3.7 Transport and utilization of glucose in the liver and in peripheral cells
The liver has a special role in many metabolic processes, and prominently so in glucose metabolism. Recall that all the glucose that is taken up from the small intestine must pass through the liver first before it can reach any other tissue. The fraction of glucose retained by the liver is regulated depending on the metabolic situation:
- If blood glucose is high, the liver extracts a relatively large fraction and uses it for conversion to glycogen or for conversion to triacylglycerol (fat).
- If blood glucose is low, the liver will only extract small amounts of glucose; in fact, release of glucose by the liver will exceed its uptake under these circumstances.
This latter behaviour is different for example from the brain, which unabashedly extracts glucose at both high and low glucose levels. This difference between the liver and other tissues is implemented at two stages:
- The uptake of glucose into the cells, and
- the phophorylation of glucose to glucose-6-phosphate.
We have discussed before that glucose passes membranes by way of specialized transporter proteins. Except in the luminal membranes of the gut and of the kidney tubules, these transporter proteins operate by facilitated diffusion, that is they simply speed up transport of glucose along its concentration gradient (Figure 3.7-1). Although such transporters are not enzymes, there is one similarity: With both enzyme reaction and with facilitated diffusion, substrate binding and dissociation are much faster than the action of the protein (the enzyme reaction, or in this case the conformational change required for translocation). Therefore, like simple enzymes, facilitated transport obeys Michaelis-Menten kinetics:
V = Vmax× [S] / (KM + [S])
You may recall (and if not, infer from the above equation) that the affinity of the protein for the substrate, which is represented by KM, controls the dependency of the activity of on the substrate concentration. In most tissues, the glucose transporters have a low KM, which means that each transporter molecule is always operating at full speed,1 irrespective of the glucose concentration. In contrast, the transporter subtype found in the liver (GLUT 2) has a higher KM, so that the rate of transport is reduced at low glucose concentration.
A similar difference is observed at the stage of phosphorylation. The liver has a special enzyme called glucokinase, which performs the same reaction as does hexokinase but differs from the latter by a higher KM value. Accordingly, phosphorylation will proceed at reduced rate at a low level of blood glucose (Figure 3.7-2), and most of the glucose will be allowed to pass the liver and make its way into the general circulation. Conversely, at high concentration, a higher amount of glucose will be extracted by the liver and fed into glycogen synthesis or fatty acid synthesis. The kinetic properties of both transport and phosphorylation therefore contribute to the regulatory function of the liver in glucose metabolism.
1: This does not mean that the overall extraction of glucose always goes at full speed in all tissues. Regulation of glucose uptake in many tissues is mediated by insulin, which changes the overall number of available transporters but not the activity of the individual transporter molecule (See section 13.1.3).