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METABOLIC EFFECTS OF THE VERY-LOW-CARBOHYDRATE DIETS: MISUNDERSTOOD “VILLAINS” OF HUMAN METABOLISM

Anssi H. Manninen
Advanced Research Press, Inc., New York, USA
Received June 22, 2004/Accepted December 10, 2004/Published (online)

Read the next post for a simplified version of this article.

ABSTRACT

During very low carbohydrate intake, the regulated and controlled production of ketone bodies causes a harmless physiological state known as dietary ketosis. Ketone bodies flow from the liver to extra-hepatic tissues (e.g., brain) for use as a fuel; this spares glucose metabolism via a mechanism similar to the sparing of glucose by oxidation of fatty acids as an alternative fuel. In comparison with glucose, the ketone bodies are actually a very good respiratory fuel. Indeed, there is no clear requirement for dietary carbohydrates for human adults. Interestingly, the effects of ketone body metabolism suggest that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. Also, the recent landmark study showed that a very-low-carbohydrate diet resulted in a significant reduction in fat mass and a concomitant increase in lean body mass in normal-weight men. Contrary to popular belief, insulin is not needed for glucose uptake and utilization in man. Finally, both muscle fat and carbohydrate burn in an amino acid flame.

INTRODUCTION

According to the American Heart Association (AHA) Nutrition Committee, "Some popular high-protein/low-carbohydrate diets limit carbohydrates to 10 to 20 g/d, which is one fifth of the minimum 100 g/day that is necessary to prevent loss of lean muscle tissue." Clearly, this is an incorrect statement since catabolism of lean body mass is reduced by ketone bodies (possibly through suppression of the activity of the branched-chain 2-oxo acid dehydrogenase), which probably explains the preservation of lean tissue observed during very-low-carbohydrate diets. Unfortunately, the leading exercise physiology textbook also claims a "low-carbohydrate diet sets the stage for a significant loss of lean tissue as the body recruits amino acids from muscle to maintain blood glucose via gluconeogenesis." Thus, it is certainly time to set the record straight.

THE KETONE BODIES ARE AN IMPORTANT FUEL

The hormonal changes associated with a low carbohydrate diet include a reduction in the circulating levels of insulin along with increased levels of glucagon. This activates phosphoenolpyruvate carboxykinase, fructose 1,6-biphosphatase, and glucose 6-phosphatase and also inhibits pyruvate kinase, 6-phosphofructo-1-kinase, and glucokinase. These changes indeed favor gluconeogenesis. However, the body limits glucose utilization to reduce the need for gluconeogenesis. In the liver in the well-fed state, acetyl CoA formed during the beta-oxidation of fatty acids is oxidized to CO2 and H2O in the citric acid cycle. However, when the rate of mobilization of fatty acids from adipose tissue is accelerated, as, for example, during very low carbohydrate intake, the liver converts acetyl CoA into ketone bodies: Acetoacetate and 3-hydroxybutyrate. The liver cannot utilize ketone bodies because it lacks the mitochondrial enzyme succinyl CoA:3-ketoacid CoA transferase required for activation of acetoacetate to acetoacetyl CoA. Therefore, ketone bodies flow from the liver to extra-hepatic tissues (e.g., brain) for use as a fuel; this spares glucose metabolism via a mechanism similar to the sparing of glucose by oxidation of fatty acids as an alternative fuel. Indeed, the use of ketone bodies replaces most of the glucose required by the brain. Not all amino acid carbon will yield glucose; on average, 1.6 g of amino acids is required to synthesize 1 g of glucose. Thus, to keep the brain supplied with glucose at a rate of 110 to 120 g/day, the breakdown of 160 to 200 g of protein (close to 1 kg of muscle tissue) would be required. This is clearly undesirable, and the body limits glucose utilization to reduce the need for gluconeogenesis and so spare muscle tissue. In comparison with glucose, the ketone bodies are a very good respiratory fuel. Whereas 100 g of glucose generates 8.7 kg of ATP, 100 g of 3-hydroxybutyrate can yield 10.5 kg of ATP, and 100 g of acetoacetate 9.4 kg of ATP. The brain will use ketone bodies whenever provided with them (i.e., whenever blood ketone body levels rise). The blood-brain barrier transporter for ketone bodies is induced during starvation or very low carbohydrate intake, further promoting the flow of ketone bodies. This transporter has a Km that exceeds the concentrations of circulating ketone bodies that occur during starvation or very low carbohydrate intake, and a Vmax well in excess of energy demands. Therefore, ketone body delivery to brain will never be limited by this transporter. However, continued use of some glucose appears obligatory and is supplied by way of hepatic gluconeogenesis. Finally, because of the inactivation of pyruvate dehydrogenase (by the low insulin concentration), the glucose that is used by tissues outside the brain is largely only partially broken down to pyruvate and lactate, which can then be recycled in the liver trough gluconeogensis. Therefore, red blood cells, for instance, which have an obligatory requirement for glucose, are not depleting the body of glucose. Interestingly, Volek et al. recently reported that a very-low-carbohydrate diet resulted in a significant reduction in fat mass and a concomitant increase in lean body mass in normal-weight men. They hypothesized that elevated beta-hydroxybutyrate concentrations may have played a minor role in preventing catabolism of lean tissue but other anabolic hormones were likely involved (e.g., growth hormone).

DIABETIC KETOACIDOSIS VS. DIETARY KETOSIS

Diabetic patients know that the detection in their urine of the ketone bodies is a danger signal that their diabetes is poorly controlled. Indeed, in severely uncontrolled diabetes, if the ketone bodies are produced in massive supranormal quantities, they are associated with ketoacidosis. In this life-threatening complication of diabetes mellitus, the acids 3-hydroxybutyric acid and acetoacetic acid are produced rapidly, causing high concentrations of protons, which overwhelm the body’s acid-base buffering system. However, during very low carbohydrate intake, the regulated and controlled production of ketone bodies causes a harmless physiological state known as dietary ketosis. In ketosis, the blood pH remains buffered within normal limits. Ketone bodies have effects on insulin and glucagon secretions that potentially contribute to the control of the rate of their own formation because of antilipolytic and lipolytic hormones, respectively. Ketones also have a direct inhibitory effect on lipolysis in adipose tissue. Interestingly, the effects of ketone body metabolism suggest that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. The large categories of disease for which ketones may have therapeutic effects are: 1) diseases of substrate insufficiency or insulin resistance; 2) diseases resulting from free radical damage; and 3) disease resulting from hypoxia.

THERE IS NO CLEAR REQUIREMENT FOR DIETARY CARBOHYDRATES FOR HUMAN ADULTS

Although some studies suggest that pre-exercise muscle glycogen stores determine capacity for prolonged exercise, there is no clear requirement for dietary carbohydrates for human adults. Current carbohydrate recommendations are based on 1) preventing ketosis, and 2) providing glucose beyond minimal needs. However, it is clear that ketosis is not harmful, except in the high levels seen in type 1 diabetes. Also, the need to provide glucose above minimal needs is exactly what has never been demonstrated. Indeed, the National Research Council has not established Recommended Dietary Allowance (RDA) for carbohydrates, probably because the human body can adapt to a carbohydrate-free diet and manufacture the glucose it needs. Nevertheless, some nutritionists contend that the carbohydrate is an essential nutrient. For example, McDonald claimed that healthy, moderately active adults require at least 200 g of carbohydrate daily to sustain normal brain metabolism and muscle function. However, the author did not provide any evidence supporting this recommendation. Low-carbohydrate diets have been avoided because of the high-fat nature of the diets and the “predicted” associated hypercholesterolemia. However, serum lipids generally improve with the low-carbohydrate diet, especially the triglyceride and HDL measurements. In sharp contrast, high-carbohydrate diets, which reduce high-density lipoprotein (HDL) cholesterol and raise triglyceride levels, exacerbate the metabolic manifestations of the insulin resistance syndrome. Finally, all fats raise HDL cholesterol. The relative potency of fatty acid classes in raising HDL cholesterol is saturated > monounsaturated > polyunsaturated. Thus, it is clear that replacement of total fat (of any fatty acid distribution) with carbohydrates results in significant reductions in HDL cholesterol. Indeed, recent studies of carbohydrate intake and its relationship to the development of CHD and type 2 diabetes have been rather revealing, showing that an increase in carbohydrate intake is related to increases in both conditions.

INSULIN IS NOT NEEDED FOR GLUCOSE UPTAKE AND UTILIZATION IN HUMANS

Contrary to popular belief supported by the leading physiology and biochemistry textbooks, there is sufficient population of glucose transporters in all cell membranes at all times to ensure enough glucose uptake to satisfy the cell’s respiration, even in the absence of insulin. Insulin can and does increase the number of these transporters in some cells but glucose uptake is never truly insulin dependent. Even under conditions of extreme ketoacidosis there is no significant membrane barrier to glucose uptake – the block occurs “lower down” in the metabolic pathway where the excess of ketones competitively blocks the metabolites of glucose entering the citric acid cycle. Thus, insulin is not needed for glucose uptake and utilization in man. In fact, the process appears to be general for all polar (water-soluble) substrates, as transporters are the mechanism by which they are transported across the highly non-polar (lipid) cell membranes. When insulin is administered to people with diabetes who are fasting, blood glucose concentrations fall. It is generally assumed that this is because insulin increases glucose uptake into tissues. However, this is not the case and is just another metabolic legend arising from in vitro rat data. It has been shown that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting hepatic glucose production.

FATS BURN IN A CARBOHYDRATE FLAME, RIGHT?

It has been claimed that carbohydrates serve as a primer for fat catabolism ("fats burn in a carbohydrate flame"). However, as pointed out by Robergs and Roberts, this is an incorrect contention. In skeletal muscle, fat certainly does not burn in a carbohydrate flame, as skeletal muscle does not have sufficient quantities of the enzymes to convert glycolytic intermediates into molecules that can be transported into the mitochondria to supplement citric acid cycle intermediates. Further, the production of acetoacyl CoA, a substrate of ketone body formation, can occur only in the liver and thus does not apply to skeletal muscle metabolism. Human skeletal muscle can oxidize at least seven amino acids: leucine, isoleucine, valine, glutamate, asparagine, aspartate and alanine. Of these amino acids, however, oxidation of only the branched chain amino acids (leucine, isoleucine and valine) appears to be increased during catabolic states such as exercise. When muscle glycogen and blood glucose concentrations are low, the incorporation of the carbon skeletons from amino acids into the citric acid cycle is important for maintaining the concentrations of the intermediates, and therefore a high rate of mitochondrial respiration. Thus, both muscle fat and carbohydrate burn in an amino acid flame. As discussed by Robergs and Roberts, amino acid catabolism during exercise is important for three reasons: 1) for free energy during exercise to fuel muscle contraction; 2) to increase concentrations of citric acid cycle intermediates and therefore support carbohydrate and lipid catabolism; and 3) to serve as gluconeogenic precursors. It has also been claimed that carbohydrate provides the only macronutrient substrate whose stored energy generates ATP non-aerobically. This is not the case, however, since several studies have shown that amino acid catabolism also provides a source of anaerobic energy production. Aspartate, for example, can be fermented to succinate or propionate. Interestingly, Ivy et al. and Saunders et al., reported that the addition of protein to a carbohydrate supplement enhanced endurance performance above that which occurred with carbohydrate alone.

http://www.sportsnutritionsociety...df/Manninen-JISSN-1-2-7-11-04.pdf

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Dean · Posted: Wed Jun 11, 2008 4:04 am Post subject:

I've produced an "easier read" of this article. I hope this helps.

METABOLIC EFFECTS OF THE VERY-LOW-CARBOHYDRATE DIETS: MISUNDERSTOOD “VILLAINS” OF HUMAN METABOLISM

Anssi H. Manninen
Advanced Research Press, Inc., New York, USA
Received June 22, 2004/Accepted December 10, 2004/Published (online)

ABSTRACT

Eating a VLC diet will produce a harmless state of ketosis, where the body will control the production of ketone bodies. These ketone bodies are produced in the liver, but cannot be used for fuel by the liver, and therefore flow out of the liver and are used by the brain. This spares the need for glucose by the brain that most nutritionists feel is so important in consumption of high levels of carbs. The body can use fat and ketones instead of glucose for many cells. The ketone bodies actually produce more ATP (more energy) than the glucose they replace. There is no clear argument for dietary glucose. Ketosis is actually beneficial for humans, especially humans with metabolic disorders like insulin resistance or glucose metabolism problems (slow metabolism). VLC diets have been shown in studies to reduce body fat, while increasing muscle. Contrary to popular belief, insulin is not needed for glucose uptake and utilization. Finally, both muscle fat and carbohydrate burn in an amino acid flame. Amino acids are used to help fat and glucose be used to fuel muscle activity.

INTRODUCTION

According to the American Heart Association (AHA) Nutrition Committee, "Some popular high-protein/low-carbohydrate diets limit carbohydrates to 10 to 20 g/d, which is one fifth of the minimum 100 g/day that is necessary to prevent loss of lean muscle tissue." Clearly, this is an incorrect statement since breakdown of muscle is reduced by ketone bodies which slow the break down of muscle. This is one reason that muscle is spared on a VLC diet. Unfortunately, the leading exercise physiology textbook also claims a "low-carbohydrate diet sets the stage for a significant loss of lean tissue as the body recruits amino acids from muscle to maintain blood glucose via gluconeogenesis." Thus, it is certainly time to set the record straight.

THE KETONE BODIES ARE AN IMPORTANT FUEL

The hormonal changes associated with a VLC diet include a reduction in the circulating levels of insulin along with increased levels of glucagon. This activates certain enzymes and also inhibits certain enzymes. These changes indeed favor gluconeogenesis (the production of glucose by the liver). However, the body limits glucose utilization to reduce the need for gluconeogenesis. In the well-fed state, the liver will use fat for fuel. However, when the breakdown of body fat is accelerated, as, for example, on a VLC diet, the liver converts some of the by products of this fat use into ketone bodies. The liver cannot use ketone bodies, and therefore, ketone bodies flow from the liver to the brain for use as a fuel; this reduces the need for glucose. Indeed, the use of ketone bodies replaces most of the glucose required by the brain. So, the liver makes glucose and ketone bodies to be used for fuel by the cells of the body. Not all amino acid can be used to make glucose in the liver. Therefore, 1.6 g of amino acids is required to make 1 g of glucose. Thus, to keep the brain supplied with glucose at a rate of 110 to 120 g/day, the breakdown of 160 to 200 g of protein (close to 1 kg of muscle tissue) would be required. This is clearly undesirable, and the body limits glucose utilization to reduce the need for gluconeogenesis and so spare muscle tissue by using ketone bodies instead of glucose. In comparison with glucose, the ketone bodies are a more efficient fuel. Whereas 100 g of glucose can make 8.7 kg of ATP, 100 g of ketone bodies can make 9.4 - 10.5 kg of ATP. So ketones are actually a better fuel for the brain, and the brain prefers to use them over glucose whenever they are present in the blood. However, continued use of some glucose is necessary by certain cells, and therefore must be made by the liver. But, when insulin levels are low, while on a VLC diet, glucose is used more efficiently by the cells that can only use glucose for fuel (like blood cells). While on a VLC diet, glucose is not broken down as far during it’s use as a fuel by the blood cells, and can therefore be recycled more rapidly by the liver to make more glucose. So the amount of glucose that the liver needs to make is reduced. Recent studies have shown a VLC diet reduces body fat, while increasing muscle. Theses studies hypothesized that elevated levels of ketone bodies may have played a minor role in preventing the break down of muscle while other hormones increased the growth of muscle (e.g., growth hormone).

DIABETIC KETOACIDOSIS VS. DIETARY KETOSIS

Diabetic patients know that the detection in their urine of the ketone bodies is a danger signal that their diabetes is poorly controlled. Indeed, in severely uncontrolled diabetes, if the ketone bodies are produced in massive quantities, they are associated with ketoacidosis. In this life-threatening complication of diabetes mellitus, the ketone bodies are produced rapidly, causing high concentrations of protons, which overwhelm the body’s acid-base buffering system. However, during very low carbohydrate intake, the regulated and controlled production of ketone bodies causes a harmless physiological state known as dietary ketosis. In ketosis, the blood pH remains buffered within normal limits. Ketone bodies have effects on insulin and glucagon secretions that potentially contribute to the control of the rate of their own formation. Ketones will even slow down the breakdown of body fat. Interestingly, the effects of ketone body metabolism suggest that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. The large categories of disease for which ketones may have therapeutic effects are: 1) diseases of slow metabolism or insulin resistance; 2) diseases resulting from free radical damage; and 3) disease resulting from hypoxia (deficiency of oxygen). All of these disease states are related to metabolic disorders, caused by high levels of glucose and insulin over one’s lifetime.

THERE IS NO CLEAR REQUIREMENT FOR DIETARY CARBOHYDRATES FOR HUMAN ADULTS

Although some studies suggest that pre-exercise muscle glycogen stores determine capacity for prolonged exercise, there is no clear requirement for dietary carbohydrates for human adults. Current carbohydrate recommendations are based on 1) preventing ketosis, and 2) providing glucose beyond minimal needs. However, it is clear that ketosis is not harmful, except in the high levels seen in type 1 diabetes. Also, the need to provide glucose above minimal needs is exactly what has never been demonstrated. Indeed, the National Research Council has not established Recommended Dietary Allowance (RDA) for carbohydrates, probably because the human body can adapt to a carbohydrate-free diet and manufacture the glucose it needs. Nevertheless, some nutritionists contend that the carbohydrate is an essential nutrient. For example, McDonald claimed that healthy, moderately active adults require at least 200 g of carbohydrate daily to sustain normal brain metabolism and muscle function. However, the author did not provide any evidence supporting this recommendation. Low-carbohydrate diets have been avoided because of the high-fat nature of the diets and the “predicted” associated high cholesterol. However, blood lipids generally improve with a VLC diet, especially the triglyceride and HDL measurements. In sharp contrast, high-carb diets, which reduce HDL cholesterol and raise triglyceride levels, cause insulin resistance. Finally, all fats raise HDL cholesterol. The best fats at doing this are saturated, then monounsaturated, and lastly polyunsaturated. Thus, it is clear that replacement of total fat (of any fatty acid distribution) with carbohydrates results in significant reductions in HDL cholesterol. Indeed, recent studies of carbohydrate intake and its relationship to the development of CHD and type 2 diabetes have been rather revealing, showing that an increase in carbohydrate intake is related to increases in both conditions. Fat doesn’t cause heart disease, sugar does.

INSULIN IS NOT NEEDED FOR GLUCOSE UPTAKE AND UTILIZATION IN HUMANS

Contrary to popular belief supported by the leading physiology and biochemistry textbooks, there is sufficient population of glucose transporters in all cell walls at all times to ensure enough glucose uptake to fuel the cell, even in the absence of insulin. The cells have the means to uptake glucose without the need of insulin. Insulin can and does increase the number of these transporters in some cells but glucose uptake is never truly insulin dependent. Even during extreme ketoacidosis there is no significant blockage to glucose getting into the cell – the block occurs later, while the cell is using the glucose for fuel. The cell prefers to use ketones and fat for fuel, and therefore the glucose is not needed as much, and therefore not taken in as much by the cell. So, on a VLC diet, it is not the low insulin that keeps glucose out of the cell, but the fact the cell has less need for glucose, instead using ketone bodies and fat for fuel. This process of cellular uptake of fuel appears to be general for all fuel, as transporters are the mechanism by which they are transported across the cell walls. When insulin is administered to people with diabetes who are fasting, blood glucose concentrations fall. It is generally assumed that this is because insulin increases glucose uptake into cells. However, this is not the case and is just another metabolic legend arising from in vitro rat data. It has been shown that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting the production of glucose by the liver. So, insulin slows down the liver from making glucose, rather than shoving the blood glucose into cells. The cells can take up the glucose by themselves. Although insulin will increase the transporters the cell uses to take in glucose, thereby indirectly aiding the cell to take up more glucose, it is not required for the process to take place.

FATS BURN IN A CARBOHYDRATE FLAME, RIGHT?

It has been claimed that carbohydrates serve as a primer for fat being used for fuel ("fats burn in a carbohydrate flame"). However, as pointed out by Robergs and Roberts, this is an incorrect contention. In skeletal muscle, fat certainly does not burn in a carbohydrate flame, as skeletal muscle does not have enough of the enzymes needed to use glucose for fuel. Further, the production of acetoacyl CoA, which is used for making ketone bodies, can occur only in the liver and thus does not apply to skeletal muscle metabolism. Therefore, ketone bodies cannot be used for fuel by the muscles. Human skeletal muscle can use at least seven amino acids for fuel. Of these amino acids, however, only the branched chain amino acids appear to be used during exercise. When muscle glycogen and blood glucose concentrations are low, amino acids will be used for fuel. Thus, both muscle fat and carbohydrate burn in an amino acid flame. As discussed by Robergs and Roberts, amino acid catabolism (muscle break down) during exercise is important for three reasons: 1) for free energy during exercise to fuel muscle contraction; 2) to aid glucose and fat in being used for fuel; and 3) to be used to make glucose by the liver. It has also been claimed that carbs fuel the muscles for anaerobic activity (for immediate short bursts of activity). This is not the case, however, since several studies have shown that amino acids also provide fuel for this type of activity.

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