In a recent Ben Greenfield podcast, Ben and his guest, Denise Minger, discussed about the Randle Cycle – which is also known as the glucose-fatty acid cycle. This cycle describes the competition between metabolic fuels.
I read a few papers about the Randle Cycle as it sparked my interest. In this post I’m going into the specifics of one of these papers. I suspect that many people are confused about how this works.
This paper is a review published in The American Journal of Physiology (APS), Endocrinology and Metabolism and it’s open access. 
The Randle Cycle
In 1963, Lancet published a paper by Randle et al. that proposed a “glucose-fatty acid cycle” to describe fuel flux between and fuel selection by tissues. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Since then, the principle has been confirmed by many investigators. At the same time, many new mechanisms controlling the utilization of glucose and fatty acids have been discovered.
You can read the initial paper here (requires subscription). You may access it for free through your library. 
For example, it was known that the high insulin/glucagon ratio of the postabsorptive state promotes lipid and carbohydrate storage. And it was also known that a high glucagon/insulin ratio, characteristic of the fasted state, stimulates adipose tissue lipolysis and hepatic glucose production to preserve glucose supply to those tissues that rely exclusively on this sugar.
Lower carbohydrate intake may lead to lower postabsorptive insulin/glucagon ratio.
Another aspect of the Randle cycle often not appreciated is the inhibition of adipose tissue lipolysis by glucose and insulin via a mechanism involving stimulation of glucose uptake and reesterification of fatty acids in the presence of glucose-derived glycerol 3-phosphate 
Simply put, circulating glucose and insulin inhibit fat breakdown and promote triglyceride synthesis, while at the same time promotes glucose uptake by tissues, as needed.
One of the major points in the Randle Cycle is that, under normal conditions, only one of the fuels – fats or carbohydrates – may be predominantly oxidized. There are some exceptions. Keep reading.
Glucose is Spared and Rerouted
In the fasted state, 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. In addition, inhibition of glucose oxidation at the level of pyruvate dehydrogenase (PDH) preserves pyruvate and lactate, both of which are gluconeogenic precursors. 
Conversely to the fed and the post-absorptive state, the fasted stated is characterized by increased oxidation of fatty acids and ketones (in normal people and under normal circumstances).
As pointed out by researchers, the inhibition of glucose oxidation by fatty acids is not restricted to the fasted state. It may happen under feeding conditions (after high fat meals) and during exercise when fatty acids and ketones are oxidized as well. In such conditions, glucose that is not oxidized contributes and may explain the rapid resynthesis of glycogen post-exercise.   
The mechanism of post-exercise glycogen resynthesis seems not to be significantly different in fat-adapted vs. non-fat adapted athletes, a mechanisms which is described in detailed in a recent paper by Volek and colleagues . I reviewed the paper in this post.
Fatty Acids and PPARs Activity
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. 
PPARα’s expression in the liver, heart, and kidneys promotes the transcription of genes involved in beta oxidation and fatty acid uptake. PPARα also controls lipid metabolism by regulating LPL (lipoprotein lipase) expression.
Stress Overrides Fatty Acid Inhibition of Glucose Metabolism
Under normal, fed and fasted, states and when there is no immediate acute stress, only one of the fuels is predominantly oxidized. However, there are exceptions.
Under hemodynamic stress conditions, the inhibition of carbohydrate oxidation by fatty acids is abrogated. 
AMPk is activated when the AMP/ATP is higher. The purpose of AMPk is to regulate/restore energy levels.
Exercise and physical activity lead to AMPK activation in skeletal muscle, and the extent of this activation depends on the intensity and duration of exercise. Similarly, oxygen deprivation activates AMPK, as is the case in the ischemic heart. Once activated, AMPK regulates energy balance by turning on catabolic ATP-generating pathways (fatty acid oxidation and glycolysis) while switching off anabolic ATP-consuming processes (lipid and protein synthesis).  
When oxygen is available, AMPk activation promotes fatty acid oxidation.
Under these conditions, efficient utilization of both substrates maximizes ATP production, providing an immediate metabolic adaptation to the stress conditions responsible for AMPK activation and protecting the heart during ischemic stress. Therefore, AMPK overrules the biochemical mechanisms involved in the Randle cycle, and inhibition of glucose uptake by fatty acids no longer prevails. 
Another situation when both fats and carbs are recruited for oxidation has been observed in hearts stimulated with adrenaline.
Stimulation of heart glycolysis by this hormone and its second messenger cyclic AMP overrules the control by other oxidizable substrates (30, 38, 183). This results from a concerted action of adrenergic receptor activation on glucose uptake, glycogen breakdown, PFK flux, and PDH activity mediated by cyclic AMP and intramitochondrial [Ca ] accumulation.  
In addition, epinephrine promotes fatty acid oxidation as a result of ACC inactivation by the cyclic AMP-dependent protein kinase (PKA; see below). Under these conditions, the heart oxidizes both glucose and fatty acids, but it uses carbohydrates to sustain the large increase in heart function induced by epinephrine. 
Mitochondrial Events Control Fuel Selection
Cell respiration is enhanced when fatty acids are used. The NADH/NAD+ ratio increases significantly. Mitochondrial membrane potential also increases. This leads to an excess of energy production.
However, increased energy supply does not entirely explain the stimulation of respiration, because at any given rate of respiration, ΔΨ is significantly lower with fatty acids, indicating increased energy consumption and/or a loss of efficiency of oxidative phosphorylation. 
When fatty acids are oxidized over glucose, there are more electrons being transferred to complex 2 of the respiratory chain, rather than complex 1.
This difference is reflected in a less efficient oxidative phosphorylation (ATP/O), because electrons entering complex 1 result in a higher ATP/O ratio than those entering complex 2, being equivalent to a form of “intrinsic uncoupling.” A loss of efficiency could also result from “redox slipping,” i.e., inefficient coupling between electron and proton fluxes, or from proton leak across the mitochondrial inner membrane, which also contributes to the stimulation of respiration by fatty acids. 
There are many references cited here. For the full list, please see the article .
To maintain ΔΨ and ATP synthesis, mitochondria have no other choice but to increase respiration. Moreover, high values of ΔΨ can prevent normal electron flow and lead to reversed electron flow and eventually to enhanced production of reactive oxygen species (ROS) (Fig. 7). Therefore, by oxidizing fatty acids, mitochondria increase their respiration, their membrane potential, and the production of ROS. 
The authors explain the potential mechanisms by which mitochondria may prefer the oxidation of fatty acids over glucose. As further noted, when fatty acids and glucose flood the system – like when following a ‘balanced’ diet – glucose toxicity and pathologic conditions may arise.
High values of ΔΨ lead to proton leak, reversed electron flow, and ROS production (Fig. 7). As described above, active fatty acid oxidation induces such a state. Flooding the system with glucose on top of fatty acids is expected to induce considerable damage to the mitochondria if energy demand is not concomitantly increased. An overabundant diet rich in carbohydrates and fat should force-feed electrons from glucose into the respiratory chain, in which the already prevailing high ΔΨ prevents electron flow. 
Such high energy supply, if not used, will further worsen the jamming of electrons in the respiratory chain and eventually result in massive ROS production and mitochondrial damage (Fig. 7). 
Glucose toxicity and mitochondria damage may be avoided through physical exercise, when the energy produced would be matched by the energy utilized. In this case, ΔΨ will decrease. The authors wonder whether glucose tolerance/insulin resistance is not a mechanism to protect against glucose toxicity. In a similar context, I wrote about insulin resistance viewed from an evolutionary perspective.
Moreover, they discuss the possibility of muscle insulin resistance being the result of lower oxidation of fatty acids in the mitochondria. Since they are available and cannot be oxidized, they are used for the synthesis of DAG (diacylglycerol and ceramide), leading to stress-induced protein kinases that inhibit insulin signaling   
Accurate picture of the mitochondrial wreckage of many folks today:
The slowly progressing pathological process could be the consequence of a continuous overabundant diet enriched in both carbohydrate and lipid, unmatched by physical activity. In the mitochondria, the redox pressure from both substrates would provoke a continuous production of ROS, resulting first in minimal damage but deteriorating with time into more extensive and irreversible lesions. 
In a previous write-up I outlined a few reasons against a dietary approach that emphasizes macronutrient intake, the IIFYM (if it fits your macros). Moreover, not restricting one or the other (fats or carbohydrates) may lead to competition between fuels if energy production is unmatched by energy utilization. Lipolysis would be minimized, while glucose toxicity and pathological conditions would arise.
Thoughts and comments below.
- Hue, L., & Taegtmeyer, H. (2009). The Randle cycle revisited: a new head for an old hat. American Journal of Physiology-Endocrinology and Metabolism, 297(3), E578-E591.
- Randle, P. J., Garland, P. B., Hales, C. N., & Newsholme, E. A. (1963). The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. The Lancet, 281(7285), 785-789.
- Garland, P. B., Newsholme, E. A., & Randle, P. J. (1962). Effect of fatty acids, ketone bodies, diabetes and starvation on pyruvate metabolism in rat heart and diaphragm muscle.
- Hue, L., & Rider, M. H. (1987). Role of fructose 2, 6-bisphosphate in the control of glycolysis in mammalian tissues. Biochemical Journal, 245(2), 313.
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- Gaesser, G. A., & Brooks, G. A. (1980). Glycogen repletion following continuous and intermittent exercise to exhaustion. Journal of Applied Physiology, 49(4), 722-728.
- Volek, J. S., Freidenreich, D. J., Saenz, C., Kunces, L. J., Creighton, B. C., Bartley, J. M., … & Lee, E. C. (2016). Metabolic characteristics of keto-adapted ultra-endurance runners. Metabolism, 65(3), 100-110.
- Hutber, C. A., Hardie, D. G., & Winder, W. W. (1997). Electrical stimulation inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase. American Journal of Physiology-Endocrinology And Metabolism, 272(2), E262-E266.
- Kudo, N., Gillespie, J. G., Kung, L., Witters, L. A., Schulz, R., Clanachan, A. S., & Lopaschuk, G. D. (1996). Characterization of 5′ AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochimica et Biophysica Acta (BBA)-Lipids and Lipid Metabolism, 1301(1), 67-75.
- Depre, C., Ponchaut, S., Deprez, J., Maisin, L., & Hue, L. (1998). Cyclic AMP suppresses the inhibition of glycolysis by alternative oxidizable substrates in the heart. Journal of Clinical Investigation, 101(2), 390.
- McCormack, J. G., & Denton, R. M. (1984). Role of Ca2+ ions in the regulation of intramitochondrial metabolism in rat heart. Evidence from studies with isolated mitochondria that adrenaline activates the pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes by increasing the intramitochondrial concentration of Ca2+. Biochem. J, 218, 235-247.
- Goodwin, G. W., Taylor, C. S., & Taegtmeyer, H. (1998). Regulation of energy metabolism of the heart during acute increase in heart work. Journal of Biological Chemistry, 273(45), 29530-29539.
- Harmancey, R., Wilson, C. R., & Taegtmeyer, H. (2008). Adaptation and maladaptation of the heart in obesity. Hypertension, 52(2), 181-187.
- Morino, K., Petersen, K. F., & Shulman, G. I. (2006). Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes, 55(Supplement 2), S9-S15.