In the fed state (see Figure 5.6), when there is an ample supply of metabolic fuels from the gut, the main processes occurring are synthesis of reserves of triacylglycerol and glycogen; glucose is in plentiful supply and is the main fuel for most tissues. By contrast, in the fasting state (see Figure 5.7) the reserves of triacylglycerol and glycogen are mobilized for use, and glucose, which is now scarce, must be spared for use by the brain and red blood cells.
As discussed in section 5.3, the principal hormones involved are insulin in the fed state and glucagon in the fasting state. Adrenaline and noradrenaline share many of the actions of glucagon, and act to provide an increased supply of metabolic fuels from triacylglycerol and glycogen reserves in response to fear or fright, regardless of whether or not fuels are being absorbed from the gut.
In liver and muscle, insulin and glucagon act to regulate the synthesis and breakdown of glycogen, as shown in Figure 10.6. They also regulate glycolysis (stimulated by insulin and inhibited by glucagon) and gluconeogenesis (inhibited by insulin and stimulated by glucagon). The result of this is that in the fed state the liver takes up and utilizes glucose, to form either glycogen or triacylglycerols, which are exported to other tissues in VLDL. By contrast, in the fasting state the liver exports glucose formed from the breakdown of both glycogen and gluconeogenesis. As discussed in section 5.5.3, in the fasting state the liver also oxidizes fatty acids and exports ketone bodies for use by other tissues.
10.5.1 HORMONAL CONTROL OF ADIPOSE TISSUE METABOLISM
As shown in Figure 10.11, insulin has three actions in adipose tissue in the fed state:
• Stimulation of glucose uptake. In the absence of insulin, glucose transporters in adipose tissue are in intracellular vesicles. An early response to insulin is migration of
these vesicles to the cell surface, where they fuse with the cell membrane, exposing glucose transporters. This results in an increased rate of glucose uptake, and hence increased glycolysis (section 5.4.1) and increased availability of acetyl CoA for fatty acid synthesis (section 5.6.1). In the fasting state, when insulin secretion is low, little or no glucose is taken up into adipose tissue cells.
There is a continuous release of non-esterified fatty acids from adipose tissue. In the fed state most of the fatty acids are taken up by the liver, re-esterified to form triacylglycerol and exported in VLDL (section 18.104.22.168). This apparently futile (and ATP-expensive) cycling between lipolysis in adipose tissue and re-esterification in the liver permits increased utilization of fatty acids as fuel in muscle by increasing the rate of fatty acid uptake into muscle without the need to increase the rate of lipolysis. As discussed in section 10.6, the extent to which muscle utilizes fatty acids is determined to a considerable extent by the intensity of physical activity, rather than by their availability.
The liver synthesizes fatty acids in the fed state, and oxidizes them in the fasting state. The direction of metabolic flux (lipogenesis or lipolysis) is controlled both in response to insulin and glucagon and also by intracellular concentrations of substrates.
• In the fed state, insulin stimulates glycolysis (and inhibits gluconeogenesis), leading to increased formation of pyruvate, which results in increased formation of acetyl
CoA, and hence increased formation of citrate, which is exported to the cytosol for fatty acid synthesis (see Figure 5.27 and section 5.6.1).
Pyruvate dehydrogenase is inhibited in response to increased acetyl CoA, and also an increase in the NADH/NAD+ ratio in the mitochondrion. The concentration of acetyl CoA will be high when ^-oxidation of fatty acids is occurring, and there is no need to utilize pyruvate as a metabolic fuel. Similarly, the NADH/NAD+ ratio will be high when there is an adequate amount of metabolic fuel being oxidized in the mitochondrion, so that again pyruvate is not required as a source of acetyl CoA. Under these conditions pyruvate will mainly be carboxylated to oxaloacetate for gluconeogenesis (section 5.7).
The regulation of pyruvate dehydrogenase is the result of phosphorylation of the enzyme (see Figure 10.5). Pyruvate dehydrogenase kinase is allosterically activated by acetyl CoA and NADH, and catalyses the phosphorylation of pyruvate dehydrogenase to an inactive form. Pyruvate dehydrogenase phosphatase acts constantly to dephosphorylate the inactive enzyme, so restoring its activity and maintaining sensitivity to changes in the concentrations of acetyl CoA and NADH.
As discussed in section 5.6.1, citrate leaves the mitochondria to act as a source of acetyl CoA for fatty acid synthesis only when there is an adequate amount to maintain citric acid cycle activity. As citrate accumulates in the cytosol, it acts as a feed-forward activator of acetyl CoA carboxylase, increasing the formation of malonyl CoA.
Fatty acyl CoA in the cytosol implies a high rate of fatty acid uptake from the bloodstream; fatty acyl CoA inhibits acetyl CoA carboxylase and so reduces the rate of malonyl CoA synthesis and fatty acid synthesis.
As well as being the substrate for fatty acid synthesis, malonyl CoA has an important role in controlling ^-oxidation of fatty acids. Malonyl CoA is a potent inhibitor of carnitine palmitoyl transferase 1, the mitochondrial outer membrane enzyme that regulates uptake of fatty acyl CoA into the mitochondria (section 5.5.1). This means that, under conditions in which fatty acids are being synthesized in the cytosol, there will not be uptake into the mitochondria for ^-oxidation. (See also section 10.6.2.1 for a discussion of the role of malonyl CoA in regulating muscle fuel selection.)
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...