The Randle Cycle

In this article we will examine an interesting metabolic phenomenon between fat use and glucose use (as well as other substrates) that provide our body, and more directly, our cells with energy. This metabolic phenomenon was originally called the Randle Cycle, but is also known as the Glucose-Fatty Acid Cycle and is a delicate balance as our body dances from one substrate use to another. In this article, we will cover what the Randle Cycle is, as well as its physiology, and its pathophysiological implications.

What is the Randle Cycle?

The Randle Cycle is a metabolic phenomenon named in 1963 by a group of researchers, headed by Dr. Philip Randle [1]. This cycle is, as mentioned, also known as the Glucose-Fatty Acid Cycle, because it involves the shift from either substrate depending on the circumstances presented to the body; this is, of course, a rudimentary understanding of the complexity of the Randle Cycle, but that is what it is, simply [1].

Physiology of the Randle Cycle

Before we go into the details of the Randle Cycle, we should familiarize ourselves with the basic understanding that our body uses glucose and fatty acid for energy (aka, keep us alive, as well as perform). To use these substrates, our body uses a variety of metabolic pathways. For glucose, our cells employ the metabolic pathway glycolysis to use glucose molecules as intermediates to produce energy, via ATP (primarily) [2]. This is the primary pathway for glucose, yet there are others; we will leave it here for the time being. On the other hand, fatty acid metabolism is dictated by beta-oxidation that then leads to the same beginning product as aerobic glucose metabolism (Acetyl CoA) to the TCA Cycle [3].

So, now we understand, in brevity, the pathways of glucose and fatty acid use for energy, and now we can investigate the Randle Cycle in more detail.

Glycolysis is the pathway glucose uses to create ATP for cellular energy. There is no need to know all of the biochemical undergoings here - simply that glucose is eventually converted to pyruvate (in this instance).

B-Oxidation is the primary pathway of fat metabolism, but again, do not focus on all the biochemical intermediates, just know its primary end product is Acetyl CoA.

Fasted State/Steady State Exercise/High Fat Intake

During a fasted state (or prolonged, steady state exercise, or high fat meals), the body relies heavily on fatty acid release from fat cells, through lipolysis, to spare glucose use [1][5]. In liver, fatty acids are then used to fulfill energy need, but are also used to form ketone bodies through ketogenesis [1]. This sudden rise in fatty acid related substrates decreases oxidation of glucose via regulation of the pyruvate dehydrogenase complex (PDH), phosphofructokinase-1 (PFK-1) and glucose uptake and therefor increasing available pyruvate and lactate for gluconeogenesis in the liver and oxidation in the liver and heart [1][4].

Being in a fasted state, as mentioned, increases lipolysis from adipocytes (fat cells) and fatty acids enter the blood stream. Their uptake by other tissues is debated, but thought to occur by diffusion, passive via the permeable membrane or facilitated via fatty acid membrane proteins [6][7][8]. Once in the cell, fatty acids undergo beta-oxidation to form acetyl CoA to undergo the TCA cycle [6][9]. In liver, specifically, acetyl CoA can undergo ketogenesis or be oxidized for hepatic fuel via TCA [9][10]. An increased reliance on fatty acids leads to a decreased reliance on glycolysis and glucose, so glucose is either used for gluconeogenesis, in liver, or is stored as glycogen, as well as intake into the cells is decreased [1][11]. Interestingly, the entrance of fatty acids is regulated through a few different cellular mechanisms, outlined next.

Pyruvate Dehydrogenase Complex (PDH)

PDH is a multi-subunit enzyme that controls flux of pyruvate, from the cytoplasm and glycolysis, into the mitochondrion [9]. When fatty acids are high, as in a fasted state, PDH complex is inhibited by increased phosphorylation by the Pyruvate Kinase enzyme, a negative regulator of PDH, and decreased dephosphorylation via the Pyruvate Phosphatase enzyme [9].

This phenomenon is caused by high concentrations of acetyl CoA and NADH in mitochondria, indicating fatty acid delivery of both molecules to the TCA is sufficient; this decreases the need for glucose derived pyruvate, slowing PDH allowance of pyruvate into the cell [9]. Also, a low level of mitochondrial calcium (Ca++) also reduces the activity of Pyruvate Phosphatase [9].

Pyruvate, off of Glycolysis, enters the mitochondrion and is oxidized by PDH (at 2) to create acetyl CoA, if glucose use is favored. If fat use is in action, PDH enzyme is less active, because acetyl CoA levels are met by B-Oxidation.

Phosphofructokinase-1 (PFK-1) & Phosphofructokinase-2 (PFK-2)/Fructose-1,6-Bisphosphatase (F-1,6-BP)

To a lesser degree, the enzyme PFK-1 is also inhibited by fatty acids through a similar reason as PDH, but via a different signaling molecule. PFK-1 is inhibited by increases in citrate, which comes off the oxidation of acetyl CoA in the TCA cycle [1][12]. This same mechanism is used to explain the inhibition of PFK-2 in liver and other tissues; which, when high, inhibits gluconeogenesis (in liver, only), so an inhibition of PFK-2 would leave open the possibility for gluconeogenesis [1][13][14]. Not only that, PFK-2 also inhibits PFK-1 via the reduced levels of fructose-2,6-bisphosphate, which would normally attach to PFK-1; these reduced levels of fructose-2,6-bisphosphate also stimulate the back reaction through Fructose-2,6-Bisphosphatase and Fructose-1,6-Bisphosphosphatase (F-1-P ß F-2,6-BP and F-1-P ß F-1,6-BP) in gluconeogenesis [14][15][17].

Both images explain the same scenario, in which high citrate levels, off of the TCA cycle (3rd image), decrease the effectiveness of PFK-1 and PFK-2, leading to lower Glycolysis flux and due to decreased G-2,6-BP, increased F-1,6-BPase activity - leading to gluconeogenesis. 

Glucose Uptake

It may also be that when fatty acid oxidation is high, glucose uptake into the muscle or liver cells is reduced. However, while largely accepted, we are still unsure if such a mechanism is the primary and most powerful down regulator of glucose use or a smaller player that has minor contributions.

Fasted State/Steady State Exercise/High Fat Intake

Now, during a fed state, the reverse Randle Cycle assumes many of the opposite conclusions as glucose levels increase, so fat oxidation decreases and lipogenesis increases in the adipocytes. Naturally, a decrease in fatty acid oxidation in tissue leads to heavier reliance on glycolysis as glucose is taken up from the blood [1]. The greatest driver of this heavier glucose dependency is insulin [1][5]. As a result, gluconeogenesis and ketogenesis are less prevalent as there is ample glucose and decreased lipolysis [5].

By this mechanism, glucose uptake is higher and the subsequent post-glycolysis pyruvate is fed into the mitochondria to be oxidized by PDH to acetyl CoA [18]. However, in liver, more glucose means higher levels of glycerol-3-phosphate which can be used to synthesize triacylglycerol (fat) molecules to be stored; if this occurs, there is an increased activity in the Pentose Phosphate Pathway, as well, as NADPH is needed to be synthesized for other fatty acid synthesis to occur [18].

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