that can translocate to the cell membrane when insulin binds to its receptor. When the insulin signal is withdrawn, the GLUT4 proteins return to their intracellular pool. Based loosely on Shepherd & Kahn (1999).

transporter GLUT4, sequestered in membrane vesicles within the cell. When insulin binds to its receptor, these vesicles move to, and become incorporated in, the cell membrane and therefore the amount of GLUT4 available for glucose transport into the cell is increased. When insulin action ceases, these transporters recycle into intracellular vesicles (Fig. 2.5).

2.2.1.2 Amino acids

The concentration of most amino acids is considerably higher inside cells than outside: this is illustrated in Table 2.2 for some amino acids in skeletal muscle. This implies the existence of active transporters to move amino acids into the cells up a concentration gradient. In fact, like glucose in the small intestine, amino acids are mostly actively transported by sodium-linked carriers. Again, therefore, energy is required to pump the sodium ions out and maintain their concentration gradient. There are a number of amino acid transporters, common to the intestinal cells and to many other tissues. Each has a fairly broad specificity and transports a number of amino acids. They are described further in Table 2.3.

2.2.1.3 Fatty acids

Fatty acids arrive at cells in two ways. They may come in the form of non-esteri-fied fatty acids that have been carried through the plasma bound to albumin. Alternatively they may be liberated from triacylglycerol in the plasma (carried in lipoprotein particles, to be discussed further in Chapter 9) by the enzyme lipoprotein lipase attached to the endothelial cells that line the capillaries. They cross the endothelial cell lining and enter cells (e.g. liver, skeletal muscle, cardiac muscle, adipose tissue) down a concentration gradient, which is generated by

Table 2.2 Free amino acids in skeletal muscle.

Amino acids are found free (i.e. not as constituents of proteins) both in plasma and in the intracellular water of tissues. They may be present at considerably higher concentrations inside cells than out, reflecting the presence of active transport mechanisms for their entry into cells. The best data are available for skeletal muscle since small samples can be taken from human subjects with a special needle with a cutting edge. The sample (biopsy) is then frozen rapidly in liquid nitrogen to prevent further metabolism, and the amino acids are analysed. A correction is made for the amount of amino acid present in extracellular fluid (using the measurement of Cl- ions, which are present mainly in the extracellular fluid). Some typical results are given below:

Table 2.2 Free amino acids in skeletal muscle.

Amino acids are found free (i.e. not as constituents of proteins) both in plasma and in the intracellular water of tissues. They may be present at considerably higher concentrations inside cells than out, reflecting the presence of active transport mechanisms for their entry into cells. The best data are available for skeletal muscle since small samples can be taken from human subjects with a special needle with a cutting edge. The sample (biopsy) is then frozen rapidly in liquid nitrogen to prevent further metabolism, and the amino acids are analysed. A correction is made for the amount of amino acid present in extracellular fluid (using the measurement of Cl- ions, which are present mainly in the extracellular fluid). Some typical results are given below:

Amino acid

Plasma

Intracellular

Ratio intra-

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