Introduction
The Randle cycle, also known as the glucose-fatty acid cycle, describes how mammalian organs choose between glucose and fatty acids for fuel. Proposed in 1963 by Randle and colleagues, this cycle highlights the competition between these two substrates for oxidation, primarily in muscle and adipose tissue. The Randle cycle is a biochemical mechanism that controls fuel selection and adapts substrate supply and demand in normal tissues in coordination with hormones controlling substrate concentrations in the circulation. It's important to note that the Randle cycle is not a metabolic cycle like the citric acid cycle but rather a reciprocal control between glucose and fatty acid metabolism.
Historical Context and Discovery
In 1963, Philip Randle, Peter Garland, Nick Hales, and Eric Newsholme proposed a "glucose-fatty acid cycle," which describes fuel flux between and fuel selection by mammalian organs. Their research, published in The Lancet, laid the groundwork for understanding how the body prioritizes fuel sources. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Randle and colleagues demonstrated that the utilization of one nutrient inhibited the use of the other directly and without hormonal mediation in isolated heart and skeletal muscle preparations. This nutrient-mediated fine-tuning complements the coarser hormonal control already known to influence fuel metabolism.
The Biochemical Mechanism
The Randle cycle operates through a series of interconnected biochemical events. The primary concept is that increased fatty acid oxidation inhibits glucose utilization, and vice versa.
Inhibition of Glucose Utilization by Fatty Acids
When fatty acids are abundant, their oxidation leads to an increase in the mitochondrial ratios of [acetyl-CoA]/[CoA] and [NADH]/[NAD+]. These changes inhibit pyruvate dehydrogenase (PDH), a crucial enzyme in glucose oxidation. The inhibition of PDH preserves pyruvate and lactate, both of which are gluconeogenic precursors. The accumulation of cytosolic citrate, which in turn inhibits 6-phosphofructo-1-kinase (PFK-1), followed by an increase in glucose 6-phosphate, which eventually inhibits hexokinase.
Randle demonstrated that impairment of glucose metabolism by fatty acid (or ketone body) oxidation was mediated by a short-term inhibition of several glycolytic steps, namely glucose transport and phosphorylation, 6-phosphofructo-1-kinase (PFK-1), and PDH. The extent of inhibition is graded and increases along the glycolytic pathway, being most severe at the level of PDH and less severe at the level of glucose uptake and PFK.
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Regulation of Pyruvate Dehydrogenase (PDH)
The control of PDH activity is complex and involves control by substrates and products, covalent modification by reversible phosphorylation, and long-term adaptation of transcript and protein levels. PDH activity is also controlled by reversible phosphorylation of three serine residues in the α-subunit of E1 (pyruvate decarboxylase), one of the three components of the PDH complex. Dedicated mitochondrial kinases [pyruvate dehydrogenase kinase (PDK)] phosphorylate and inactivate PDH, whereas pyruvate dehydrogenase phosphatases (PDPs) have the opposite effect. Four and two different isoforms of PDK and PDP, respectively, with different tissue expression and phosphorylation site specificity are known. PDH substrates and products also control PDK activity. Pyruvate, or its analog dichloroacetate, inhibits, whereas acetyl-CoA and NADH stimulate PDK, with isoform-specific differences in sensitivity.
Inhibition of Fatty Acid Oxidation by Glucose
The reciprocal aspect of the Randle cycle, the inhibition of fatty acid oxidation by glucose, involves the stimulation of glucose uptake and the re-esterification of fatty acids in adipose tissue. This process requires glucose-derived glycerol 3-phosphate.
Impact on Adipose Tissue Lipolysis
Another aspect of the Randle cycle often not appreciated is the inhibition of adipose tissue lipolysis by glucose and insulin. This occurs via a mechanism involving stimulation of glucose uptake and reesterification of fatty acids in the presence of glucose-derived glycerol 3-phosphate.
The Randle Cycle in Different Metabolic States
The Randle cycle is not restricted to the fasting state and is readily observed in the fed state after a high-fat meal or during exercise, when plasma concentrations of fatty acids or ketone bodies increase.
Fasted State
In the fasted state, the activation of lipolysis provides tissues with fatty acids, which become the preferred fuel for respiration. In the liver, β-oxidation of fatty acids fulfills the local energy needs and may lead to ketogenesis. As “predigested fatty acids,” ketone bodies are preferentially oxidized in extrahepatic tissues. By inhibiting glucose oxidation, fatty acids and ketone bodies so contribute to a glucose-sparing effect, an essential survival mechanism for the brain during starvation.
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Fed State and Exercise
In the fed state after a high-fat meal or during exercise, plasma concentrations of fatty acids or ketone bodies increase. Under these conditions, part of the glucose that is not oxidized is rerouted to glycogen, which may explain the rapid resynthesis of muscle glycogen after exercise. Rerouting of glucose toward glycogen also explains the increased glycogen content in muscles found in starvation or diabetes. Similarly, pyruvate in excess of the mitochondrial oxidative capacity (suggested by high levels of acetyl-CoA) is carboxylated and used by the anaplerotic route to form oxaloacetate.
Dysregulation and Pathophysiology
The glucose-fatty acid cycle also provides an explanation for the pathophysiology of dysregulated fuel metabolism, referred to as “fatty acid syndrome” in the original article. Dysregulation of free fatty acid metabolism is a key event responsible for insulin resistance and type 2 diabetes. According to the glucose-fatty acid cycle of Randle, preferential oxidation of free fatty acids over glucose plays a major role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.
Insulin Resistance and Type 2 Diabetes
A persistent increase of free fatty acids in the serum, which is seen in shock, heart failure, and aging, indicates a bad prognosis. Free fatty acids are harmful because, in the Randle effect, increasing the amount of fat in the bloodstream decreases the ability of cells to metabolize glucose; glucose tolerance decreases, as in diabetes, except that the response to fat is instantaneous.
Several studies have suggested that local accumulation of fat metabolites such as ceramides, diacylglycerol or acyl-CoA, inside skeletal muscle and liver, may activate a serine kinase cascade leading to defects in insulin signalling and glucose transport.
Metabolic Inflexibility
Upregulation of PDK by genetic manipulation or in response to high-fat diet, starvation, or insulin deficiency keeps glucose oxidation at a low level, whereas fatty acid oxidation is increased. This situation mimics a state of “metabolic inflexibility” (failure to adapt metabolism to the fasted-to-fed state transition), which is a feature of insulin resistance. Conversely, the blood glucose level in starved PDK4-deficient mice is lower than in the wild types, probably because the active PDH diverts pyruvate, a gluconeogenic substrate, to acetyl-CoA.
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The Role of PPARs
The discovery that fatty acids exert transcriptional effects has added another new regulatory dimension to the glucose-fatty acid cycle. Certain fatty acids can bind to peroxisome proliferator-activated receptors (PPARs), a class of transcription factors endowed with hypolipidemic action, which regulate lipid metabolism through their long-term transcriptional effects. PPARs do not act on one single target but rather orchestrate several pathways whereby nutrients regulate their own metabolism. The three members of the PPAR family (PPARα, -β or -δ, and -γ) differ by their effects and their tissue distribution.
PPARα is the target of hypolipidemic fibrate drugs that induce peroxisomal proliferation in rodents. It is expressed mainly in liver, kidney, and heart and stimulates the transcription of genes that are involved in fatty acid uptake and in mitochondrial and peroxisomal β-oxidation of fatty acids. These transcriptional “feedforward” effects allow fatty acids to prime specific organs for fatty acid oxidation.
The Randle Cycle and Exercise
During exercise, the Randle cycle plays a crucial role in regulating substrate utilization. Glucose and fatty acids are the main energy sources for oxidative metabolism in endurance exercise. Although a reciprocal relationship exists between glucose and fatty acid contribution to energy production for a given metabolic rate, the controlling mechanism remains debatable. Randle et al.’s (1963) glucose-fatty acid cycle hypothesis provides a potential mechanism for regulating substrate interaction during exercise. Increasing fatty acid availability attenuates carbohydrate oxidation during exercise, mainly via sparing intramuscular glycogen. However, there is little evidence for a direct inhibitory effect of fatty acids on glucose oxidation.
Practical Implications and Dieting
The Randle Cycle often has a negative connotation, that it is somehow a bad thing. However, the macronutrient profile of milk really helps drive this point home - as milk is one of the most nutrient-rich superfoods there is, and humans have utilized it for thousands of years for survival. It contains both carbs and fat, and this did not lead to diabetes formation when your Great Grandma milked her cow in the backyard. Eating carbs and fat together does not automatically lead to fat gain, nor is it automatically going to give you diabetes. The relative amounts of carbs and fat in a given meal (and in a given day) can certainly impact energy levels, digestion, and body composition. But the amount of fat and carbs you consume in a given day will be person dependent. There is not a single macro split that will work for everyone - this requires some personal experimentation. The combo of carbs and fat makes food taste good! And this isn't inherently a bad thing, as we should enjoy how our food tastes. You don't have to 24/7 struggle to be healthy.
Dietary Strategies
Some suggest that when eating, it is best not to mix fats with carbs and vice versa, and that when we eat carbs we shut down lipolysis mostly due to higher insulin:glucagon ratios. Since humans are great at storing fat, this also means that whatever fat we ingest along with our carbs is going to go right to storage and stay there until we get that insuling:glucagon ratio back down and stimulate lipolysis. Eating high-insulinogenic carbs and fat together (hello, Western Diet) is what makes people fat. The high levels of insulin prevent lipolysis and [in the fed state], if you’re not oxidizing fat, you’re probably storing it all.
If you’re going to eat foods that stimulate insulin (pasta, bread, oatmeal, yadda, yadda, yadda), it’s probably best to eat these with other foods that are very low-fat, and in the morning. If you’re going to eat fats, make sure to watch the carb content (low sugar, high fiber). Protein probably won’t make a huge difference one way or another.
Recent Advances and Future Directions
Much has been learned during the last four decades about the cross-talk between pathways of energy substrate metabolism. There is a growing recognition that a persistent increase of free fatty acids in the serum, which is seen in shock, heart failure, and aging, indicates a bad prognosis, but there is no generally recognized explanation for the fact that free fatty acids are harmful. The type of fuel used to provide the energy is crucial.
Recent studies have focused on the role of PGC-1α and PGC-1β, transcriptional coactivators involved in mitochondrial biogenesis and oxidative phosphorylation. Abnormal expression or function of PGC-1α and PGC-1β can potentially explain the quartet of muscle, liver, fat, and β cell dysfunction in T2DM.
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