The glucose fatty acid cycle is also called the Randle cycle after its discoverer, Philip Randle, and was originally observed in the hearts of rats. Nutritionally, the Randle cycle is important to understand because it explains the interaction between glucose and fatty acids as fuel substrates for muscular energy production1. This information can in turn provide useful in speculating how carbohydrate and fat intakes could effect energy partitioning and weight changes in humans. The cycle is not a classic metabolic cycle in that it does not involve the conversion of glucose to fatty acids as may be inferred from its name. Instead, the glucose fatty acid cycle is a series of regulatory metabolic steps that allow fuel optimisation by muscle such that glucose is not utilised when conditions required at times of need for other tissues such as the brain.
In the post-absorptive state, glucose and insulin levels fall and non-esterified free fatty acids become the preferred fuel substrate for muscle cells. Under these conditions, adrenaline, noradrenaline and glucagon stimulate hormone sensitive lipase to release fatty acids from triglycerides stored in adipose tissue to plasma, where muscle uptake is proportional to plasma levels. The oxidation of fatty acids in muscle tissue increases concentrations of acetyl-CoA and the NADH/NAD+ ratio which inhibits pyruvate dehydrogenase through phosphorylation of pyruvate dehydrogenase kinase. This decreases the oxidation of pyruvate and therefore inhibits glycolysis. The high acetyl-CoA concentrations also increase production of citrate, which potentiates the inhibition of phosphofructosokinase by ATP and this further slows glucose flux through glycolysis. Inhibition of glycolysis causes a build up of glucose-6-phosphate which allosterically inhibits hexokinase and the cellular build up of free glucose inhibits further uptake.
When glucose levels rise in the postprandial state, insulin levels rise concomitantly. Insulin inhibits the breakdown of triglycerides to fatty acids in adipose tissue via an inhibitory effect on hormone sensitive lipase. At the same time insulin stimulates the conversion of fatty acids to triglycerides in the liver, and circulating non-esterified free fatty acid levels fall. The fall in the concentration of free fatty acids reduces their uptake from plasma to muscle cells, which decrease their subsequent oxidation. Reductions in the levels of citrate, acetyl-CoA and the NADH/NAD+ ratio decrease the inhibitory effect on glycolysis and at the same time, insulin increases the uptake of glucose from plasma to the muscle cells. This results in an increase in flux though glycolysis as the muscle cells switch fuel substrate utilisation to glucose. Insulin is therefore a key regulatory step in cellular energy substrate utilisation.
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