The fed state

During the 3—4 hours after a meal, there is an ample supply of metabolic fuel entering the circulation from the gut (Figure 5.6). Glucose from carbohydrate digestion (section 4.2.2) and amino acids from protein digestion (section 4.4.3) are absorbed into the portal circulation, and to a considerable extent the liver controls the amounts that enter the peripheral circulation. By contrast, the products of fat digestion are absorbed into the lymphatic system as chylomicrons (sections 4.3.2.2 and 5.6.2.1), and are available to peripheral tissues before the liver exerts control. Much of the triacylglycerol in chylomicrons goes directly to adipose tissue for storage; when there is a plentiful supply of glucose, it is the main metabolic fuel for most tissues.

Figure 5.6 An overview of metabolism in the fed state.

The increased concentration of glucose and amino acids in the portal blood stimulates the P-cells of the pancreas to secrete insulin, and suppresses the secretion of glucagon by the a-cells of the pancreas. Insulin has four main actions:

  • Increased uptake of glucose into muscle and adipose tissue. This is effected by recruitment to the cell surface of glucose transporters that are in intracellular vesicles in the fasting state.
  • Stimulation of the synthesis of glycogen (section 5.5.3) from glucose in both liver and muscle, by activation of glycogen synthetase (section 10.5).
  • Stimulation of fatty acid synthesis in adipose tissue (section 5.6.1) by activation of acetyl CoA carboxylase (section 10.5) and parallel inactivation of hormonesensitive lipase.
  • Stimulation of amino acid uptake into tissues, leading to an increased rate of protein synthesis.

In the liver, glucose uptake is by carrier-mediated diffusion and metabolic trapping as glucose 6-phosphate (section 3.2.2.2), and is independent of insulin. The uptake of glucose into the liver increases very significantly as the concentration of glucose in the portal vein increases, and the liver has a major role in controlling the amount of glucose that reaches peripheral tissues after a meal. There are two isoenzymes that catalyse the formation of glucose 6-phosphate in liver:

• Hexokinase has a Km of approximately 0.15 mmol/L. This enzyme is saturated, and therefore acting at its V , under all conditions. It acts mainly to ensure an

adequate uptake of glucose into the liver to meet the demands for liver metabolism.

• Glucokinase has a K of approximately 20 mmol/L. This enzyme will have very low activity in the fasting state, when the concentration of glucose in the portal blood is between 3 and 4 mmol/L. However, after a meal the portal concentration of glucose may well reach 20 mmol/L or higher, and under these conditions glucokinase has significant activity and there is increased formation of glucose 6-phosphate in the liver. Most of this will be used for synthesis of glycogen (section 5.5.3), although some will also be used for synthesis of fatty acids that will be exported in very low-density lipoprotein (section 5.6.2.2). (See also Problem 2.1 for the role of glucokinase in the pancreatic (3-islet cells.)

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