Ketosis(Redirected from Nutritional ketosis)
Ketosis is a metabolic state in which some of the body's energy supply comes from ketone bodies in the blood, in contrast to a state of glycolysis in which blood glucose provides energy. Ketosis is a result of metabolizing fat to provide energy.
|Ketone bodies: acetone, acetoacetic acid, and beta-hydroxybutyric acid|
Ketosis is a nutritional process characterised by serum concentrations of ketone bodies over 0.5 mM, with low and stable levels of insulin and blood glucose. It is almost always generalized with hyperketonemia, that is, an elevated level of ketone bodies in the blood throughout the body. Ketone bodies are formed by ketogenesis when liver glycogen stores are depleted (or from metabolising medium-chain triglycerides). The main ketone bodies used for energy are acetoacetate and β-hydroxybutyrate, and the levels of ketone bodies are regulated mainly by insulin and glucagon. Most cells in the body can use both glucose and ketone bodies for fuel, and during ketosis, free fatty acids and glucose synthesis (gluconeogenesis) fuel the remainder.
Longer-term ketosis may result from fasting or staying on a low-carbohydrate diet (ketogenic diet), and deliberately induced ketosis serves as a medical intervention for various conditions, such as intractable epilepsy, and the various types of diabetes. In glycolysis, higher levels of insulin promote storage of body fat and block release of fat from adipose tissues, while in ketosis, fat reserves are readily released and consumed. For this reason, ketosis is sometimes referred to as the body's "fat burning" mode.
Ketosis and ketoacidosis are similar, but ketoacidosis is an acute life-threatening state requiring prompt medical intervention while ketosis can be physiological. However, there are situations (such as treatment-resistant epilepsy) where ketosis can be rather beneficial to health.
Ketone bodies are acidic, but acid-base homeostasis in the blood is normally maintained through bicarbonate buffering, respiratory compensation to vary the amount of CO2 in the bloodstream, hydrogen ion absorption by tissue proteins and bone, and renal compensation through increased excretion of dihydrogen phosphate and ammonium ions. Prolonged excess of ketone bodies can overwhelm normal compensatory mechanisms, defined as acidosis if blood pH falls below 7.35.
There are two major causes of ketoacidosis:
- Most commonly, ketoacidosis is diabetic ketoacidosis (DKA), resulting from increased fat metabolism due to a shortage of insulin. It is associated primarily with type I diabetes, and may result in a diabetic coma if left untreated.
- Alcoholic ketoacidosis (AKA) presents infrequently, but can occur with acute alcohol intoxication, most often following a binge in alcoholics with acute or chronic liver or pancreatic disorders. Alcoholic ketoacidosis occurs more frequently following methanol or ethylene glycol intoxication than following intoxication with uncontaminated ethanol.
Ketosis is deliberately induced by use of a ketogenic diet as a medical intervention in cases of intractable epilepsy. Other uses of low-carbohydrate diets remain controversial. Carbohydrate deprivation to the point of ketosis has been argued to have both negative and positive effects on health.
Adipose tissue can be used to store fatty acids for regulating temperature and energy. These fatty acids can be released by adipokine signaling of high glucagon and epinephrine levels, which inversely corresponds to low insulin levels. High glucagon and low insulin correspond to times of fasting or to times when blood glucose levels are low. Fatty acids must be metabolized in mitochondria, so coenzyme A is bound to the fatty acid to produce acyl-CoA. The acyl-CoA are able to enter the mitochondria. These fatty acids are used as fuel in cells through β-oxidation, which gives a large energy payout per acyl-CoA molecule that is formed from the β-oxidation of a fatty acid.
As β-oxidation begins, FAD dehydrogenates acyl-CoA to form trans-Δ2-enoyl-CoA and FADH2. Acyl-CoA Dehydrogenase catalyses a double bond in this step. Next, trans-Δ2-enoyl-CoA is hydrogenated by enoyl CoA hydratase to form L-β-hydroxyacyl CoA. NAD+ and the enzyme 3-hydroxyacyl-CoA dehydrogenase oxidize L-β-hydroxyacyl CoA to form β-ketoacyl CoA and NADH. Lastly, the β-ketoacyl CoA is cleaved by a thiol group in CoA to form another acyl-CoA and an acetyl-CoA. This reaction is catalyzed by thiolase. The acyl-CoA is two carbons shorter than before, so it enters β-oxidation again until it all converts into acetyl-CoA.
The acetyl-CoA enters the citric acid cycle and undergoes an aldol condensation with oxaloacetate to form citrate. The citric acid cycle is a key pathway for metabolism. It provides precursors for many amino acids as steps in the cycle. It also allows high energy molecules to form; 3x NADH, FADH2, and GTP/ATP are all produced by one iteration of the cycle. This is equivalent to 10 ATP. Acetyl-CoA undergoes this process in any cell, while liver cells can also undergo a different process: ketogenesis.
In the liver, acetyl-CoA can undergo ketogenesis to form ketone bodies. They are produced in mitochondria, and usually occur in response to low blood glucose levels. In the mitochondria, the acetyl-CoA does not enter the citric acid cycle when the amount of acetyl-CoA widely exceeds that of oxaloacetate, as the first step cannot proceed. Along with the fatty acids, deaminated ketogenic amino acids can be converted into intermediates in the citric acid cycle and produce ketone bodies.
Ketogenesis produces one ketone body per two acetyl-CoA. Two acetyl-CoA condense to form acetoacetyl-CoA via thiolase. Acetoacetyl-CoA momentarily combines with another acetyl-CoA via HMG-CoA synthase to form hydroxy-β-methylglutaryl-CoA. Hydroxy-β-methylglutaryl-CoA forms acetoacetate via HMG-CoA lyase. Acetoacetate can then reversibly convert to D-β-hydroxybutyrate via D--β-hydroxybutyrate dehydrogenase. Another option here is acetoacetate can spontaneously degrade to acetone and carbon dioxide. From here, all three ketone bodies (acetoacetate, D--β-hydroxybutyrate, and acetone) have been formed, but acetoacetate and D--β-hydroxybutyrate are in much greater concentrations.
Whether ketosis is taking place can be checked by using special urine test strips such as Ketostix. The strips have a small pad on the end, which the user dips in a fresh urine specimen. Within seconds, the strip changes color to indicate the level of acetoacetate ketone bodies, which reflects the degree of ketonuria, which, in turn, gives a rough estimate of the level of hyperketonemia in the body (see table below). Alternatively, some products targeted to diabetics such as the Abbott Precision Xtra or the Nova Max can be used to take a blood sample and measure the β-hydroxybutyrate ketone levels directly. Normal serum reference ranges for ketone bodies are 0.5–3.0 mg/dL, equivalent to 0.05–0.29 mmol/L.
Also, when the body is in ketosis, one's breath may smell of acetone. This is due to the breakdown of acetoacetic acid into acetone and carbon dioxide exhaled through the lungs. Acetone is the chemical responsible for the smell of nail polish remover and some paint thinners.
|Designation||Approximate serum concentration|
|0||Negative||Reference range: 0.5–3.0||0.05–0.29|
|1+||5 (interquartile range
|0.5 (IQR: 0.1–0.9)|
|2+||Ketonuria||7 (IQR: 2–19)||0.7 (IQR: 0.2–1.8)|
|3+||30 (IQR: 14–54)||3 (IQR: 1.4–5.2)|
The concentration of ketone bodies may vary depending on diet, exercise, degree of metabolic adaptation and genetic factors. Ketosis can be induced when a ketogenic diet is followed for more than 3 days. This induced ketosis is sometimes called nutritional ketosis. This table shows the concentrations typically seen under different conditions
|blood concentration (millimolar)||Condition|
|< 0.2||not in ketosis|
|0.2 - 0.5||slight/mild ketosis|
|0.5 - 3.0||induced/nutritional ketosis|
|2.5 - 3.5||post-exercise ketosis|
|3.0 - 6.0||starvation ketosis|
|15 - 25||ketoacidosis|
Note that urine measurements may not reflect blood concentrations. Urine concentrations are lower with greater hydration, and after adaptation to a ketogenic diet the amount lost in the urine may drop while the metabolism remains ketotic. Most urine strips only measure acetoacetate, while when ketosis is more severe the predominant ketone body is β-hydroxybutyrate. Unlike glucose, ketones are excreted into urine at any blood level. Ketoacidosis is a metabolic derangement that cannot occur in a healthy individual who can produce insulin, and should not be confused with physiologic ketosis.
Some clinicians regard eliminating carbohydrates as unhealthy and dangerous. However, it is not necessary to eliminate carbohydrates from the diet completely to achieve ketosis. Other clinicians regard ketosis as a safe biochemical process that occurs during the fat-burning state. Ketosis, which is accompanied by gluconeogenesis (the creation of glucose de novo from pyruvate), is the specific state that concerns some clinicians. However, it is unlikely for a normally functioning person to reach life-threatening levels of ketosis, defined as serum beta-hydroxybutyrate (B-OHB) levels above 15 millimolar (mM) compared to ketogenic diets among non diabetics, which "rarely run serum B-OHB levels above 3 mM." This is avoided with proper basal secretion of pancreatic insulin. People who are unable to secrete basal insulin, such as type 1 diabetics and long-term type II diabetics, are liable to enter an unsafe level of ketosis, eventually resulting in a coma that requires emergency medical treatment. The anti-ketosis conclusions have been challenged by a number of doctors and advocates of low-carbohydrate diets, who dispute assertions that the body has a preference for glucose and that there are dangers associated with ketosis.
The Inuit are often cited as an example of a culture that has lived for hundreds of years on a low-carbohydrate diet. However, in multiple studies the traditional Inuit diet has not been shown to be a ketogenic diet. Not only have multiple researchers been unable to detect any evidence of ketosis resulting from the traditional Inuit diet, but the ratios of fatty-acid to glucose were observed at well below the generally accepted level of ketogenesis. Furthermore, studies investigating the fat yields from fully dressed wild ungulates, and the dietary habits of the cultures who rely on them, suggest that they are too lean to support a ketogenic diet. With limited access to fat and carbohydrates, cultures such as the Nunamiut Eskimos—who relied heavily on caribou for subsistence—annually traded for fat and seaweed with coastal-dwelling Taremiut.
Some Inuit consume as much as 15–20% of their calories from carbohydrates, largely from the glycogen found in raw meats. Furthermore, the blubber, organs, muscle and skin of the diving marine mammals that the Inuit eat have significant glycogen stores that are able to delay postmortem degradation, particularly in cold weather.
Moreover, recent studies show that the Inuit have evolved a number of rare genetic adaptations that make them especially well suited to eat large amounts of omega-3 fat. And earlier studies showed that the Inuit have a very high frequency—68% to 81% in certain arctic coastal populations—of an extremely rare autosomal recessive mutation of the CPT1A gene—a key regulator of mitochondrial long-chain fatty-acid oxidation—which results in a rare metabolic disorder known as carnitine palmitoyltransferase 1A (CPT1A) deficiency and promotes hypoketotic hypoglycemia—low levels of ketones and low blood sugar. The condition presents symptoms of a fatty acid and ketogenesis disorder. However, it appears highly beneficial to the Inuit as it shunts free fatty acids away from liver cells to brown fat, for thermogenesis. Thus the mutation may help the Inuit stay warm by preferentially burning fatty acids for heat in brown fat cells. In addition to promoting low ketone levels, this disorder also typically results in hepatic encephalopathy (enlarged liver) and high infant mortality. Inuit have been observed to have enlarged livers with an increased capacity for gluconeogenesis, and have greater capacity for excreting urea to remove ammonia, a toxic byproduct of protein breakdown. Ethnographic texts have documented the Inuit's customary habit of snacking frequently  and this may well be a direct consequence of their high prevalence of the CPT1A mutation as fasting, even for several hours, can be deleterious for individuals with that allele, particularly during strenuous exercise. The high frequency of the CPT1A mutation in the Inuit therefore suggests that it is an important adaptation to their low carbohydrate diet and their extreme environment.
In addition to the seaweed and glycogen carbohydrates mentioned above, the Inuit can access many plant sources. The stomach contents of caribou contain a large quantity of partially digested lichens and plants, which the Inuit once considered a delicacy. They also harvested reindeer moss and other lichens directly. The extended daylight of the arctic summer led to a profusion of plant life, and they harvested plant parts including berries, roots and stems, as well as mushrooms. They preserved some gathered plant life to eat during winter, often by dipping it in seal fat.
While it is believed that carbohydrate intake after exercise is the most effective way of replacing depleted glycogen stores, studies have shown that, after a period of 2–4 weeks of adaptation, physical endurance (as opposed to physical intensity) is unaffected by ketosis, as long as the diet contains high amounts of fat, relative to carbohydrates. Some clinicians refer to this period of keto-adaptation as the "Schwatka imperative" after Frederick Schwatka, the explorer who first identified the transition period from glucose-adaptation to keto-adaptation.
In dairy cattle, ketosis is a common ailment that usually occurs during the first weeks after giving birth to a calf. Ketosis is in these cases sometimes referred to as acetonemia. A study from 2011 revealed that whether ketosis is developed or not depends on the lipids a cow uses to create butterfat. Animals prone to ketosis mobilize fatty acids from adipose tissue, while robust animals create fatty acids from blood phosphatidylcholine (lecithin). Healthy animals can be recognized by high levels of milk glycerophosphocholine and low levels of milk phosphocholine. Point of care diagnostic tests are available and are reasonably useful.
In sheep, ketosis, evidenced by hyperketonemia with beta-hydroxybutyrate in blood over 0.7 mmol/L, occurs in pregnancy toxemia. This may develop in late pregnancy in ewes bearing multiple fetuses, and is associated with the considerable glucose demands of the conceptuses. In ruminants, because most glucose in the digestive tract is metabolized by rumen organisms, glucose must be supplied by gluconeogenesis, for which propionate (produced by rumen bacteria and absorbed across the rumen wall) is normally the principal substrate in sheep, with other gluconeogenic substrates increasing in importance when glucose demand is high or propionate is limited. Pregnancy toxemia is most likely to occur in late pregnancy because most fetal growth (and hence most glucose demand) occurs in the final weeks of gestation; it may be triggered by insufficient feed energy intake (anorexia due to weather conditions, stress or other causes), necessitating reliance on hydrolysis of stored triglyceride, with the glycerol moiety being used in gluconeogenesis and the fatty acid moieties being subject to oxidation, producing ketone bodies. Among ewes with pregnancy toxemia, beta-hydroxybutyrate in blood tends to be higher in those that die than in survivors. Prompt recovery may occur with natural parturition, Caesarean section or induced abortion. Prevention (through appropriate feeding and other management) is more effective than treatment of advanced stages of ovine ketosis.
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