Abstract
Ketone bodies are produced in the liver and are utilized in other tissues in the body as an energy source when hypoglycemia occurs in the body. There are three ketone bodies: acetoacetate, beta hydroxy butyrate, and acetone. Ketone bodies are usually present in the blood, and their level increases during fasting and starvation. They are also found in the blood of neonates and pregnant women. In diabetic ketoacidosis, high levels of ketone bodies are produced in response to low insulin levels and high levels of counter-regulatory hormones.
Introduction
K
Diabetic ketoacidosis
Diabetic ketocidosis may be the presenting feature in a patient not previously recognized as having diabetes. 3 In a patient with known diabetes, it may be precipitated by omitting insulin doses, or by the insulin dose becoming inadequate because of an increase in hormones with opposing action, due to intercurrent infection, trauma, or unusual physical or psychological stress. 4 The clinical features are dehydration, ketosis, and hyperventilation. The degree of hyperglycemia does not correlate with the severity of the metabolic disturbance in diabetic ketoacidosis (DKA), and in some patients, it may not be very high (e.g., in children, pregnant women, malnourished or alcoholic patients). Ketoacidosis is due to insulin deficiency, accompanied by raised plasma concentrations of the counter-regulatory hormones (adrenaline, cortisol, growth hormone, and glucagon) The changes in these circulating hormones result in hyperglycemia and in mobilization of free fatty acids from adipose tissue, and, subsequently, increased ketone body production in the liver. 5 The major metabolic abnormalities result from hyperglycemia or ketoacidosis or both. 6 Hyperglycemia causes extracellular hyperosmolarity, which, in turn, leads to intracellular dehydration as well as to an osmotic diuresis. The osmotic pressure diuresis causes loss of water, sodium, potassium, calcium, and other inorganic constituents, and leads to a fall in circulating blood volume. Ketone bodies stimulate the chemoreceptor trigger zone, so vomiting may exacerbate all these effects. The increased production of ketone bodies causes a metabolic acidosis with associated hyperkalaemia. Lactic acidosis and pre-renal uaemia may also be present. DKA is a state of absolute or relative insulin deficiency that is aggravated by ensuing hyperglycemia, dehydration, and acidosis-producing derangements in intermediary metabolism. 7 The most common causes are underlying infection, disruption of insulin treatment, and new onset of diabetes. DKA is typically characterized by hyperglycemia over 300 mg/dL, low bicarbonate level (<15 mEq/L), and acidosis (pH <7.30) with ketonemia and ketonuria. While definitions vary, moderate DKA can be categorized by pH <7.2 and serum bicarbonate <10 mEq/L; whereas severe DKA has pH <7.1 and bicarbonate <5 mEq/L. Mental status changes can be seen with mild-to-moderate DKA with more severe deterioration in mental status typical with moderate-to-severe diabetic ketoacidosis. The hallmark of potentially fatal DKA is when severe insulin deficiency causes free fatty acids to pour out of adipose tissue and undergo conversion in the liver to the ketone bodies, D-hydroxybutyrate (R-3-hydroxybutyrate) and acetoacetate. In this condition, ketone bodies can reach 25 mM in blood, causing blood bicarbonate to fall to near zero, resulting in severe acidosis. This and the accompanying hypovolemia due to urinary loss of water from the hyperglycemia and glycosuria, combined with loss of sodium and potassium from the ketonuria, result in death if untreated. 8
Research Studies
Genetic obesity affects neural ketone body utilization in the rat brain
It has been shown that ketone bodies are utilized for the synthesis of lipidic substances, and these are responsible for causing metabolic disorders in the nervous system. 9
Lipogenesis and streptozocin-induced diabetes
A study in streptozocin-induced diabetic rats concluded that in streptozocin-induced diabetes, ketosis can not stimulate hepatic lipogenesis via cytosolic activation of acetoacetate. 10
Ketone bodies are beneficial in patients with Alzheimer's disease
It has been observed that in patients with Alzheimer's disease (AD), there is a region-specific decline in brain glucose metabolism. 11 The preferred energy source of the brain is glucose, and it mainly depends on glucose as an energy substrate. Therefore, impairment of glucose metabolism can have profound effects on brain function. This impairment of glucose metabolism in patients with AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies, which include acetoacetate, β-hydroxybutyrate, and acetone. Ketone bodies are usually produced from fat stores when glucose supplies are limited, such as during starvation and fasting. 12 Ketone bodies have been induced both by direct infusion and by the administration of high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of ketone bodies can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of Ketone bodies and ketosis represents a promising new area of Alzeimer's disease research. 13
Role of ketone bodies in epilepsy
Seizures that are resistant to standard treatments remain a major clinical problem. Such types of patients who are resistant to standard medications are advised to consume high-fat, low-carbohydrate ketogenic diets that produce ketone bodies such as acetoacetate, beta hydroxybutyrate, and acetone. The exact mechanisms of the diet are unknown, but ketone bodies are considered as contributing to anti-convulsant antiepileptic effects. Ketone bodies may be useful in the treatment of epilepsy. 14
Neuroprotective and disease-modifying effects of the ketogenic diet
The ketogenic diet is prescribed for patients with epilepsy. There is evidence that the ketogenic diet is effective in neurodegenerative disorders such as Parkinson disease and AD. Furthermore, it may be useful in traumatic brain injury and stroke. Neuroprotective effects of ketone bodies are evident from various studies carried out in animal models and isolated cells. Ketone bodies confer neuroprotection against diverse types of cellular injury. Ketone bodies have demonstrated neuroprotective effects, but the mechanism is not defined. It has been suggested that neuroprotection may be due to energy reserves which resist metabolic changes in the brain. 15
Discussion
One possible fate for the fatty acids released as a result of triacylglycerol breakdown is conversion to ketone bodies. 16 Ketone bodies, unlike fatty acids, cross the blood-brain barrier. Ketone bodies, unlike glucose, can be synthesized from acetyl-Coenzyme A. Ketone bodies can, therefore, provide energy to the brain when glucose availability is limited. 17 Ketone bodies are synthesized from acetyl-Coenzyme A in liver mitochondria by a short pathway beginning with thiolase. One control for the production of ketone bodies is feed-back regulation of high levels of acetyl-Coenzyme A favoring the thiolase condensation reaction that forms acetoacetyl-Coenzyme A, rather than the thiolase cleavage reaction which produces additional acetyl-Coenzyme A. Ketone bodies are converted back to acetyl-Coenzyme A using ketoacyl-Coenzyme A transferase. Liver mitochondria lack this enzyme; starvation causes the brain and some other tissues to increase the synthesis of ketoacyl-Coenzyme A transferase, and, therefore, to increase their ability to use these compounds for energy.
Regulation of ketone bodies
Ketone bodies accumulate in the plasma in conditions of fasting and uncontrolled diabetes. The initiating event is a change in the molar ratio of glucagon: insulin. Insulin deficiency triggers the lipolytic process in adipose tissue with the result that free fatty acids pass into the plasma for uptake by the liver and other tissues. Glucagon appears to be the primary hormone involved in the induction of fatty acid oxidation and ketogenesis in the liver. It acts by acutely lowering hepatic malonyl-CoA concentrations as a consequence of inhibitory effects exerted in the glycolytic pathway and on acetyl-Coenzyme A carboxylase. The fall in malonyl-CoA concentration activates carnitine acyltransferase I, which facilitates the transport of long-chain fatty acids through the inner mitochondrial membrane to the enzymes of fatty acid oxidation and ketogenesis. The latter are high-capacity systems assuring that fatty acids entering the mitochondria are rapidly oxidized to ketone bodies. Thus, the rate-controlling step for ketogenesis is carnitine acyltransferase I. Administration of food after a fast, or of insulin to the diabetic subject, reduces plasma-free fatty acid concentrations, increases the liver concentration of malonyl-CoA, inhibits carnitine acyltransferase I, and reverses the ketogenic process. 18
Footnotes
Author Disclosure Statement
No competing financial interests exist.