In this post and the next, my aim is to explore the contentious issue of the optimum of balance of fat and carbohydrate in an endurance runner’s diet, focussing on evidence for the effects on training adaptation, on running performance, and on overall health. In my previous two posts I have addressed specific aspects of nutrition: the advantages and disadvantage of training in a fasted state; and nutritional strategies to minimise risk of chronic inflammation. Both of those topics are relevant to the current discussion, so I will start by summarising the conclusions from those posts.
The evidence regarding training in the fasted, glycogen depleted state leads to the conclusion that it is likely to enhance capacity to utilise fats, which is advantageous for an ultra-marathoner and perhaps also for marathoners. Under some circumstances, it might also produce enhancement of aerobic enzymes. However, a high fat diet abolishes these advantages of training in the fasted state. Furthermore, training in a glycogen depleted state increases the risk of excessive elevation of cortisol during either intense or prolonged training sessions. Overall, I do not think the benefit justifies the risks, especially as much of the benefit might be obtained from increasing the amount of fat in the diet
With regard to inflammation, while acute inflammation promotes tissue repair after training, chronic inflammation is not only associated with the overtraining syndrome but also carries a serious risk of long term cardiovascular disease. The evidence indicates that two worthwhile nutritional strategies are minimization of high Glucose Index carbohydrates (which promote a spike of insulin which can be associated with release of arachidonic acid, which is pro-inflammatory) and the consumption of approximately equal proportions of non-inflammatory omega 3 and pro-inflammatory omega 6 fats. Thus, the need to avoid chronic inflammation indicates which carbohydrates and which fats are healthy, but does not address the question of the optimum proportion of fat to carbohydrate. In recent decades, many endurance athletes have favoured a high carbohydrate diet but in recent time, the high fat/ high protein Paleo diet has attracted attention, based on the speculation that our primitive ancestors adapted via evolution to such a diet.
Why is the debate so controversial?
The advocates of a high intake of carbohydrates, and advocates of low carbohydrate/high fat diet such as the Paleo diet can each assemble evidence, from both anecdotes and from systematic scientific study to support their cases. Resolution of the debate is elusive because the evidence appears contradictory. The reason why the evidence is confusing becomes clear when you examine the complexity of the network of metabolic processes, including the catabolic processes by which fuel stores and body tissue are broken down to produce energy, and the anabolic processes by which tissues are repaired, strengthened and develop increased metabolic capacity. There are multiple pathways by which a particular metabolic goal can be achieved. This allows flexibility, but the choice of a particular fuel source, or a particular source of building material for anabolic processes has diverse knock-on effects. In many instances, the stimulation or inhibition of a particular metabolic pathway depends on the release of a particular hormone, and the relevant hormones can have diverse effects extending beyond the immediate metabolic goal. Genes, past training experiences and diet all influence the outcome. Therefore it is not surprising that evidence from studies of the effects of diet on small groups of individuals give differing results depending on the features of those individuals, Conversely, attempting to apply conclusions from epidemiological studies of large populations to an individual might be misleading. However, the picture is not hopeless. I think that sound, though nonetheless tentative, conclusions can be drawn from the existing evidence. Some understanding of the inter-locking networks of catabolic and anabolic pathways helps in achieving a sensible application of these conclusion to one’s own situation.
Catabolic and anabolic processes
Successful training demands a balance between catabolism: the break-down of carbohydrates, fats or proteins to yield the energy required to fuel muscle contraction, and also the process of autophagy, required to remove debris from cells; and anabolism: the building of body tissues to repair damage suffered during training, build new tissue, and develop increased metabolic capacity. Although the details of the biochemical pathways are complex, the broad outline is fairly easy to grasp, provided one avoids being bamboozled by the names of the molecules.
Figure 1 illustrates the cardinal role in both catabolism and anabolism played by the cyclic pathway known as the Krebs cycle, named after Hans Krebs, the biochemist who delineated it. For our present purpose, there are two important things to observe in this map of the metabolic pathways. First, the catabolic pathways by which the three major types of fuel (carbohydrate, fats and proteins) are burned to generate energy, converge onto the Krebs cycle. Training that produces an increase in the enzymes that carry out the biochemical transformations that make up the Krebs cycle will increase the capacity to utilise any one of the three types of fuel, but the question of which fuel is selected in particular circumstances depends on availability of the raw material and on the hormonal milieu. Secondly, some of the key anabolic pathways which produce amino acids, (the building blocks of proteins) and also many other substances essential for various bodily functions, begin as off-shoots of this cyclic pathway.
The enzymes that carry out the reactions of the Krebs cycle are located in mitochondria, the sub-cellular powerhouses in which the energy rich molecule ATP is produced as a result of oxidation of fuel. The cycle starts with the combination of a molecule containing 4 carbon atoms, oxaloacetate, with a fuel fragment containing 2 carbon atoms, known as an acetyl group, which has been generated by the first steps in the catabolism of carbohydrate, fat or protein. The combination of the 4-carbon oxaloacetate with the 2-carbon acetyl group produces citrate, which contains 6 carbon atoms. The citrate then enters a series of eight chemical transformations catalysed by enzymes. In two of these transformations a carbon atom is removed and combined with oxygen to produce carbon dioxide. By the time the original 6-carbon molecule completes the cycle it has been converted back to the 4-carbon oxaloacetate, and is ready to repeat the cycle.
There are several important outputs from the cycle. Most important for the role of the Krebs cycle in the generation of energy is the transfer of hydrogen atoms (carried by the coenzyme, NAD) to a complex of enzymes known as cytochromes, which are the key components of a system known as the electron transport chain. The hydrogen atoms feed electrons into this chain thereby providing the energy to create the high energy molecule ATP from its precursor ADP. ATP fuels virtually all of the energy-demanding activities of the cell, including muscle contraction.
Furthermore various other metabolic pathways branch off from intermediate stages in the Krebs cycle. Several of these pathways result in the synthesis of amino acids. These are required not only for the building of proteins but also serve many other roles. One of the most important is glutamine, highlighted in blue in figure 1. Glutamine is the most abundant amino acid in the body. It is mainly produced in muscle, but serves as a key fuel for the cells lining the gut. It also plays a key role in the transmission of long-range communication within the brain. However glutamine can also be synthesized in the brain, so the brain is not critically dependent on muscle for glutamine, but it is of interest that glutamine is the one amino acids that can cross the blood-brain barrier. Glutamine is also required to fuel cells of the immune system. During intense exercise, the spin-off pathway that produces glutamine cannot cope with demand and glutamine levels fall. It is possible that the decreased availability of glutamine is one factor leading to increased susceptibility of marathon runners to minor respiratory infections. However, there is no convincing evidence that glutamine supplements reduce the prevalence of colds in marathoners.
Nonetheless, one important consequence of the spin-off of glutamine is that the Krebs cycle gets depleted of some of its intermediates, and oxaloacetate has to be topped-up if the cycle is to be sustained. This can be achieved by the direct conversion of pyruvate (high-lighted in red in figure 1) to oxaloacetate. Thus, even when fat is the main source of fuel entering the Krebs cycle, a contribution from pyruvate is required to top-up the cycle. Pyruvate also serves as the beginning point for the synthesis of several amino acids. Pyruvate is produced from glucose via glycolysis. The multiple key roles of pyruvate illustrate the essential role for glucose, even when the muscle cell is deriving most of its energy from fat.
When oxygen supply is inadequate, the Krebs cycle slows down and pyruvate is converted to lactate. During the generation of pyruvate from glucose via glycolysis, each molecule glucose yields only the 2 molecules of ATP (plus two molecules of NADH which can transfer electrons into the electron transport chain, each generating an additional 2 molecules of ATP), in contrast of the total of 36 molecules of ATP produced by the full sequence of glycolysis, the Krebs cycle and electron transport along the electron transport chain.
Although not all details are shown in figure 1, the intermediate metabolites of the Krebs cycle can also act as the starting point in the synthesis of many other substances that play a key role in the biochemical processes that occur in cells, and can also act as the precursors for the synthesis of glucose and fats.
In summary, the Krebs cycle lies at the centre of a complex network of catabolic and anabolic processes. As mentioned above, the network of pathways offers the flexibility provided by alternative ways of meeting its metabolic needs. Energy can be derived from various different sources; and there are alternative ways of synthesising the molecules required to replenish fuel stores after training; to repair the body; to increase strength by augmenting muscle and other connective tissues; and to increase metabolic capacity by synthesis of enzymes.
The response to glycogen depletion
As an illustration of the ways in which the body typically deploys these pathways to deal with particular circumstances, let us consider the situation facing an endurance runner when glycogen supplies begin to run out – the infamous ‘bonk’ that typically occurs in the final 10 Km of a marathon.
Glycogen is the storage form of carbohydrate from which glucose is released. Even if we are mainly burning fat, muscle requires some glucose to feed into the glycolytic pathway to ensure a reasonable supply of pyruvate, necessary for keeping the Krebs cycle topped up to replace the keto-glutarate that is diverted to produce glutamine. By this stage of the race, glutamine is becoming depleted, yet is needed to keep the cells of the gut wall functioning well, and also to help the kidney to maintain acid-base balance. But even more importantly, the brain needs glucose for fuel because the brain has very few other options for providing energy. So the body’s highest priority is maintaining adequate glucose levels to supply the brain.
When glycogen stores become seriously depleted, the tendency for blood glucose to fall stimulates cortisol release. This was illustrated in a study by Tabata and colleagues in which healthy young men exercised to exhaustion following a 14 hour fast. Both ACTH (which promotes cortisol release from adrenals) and cortisol itself, were increased. Cortisol stimulates the synthesis of glucose (from pyruvate and oxaloacetate) via the process known as gluconeogenesis (see figure 1) in the liver. At this stage of a marathon, the main source of the pyruvate is likely to be lactate generated in muscle and transported via the blood to the liver. Alternatively, glutamine might be converted to ketoglutarate and thence to oxaloacetate.
Because the priority is supplying the brain, not the muscles, cortisol inhibits the transport of glucose into peripheral tissues, including muscle, by keeping the glucose transporter molecules away for the cell surface. The increased level of cortisol is likely to result in further reduction of liver glycogen, because cortisol facilitates the action of adrenaline in promoting breakdown of glycogen. It is noteworthy, that under other circumstances, cortisol can facilitate the action of insulin in synthesis of glycogen, but that is unlikely to apply in states of serious glycogen depletion since the body’s priority will be maintaining blood glucose.
Because cortisol has acted to decrease the transport of glucose into muscle cells, the major input of fuel to the Krebs cycle in muscle must come from fats. There are two pathways by which fats can generate the acetyl groups that keep the Krebs cycle revolving and producing energy: beta oxidation that splits the two-carbon acetyl group from long fatty acid chains, and the production of ketones. Beta-oxidation is stimulated by cortisol. Furthermore, when liver glycogen levels are low, fats are converted to ketones in the liver, whence they are released into the blood stream. In both the brain and muscle, ketones can generate the acetyl groups required to maintain the energy supply.
Thus the body has a substantial capacity to ensure that the brain is supplied with glucose, and in extremis, with ketones. However this is achieved at the price of the elevation of cortisol. As discussed previously, Skoluda and colleagues have demonstrated endurance athletes tend to have sustained high levels of cortisol. In the long term this can lead to many adverse effects, including immune suppression, and also, somewhat paradoxically, chronic inflammation, probably mediated by a decrease in sensitivity of glucocorticoid receptors that mediate the effects of cortisol.
Thus one of the major needs of the endurance runner is enhancement of the capacity to utilise fats in preference to glucose before marked depletion of glycogen occurs. Both training itself and diet can help achieve this. In the next post, we will examine the evidence regarding the effects of diet not only on modulating the effects of training, but also on long term health.