Diabetic neuropathy

From Wikipedia, the free encyclopedia

 

Diabetic neuropathy
Specialty	Endocrinology

Diabetic neuropathies are nerve damaging disorders associated with diabetes mellitus. These conditions are thought to result from a diabetic microvascular injury involving small blood vessels that supply nerves (vasa nervorum) in addition to macrovascular conditions that can accumulate in diabetic neuropathy. Relatively common conditions which may be associated with diabetic neuropathy include third, fourth, or sixth cranial nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; a painful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy.

Signs and symptoms

Illustration depicting areas affected by diabetic neuropathy

 

Diabetic neuropathy affects all peripheral nerves including sensory neurons, motor neurons, but rarely affects the autonomic nervous system. Therefore, diabetic neuropathy can affect all organs and systems, as all are innervated. There are several distinct syndromes based on the organ systems and members affected, but these are by no means exclusive. A patient can have sensorimotor and autonomic neuropathy or any other combination. Signs and symptoms vary depending on the nerve(s) affected and may include symptoms other than those listed. Symptoms usually develop gradually over years. 

Symptoms may include the following:

• Trouble with balance
• Numbness and tingling of extremities
• Dysesthesia (abnormal sensation to a body part)
• Diarrhea
• Erectile dysfunction
• Urinary incontinence (loss of bladder control)
• Facial, mouth and eyelid drooping
• Vision changes
• Dizziness
• Muscle weakness
• Difficulty swallowing
• Speech impairment
• Fasciculation (muscle contractions)
• Anorgasmia
• Retrograde ejaculation (in males)
• Burning or electric pain

Pathogenesis

The following factors are thought to be involved in the development of diabetic neuropathy:

Microvascular disease

Vascular and neural diseases are closely related and intertwined. Blood vessels depend on normal nerve function, and nerves depend on adequate blood flow. The first pathological change in the small blood vessels is narrowing of the blood vessels. As the disease progresses, neuronal dysfunction correlates closely with the development of blood vessel abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia. Neuronal ischemia is a well-established characteristic of diabetic neuropathy. Blood vessel opening agents (e.g., ACE inhibitors, α1-antagonists) can lead to substantial improvements in neuronal blood flow, with corresponding improvements in nerve conduction velocities. Thus, small blood vessel dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy.

Advanced glycated end products

Elevated levels of glucose within cells cause a non-enzymatic covalent bonding with proteins, which alters their structure and inhibits their function. Some of these glycated proteins have been implicated in the pathology of diabetic neuropathy and other long-term complications of diabetes.

Polyol pathway

Also called the sorbitol/aldose reductase pathway, the polyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina, kidney, and nerves.

Sensorimotor polyneuropathy

Longer nerve fibers are affected to a greater degree than shorter ones because nerve conduction velocity is slowed in proportion to a nerve's length. In this syndrome, decreased sensation and loss of reflexes occurs first in the toes on each foot, then extends upward. It is usually described as a glove-stocking distribution of numbness, sensory loss, dysesthesia and night time pain. The pain can feel like burning, pricking sensation, achy or dull. A pins and needles sensation is common. Loss of proprioception, the sense of where a limb is in space, is affected early. These patients cannot feel when they are stepping on a foreign body, like a splinter, or when they are developing a callous from an ill-fitting shoe. Consequently, they are at risk of developing ulcers and infections on the feet and legs, which can lead to amputation. Similarly, these patients can get multiple fractures of the knee, ankle or foot, and develop a Charcot joint. Loss of motor function results in dorsiflexion, contractures of the toes, loss of the interosseous muscle function that leads to contraction of the digits, so-called hammer toes. These contractures occur not only in the foot but also in the hand where the loss of the musculature makes the hand appear gaunt and skeletal. The loss of muscular function is progressive.

Autonomic neuropathy

The autonomic nervous system is composed of nerves serving the heart, lungs, blood vessels, bone, adipose tissue, sweat glands, gastrointestinal system and genitourinary system. Autonomic neuropathy can affect any of these organ systems. The most commonly recognized autonomic dysfunction in diabetics is orthostatic hypotension, or becoming dizzy and possibly fainting when standing up due to a sudden drop in blood pressure. In the case of diabetic autonomic neuropathy, it is due to the failure of the heart and arteries to appropriately adjust heart rate and vascular tone to keep blood continually and fully flowing to the brain. This symptom is usually accompanied by a loss of respiratory sinus arrhythmia – the usual change in heart rate seen with normal breathing. These two findings suggest autonomic neuropathy.

GI tract manifestations include gastroparesis, nausea, bloating, and diarrhea. Because many diabetics take oral medication for their diabetes, absorption of these medicines is greatly affected by the delayed gastric emptying. This can lead to hypoglycemia when an oral diabetic agent is taken before a meal and does not get absorbed until hours, or sometimes days later when there is normal or low blood sugar already. Sluggish movement of the small intestine can cause bacterial overgrowth, made worse by the presence of hyperglycemia. This leads to bloating, gas and diarrhea.

Urinary symptoms include urinary frequency, urgency, incontinence and retention. Again, because of the retention of urine, urinary tract infections are frequent. Urinary retention can lead to bladder diverticula, stones, reflux nephropathy.

Cranial neuropathy

When cranial nerves are affected, neuropathies of the oculomotor nerve (cranial nerve #3 or CNIII) are most common. The oculomotor nerve controls all the muscles that move the eye except for the lateral rectus and superior oblique muscles. It also serves to constrict the pupil and open the eyelid. The onset of a diabetic third nerve palsy is usually abrupt, beginning with frontal or pain around the eye and then double vision. All the oculomotor muscles innervated by the third nerve may be affected, but those that control pupil size are usually well-preserved early on. This is because the parasympathetic nerve fibers within CNIII that influence pupillary size are found on the periphery of the nerve (in terms of a cross-sectional view), which makes them less susceptible to ischemic damage (as they are closer to the vascular supply). The sixth nerve, the abducens nerve, which innervates the lateral rectus muscle of the eye (moves the eye laterally), is also commonly affected but fourth nerve, the trochlear nerve, (innervates the superior oblique muscle, which moves the eye downward) involvement is unusual. Damage to a specific nerve of the thoracic or lumbar spinal nerves can occur and may lead to painful syndromes that mimic a heart attack, gallbladder inflammation, or appendicitis. Diabetics have a higher incidence of entrapment neuropathies, such as carpal tunnel syndrome.

Diagnosis

Diabetic peripheral neuropathy is the most likely diagnosis for someone with diabetes who has pain in a leg or foot, although it may also be caused by vitamin B₁₂ deficiency or osteoarthritis. A 2010 review in the Journal of the American Medical Association's "Rational Clinical Examination Series" evaluated the usefulness of the clinical examination in diagnosing diabetic peripheral neuropathy. While the physician typically assesses the appearance of the feet, presence of ulceration, and ankle reflexes, the most useful physical examination findings for large fiber neuropathy are an abnormally decreased vibration perception to a 128-Hz tuning fork (likelihood ratio (LR) range, 16–35) or pressure sensation with a 5.07 Semmes-Weinstein monofilament (LR range, 11–16). Normal results on vibration testing (LR range, 0.33–0.51) or monofilament (LR range, 0.09–0.54) make large fiber peripheral neuropathy from diabetes less likely. Combinations of signs do not perform better than these 2 individual findings. Nerve conduction tests may show reduced functioning of the peripheral nerves, but seldom correlate with the severity of diabetic peripheral neuropathy and are not appropriate as routine tests for the condition.

Classification

Diabetic neuropathy encompasses a series of different neuropathic syndromes which can be schematized in the following way:

• Focal and multifocal neuropathies:
  • Mononeuropathy
  • Amyotrophy, radiculopathy
  • Multiple lesions "mononeuritis multiplex"
  • Entrapment (e.g. median, ulnar, peroneal)
• Symmetrical neuropathies:
  • Acute sensory
  • Autonomic
  • Distal symmetrical polyneuropathy (DSPN), the diabetic type of which is also known as diabetic peripheral neuropathy (DPN) (most common presentation)

Prevention

Prevention is by good blood sugar control and exercise.

Treatment

Except for tight glucose control, treatments are for reducing pain and other symptoms.

Medication options for pain control include antiepileptic drugs (AEDs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and capsaicin cream. About 10% of people who use capsaicin cream have a large benefit.

A systematic review concluded that "tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants." A further analysis of previous studies showed that the agents carbamazepine, venlafaxine, duloxetine, and amitriptyline were more effective than placebo, but that comparative effectiveness between each agent is unclear.

The only three medications approved by the United States' Food and Drug Administration for diabetic peripheral neuropathy (DPN) are the antidepressant duloxetine, the anticonvulsant pregabalin, and the long-acting opioid tapentadol ER. Before trying a systemic medication, some doctors recommend treating localized diabetic peripheral neuropathy with lidocaine patches.

Antiepileptic drugs

Multiple guidelines from medical organizations such as the American Association of Clinical Endocrinologists, American Academy of Neurology, European Federation of Neurological Societies, and the National Institute of Clinical Excellence recommend AEDs, such as pregabalin, as first-line treatment for painful diabetic neuropathy. Pregabalin is supported by low-quality evidence as more effective than placebo for reducing diabetic neuropathic pain but its effect is small. Studies have reached differing conclusions about whether gabapentin relieves pain more effectively than placebo. Available evidence is insufficient to determine if zonisamide or carbamazepine are effective for diabetic neuropathy. The first metabolite of carbamazepine, known as oxcarbazepine, appears to have a small beneficial effect on pain. A 2014 systematic review and network meta-analysis concluded topiramate, valproic acid, lacosamide, and lamotrigine are ineffective for pain from diabetic peripheral neuropathy. The most common side effects associated with AED use include sleepiness, dizziness, and nausea.

Serotonin-norepinephrine reuptake inhibitors

As above, the serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine are recommended in multiple medical guidelines as first or second-line therapy for DPN. A 2017 systematic review and meta-analysis of randomized controlled trials concluded there is moderate quality evidence that duloxetine and venlafaxine each provide a large benefit in reducing diabetic neuropathic pain. Common side effects include dizziness, nausea, and sleepiness.

Selective serotonin reuptake inhibitor

SSRIs include fluoxetine, paroxetine, sertraline, and citalopram have been found to be no more efficacious than placebo in several controlled trials and therefore are not recommended to treat painful diabetic neuropathy. Side effects are rarely serious and do not cause any permanent disabilities. They cause sedation and weight gain, which can worsen a diabetic person's glycemic control. They can be used at dosages that also relieve the symptoms of depression, a common comorbidity of diabetic neuropathy.

Tricyclic antidepressants

TCAs include imipramine, amitriptyline, desipramine, and nortriptyline. They are generally regarded as first or second-line treatment for DPN. Of the TCAs, imipramine has been the best studied. These medications are effective at decreasing painful symptoms but suffer from multiple side effects that are dose-dependent. One notable side effect is cardiac toxicity, which can lead to fatal abnormal heart rhythms. Additional common side effects include dry mouth, difficulty sleeping, and sedation. At low dosages used for neuropathy, toxicity is rare, but if symptoms warrant higher doses, complications are more common. Among the TCAs, amitriptyline is most widely used for this condition, but desipramine and nortriptyline have fewer side effects.

Opioids

Typical opioid medications, such as oxycodone, appear to be no more effective than placebo. In contrast, low-quality evidence supports a moderate benefit from the use of atypical opioids (e.g., tramadol and tapentadol), which also have SNRI properties. Opioid medications are recommended as second or third-line treatment for DPN.

Topical agents

Capsaicin applied to the skin in a 0.075% concentration has not been found to be more effective than placebo for treating pain associated with diabetic neuropathy. There is insufficient evidence to draw conclusions for more concentrated forms of capsaicin, clonidine, or lidocaine applied to the skin.

Other

Low-quality evidence supports a moderate-large beneficial effect of botulinum toxin injections. Dextromethorphan does not appear to be effective in treating diabetic neuropathic pain. There is insufficient evidence to draw firm conclusions for the utility of the cannabinoids nabilone and nabiximols. There are some in vitro studies indicating the beneficial effect of erythropoietin on the diabetic neuropathy; however, one nerve conduction study in mild-moderate diabetic individuals showed that erythropoietin alone or in combination with gabapentin does not have any beneficial effect on progression of diabetic neuropathy.

Medical devices

Monochromatic infrared photo energy treatment (MIRE) has been shown to be an effective therapy in reducing and often eliminating pain associated with diabetic neuropathy. The studied wavelength of 890 nm is able to penetrate into the subcutaneous tissue where it acts upon a specialized part of the cell called the cytochrome C. The infrared light energy prompts the cytochrome C to release nitric oxide into the cells. The nitric oxide in turn promotes vasodilation which results in increased blood flow that helps nourish damaged nerve cells. Once the nutrient rich blood is able to reach the affected areas (typically the feet, lower legs and hands) it promotes the regeneration of nerve tissues and helps reduce inflammation thereby reducing and/or eliminating pain in the area.

Physical therapy

Physical therapy may help reduce dependency on pain relieving drug therapies. Certain physiotherapy techniques can help alleviate symptoms brought on from diabetic neuropathy such as deep pain in the feet and legs, tingling or burning sensation in extremities, muscle cramps, muscle weakness, sexual dysfunction, and diabetic foot.

Transcutaneous electrical nerve stimulation (TENS) and interferential current (IFC) use a painless electric current and the physiological effects from low frequency electrical stimulation to relieve stiffness, improve mobility, relieve neuropathic pain, reduce oedema, and heal resistant foot ulcers.

Gait training, posture training, and teaching these patients the basic principles of off-loading can help prevent and/or stabilize foot complications such as foot ulcers. Off-loading techniques can include the use of mobility aids (e.g. crutches) or foot splints. Gait re-training would also be beneficial for individuals who have lost limbs, due to diabetic neuropathy, and now wear a prosthesis.

Exercise programs, along with manual therapy, will help to prevent muscle contractures, spasms and atrophy. These programs may include general muscle stretching to maintain muscle length and a person’s range of motion. General muscle strengthening exercises will help to maintain muscle strength and reduce muscle wasting. Aerobic exercise such as swimming and using a stationary bicycle can help peripheral neuropathy, but activities that place excessive pressure on the feet (e.g. walking long distances, running) may be contraindicated.

Heat, therapeutic ultrasound, hot wax are also useful for treating diabetic neuropathy. Pelvic floor muscle exercises can improve sexual dysfunction caused by neuropathy.

Tight glucose control

Treatment of early manifestations of sensorimotor polyneuropathy involves improving glycemic control. Tight control of blood glucose can reverse the changes of diabetic neuropathy, but only if the neuropathy and diabetes are recent in onset. Conversely, painful symptoms of neuropathy in uncontrolled diabetics tend to subside as the disease and numbness progress.

Prognosis

The mechanisms of diabetic neuropathy are poorly understood. At present, treatment alleviates pain and can control some associated symptoms, but the process is generally progressive.

As a complication, there is an increased risk of injury to the feet because of loss of sensation. Small infections can progress to ulceration and this may require amputation.

Epidemiology

Globally diabetic neuropathy affects approximately 132 million people as of 2010 (1.9% of the population).

Diabetes is the leading known cause of neuropathy in developed countries, and neuropathy is the most common complication and greatest source of morbidity and mortality in diabetes. It is estimated that neuropathy affects 25% of people with diabetes. Diabetic neuropathy is implicated in 50–75% of nontraumatic amputations.

The main risk factor for diabetic neuropathy is hyperglycemia. In the DCCT (Diabetes Control and Complications Trial, 1995) study, the annual incidence of neuropathy was 2% per year but dropped to 0.56% with intensive treatment of Type 1 diabetics. The progression of neuropathy is dependent on the degree of glycemic control in both Type 1 and Type 2 diabetes. Duration of diabetes, age, cigarette smoking, hypertension, height, and hyperlipidemia are also risk factors for diabetic neuropathy.

Peripheral nervous system

From Wikipedia, the free encyclopedia

 

Peripheral nervous system
The human nervous system. Blue is PNS; yellow is CNS.
Identifiers
Acronym(s)	PNS
MeSH	D017933
TA	A14.2.00.001
FMA	9903

The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of the nerves and ganglia outside the brain and spinal cord. The main function of the PNS is to connect the CNS to the limbs and organs, essentially serving as a relay between the brain and spinal cord and the rest of the body. Unlike the CNS, the PNS is not protected by the vertebral column and skull, or by the blood–brain barrier, which leaves it exposed to toxins and mechanical injuries.

The peripheral nervous system is divided into the somatic nervous system and the autonomic nervous system. In the somatic nervous system, the cranial nerves are part of the PNS with the exception of the optic nerve (cranial nerve II), along with the retina. The second cranial nerve is not a true peripheral nerve but a tract of the diencephalon. Cranial nerve ganglia originated in the CNS. However, the remaining ten cranial nerve axons extend beyond the brain and are therefore considered part of the PNS. The autonomic nervous system exerts involuntary control over smooth muscle and glands. The connection between CNS and organs allows the system to be in two different functional states: sympathetic and parasympathetic.

Structure

The peripheral nervous system is divided into the somatic nervous system, and the autonomic nervous system. The somatic nervous system is under voluntary control, and transmits signals from the brain to end organs such as muscles. The sensory nervous system is part of the somatic nervous system and transmits signals from senses such as taste and touch (including fine touch and gross touch) to the spinal cord and brain. The autonomic nervous system is a 'self-regulating' system which influences the function of organs outside voluntary control, such as the heart rate, or the functions of the digestive system.

Somatic nervous system

The somatic system includes the sensory nervous system and the somatosensory system and consists of sensory nerves and somatic nerves, and many nerves which hold both functions. 

In the head and neck, cranial nerves carry somatosensory data. There are twelve cranial nerves, ten of which originate from the brainstem, and mainly control the functions of the anatomic structures of the head with some exceptions. One unique cranial nerve is the vagus nerve, which receives sensory information from organs in the thorax and abdomen. The accessory nerve is responsible for innervating the sternocleidomastoid and trapezius muscles, neither of which being exclusively in the head.

For the rest of the body, spinal nerves are responsible for somatosensory information. These arise from the spinal cord. Usually these arise as a web ("plexus") of interconnected nerves roots that arrange to form single nerves. These nerves control the functions of the rest of the body. In humans, there are 31 pairs of spinal nerves: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. These nerve roots are named according to the spinal vertebrata which they are adjacent to. In the cervical region, the spinal nerve roots come out above the corresponding vertebrae (i.e., nerve root between the skull and 1st cervical vertebrae is called spinal nerve C1). From the thoracic region to the coccygeal region, the spinal nerve roots come out below the corresponding vertebrae. It is important to note that this method creates a problem when naming the spinal nerve root between C7 and T1 (so it is called spinal nerve root C8). In the lumbar and sacral region, the spinal nerve roots travel within the dural sac and they travel below the level of L2 as the cauda equina.

Cervical spinal nerves (C1–C4)

The first 4 cervical spinal nerves, C1 through C4, split and recombine to produce a variety of nerves that serve the neck and back of head.

Spinal nerve C1 is called the suboccipital nerve, which provides motor innervation to muscles at the base of the skull. C2 and C3 form many of the nerves of the neck, providing both sensory and motor control. These include the greater occipital nerve, which provides sensation to the back of the head, the lesser occipital nerve, which provides sensation to the area behind the ears, the greater auricular nerve and the lesser auricular nerve. 

The phrenic nerve is a nerve essential for our survival which arises from nerve roots C3, C4 and C5. It supplies the thoracic diaphragm, enabling breathing. If the spinal cord is transected above C3, then spontaneous breathing is not possible.

Brachial plexus (C5–T1)

The last four cervical spinal nerves, C5 through C8, and the first thoracic spinal nerve, T1, combine to form the brachial plexus, or plexus brachialis, a tangled array of nerves, splitting, combining and recombining, to form the nerves that subserve the upper-limb and upper back. Although the brachial plexus may appear tangled, it is highly organized and predictable, with little variation between people. See brachial plexus injuries.

Lumbosacral plexus (L1–Co1)

The anterior divisions of the lumbar nerves, sacral nerves, and coccygeal nerve form the lumbosacral plexus, the first lumbar nerve being frequently joined by a branch from the twelfth thoracic. For descriptive purposes this plexus is usually divided into three parts:

• lumbar plexus
• sacral plexus
• pudendal plexus

Autonomic nervous system

The autonomic nervous system (ANS) controls involuntary responses to regulate physiological functions. The brain and spinal cord of the central nervous system are connected with organs that have smooth muscle, such as the heart, bladder, and other cardiac, exocrine, and endocrine related organs, by ganglionic neurons. The most notable physiological effects from autonomic activity are pupil constriction and dilation, and salivation of saliva. The autonomic nervous system is always activated, but is either in the sympathetic or parasympathetic state. Depending on the situation, one state can overshadow the other, resulting in a release of different kinds of neurotransmitters. There is a lesser known division of the autonomic nervous system known as the enteric nervous system. Located only around the digestive tract, this system allows for local control without input from the sympathetic or the parasympathetic branches, though it can still receive and respond to signals from the rest of the body. The enteric system is responsible for various functions related to gastrointestinal system.

Sympathetic nervous system

The sympathetic system is activated during a “fight or flight” situation in which mental stress or physical danger is encountered. Neurotransmitters such as norepinephrine, and epinephrine are released, which increases heart rate and blood flow in certain areas like muscle, while simultaneously decreasing activities of non-critical functions for survival, like digestion. The systems are independent to each other, which allows activation of certain parts of the body, while others remain rested.

Parasympathetic nervous system

Primarily using the neurotransmitter acetylcholine (ACh) as a mediator, the parasympathetic system allows the body to function in a “rest and digest” state. Consequently, when the parasympathetic system dominates the body, there are increases in salivation and activities in digestion, while heart rate and other sympathetic response decrease. Unlike the sympathetic system, humans have some voluntary controls in the parasympathetic system. The most prominent examples of this control are urination and defecation.

Disease

Diseases of the peripheral nervous system can be specific to one or more nerves, or affect the system as a whole.

Any peripheral nerve or nerve root can be damaged, called a mononeuropathy. Such injuries can be because of injury or trauma, or compression. Compression of nerves can occur because of a tumour mass or injury. Alternatively, if a nerve is in an area with a fixed size it may be trapped if the other components increase in size, such as carpal tunnel syndrome and tarsal tunnel syndrome. Common symptoms of carpal tunnel syndrome include pain and numbness in the thumb, index and middle finger. In peripheral neuropathy, the function one or more nerves are damaged through a variety of means. Toxic damage may occur because of diabetes (diabetic neuropathy), alcohol, heavy metals or other toxins; some infections; autoimmune and inflammatory conditions such as amyloidosis and sarcoidosis. Peripheral neuropathy is associated with a sensory loss in a "glove and stocking" distribution that begins at the peripheral and slowly progresses upwards, and may also be associated with acute and chronic pain. Peripheral neuropathy is not just limited to the somatosensory nerves, but the autonomic nervous system too (autonomic neuropathy).

Acetyl-CoA

From Wikipedia, the free encyclopedia

 

Acetyl-CoA

Names
IUPAC name S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3,3-dimethylbutanoyl]amino]propanoylamino]ethyl] ethanethioate
Identifiers
CAS Number	72-89-9
3D model (JSmol)	Interactive image Interactive image
ChEBI	CHEBI:15351
ChemSpider	392413
ECHA InfoCard	100.000.719
IUPHAR/BPS	3038
KEGG	C00024
MeSH	Acetyl+Coenzyme+A
PubChem CID	444493
Properties
Chemical formula	C23H38N7O17P3S
Molar mass	809.57 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for energy production. Coenzyme A (CoASH or CoA) consists of a β-mercaptoethylamine group linked to the vitamin pantothenic acid through an amide linkage  and 3'-phosphorylated ADP. The acetyl group (indicated in blue in the structural diagram on the right) of acetyl-CoA is linked to the sulfhydryl substituent of the β-mercaptoethylamine group. This thioester linkage is a "high energy" bond, which is particularly reactive. Hydrolysis of the thioester bond is exergonic (−31.5 kJ/mol).

CoA is acetylated to acetyl-CoA by the breakdown of carbohydrates through glycolysis and by the breakdown of fatty acids through β-oxidation. Acetyl-CoA then enters the citric acid cycle, where the acetyl group is oxidized to carbon dioxide and water, and the energy released is captured in the form of 11 ATP and one GTP per acetyl group.

Konrad Bloch and Feodor Lynen were awarded the 1964 Nobel Prize in Physiology and Medicine for their discoveries linking acetyl-CoA and fatty acid metabolism. Fritz Lipmann won the Nobel Prize in 1953 for his discovery of the cofactor coenzyme A.

Direct synthesis

The acetylation of CoA is determined by the carbon sources.

Extramitochondrial

• At high glucose levels, glycolysis takes place rapidly, thus increasing the amount of citrate produced from the tricarboxylic acid cycle. This citrate is then exported to other organelles outside the mitochondria to be broken into acetyl-CoA and oxaloacetate by the enzyme ATP citrate lyase (ACL). This principal reaction is coupled with the hydrolysis of ATP.
• At low glucose levels:
  • CoA is acetylated using acetate by acetyl-CoA synthetase (ACS), also coupled with ATP hydrolysis.
  • Ethanol also serves as a carbon source for acetylation of CoA utilizing the enzyme alcohol dehydrogenase.
  • Degradation of branched-chain ketogenic amino acids such as valine, leucine, and isoleucine occurs. These amino acids are converted to α-ketoacids by transamination and eventually to isovaleryl-CoA through oxidative decarboxylation by an α-ketoacid dehydrogenase complex. Isovaleryl-CoA undergoes dehydrogenation, carboxylation and hydration to form another CoA-derivative intermediate before it is cleaved into acetyl-CoA and acetoacetate.

Intramitochondrial

Pyruvate dehydrogenase complex reaction

• At high glucose levels, acetyl-CoA is produced through glycolysis. Pyruvate undergoes oxidative decarboxylation in which it loses its carboxyl group (as carbon dioxide) to form acetyl-CoA, giving off 33.5 kJ/mol of energy. The oxidative conversion of pyruvate into acetyl-CoA is referred to as the pyruvate dehydrogenase reaction. It is catalyzed by the pyruvate dehydrogenase complex. Other conversions between pyruvate and acetyl-CoA are possible. For example, pyruvate formate lyase disproportionates pyruvate into acetyl-CoA and formic acid.

β-Oxidation of fatty acids

• At low glucose levels, the production of acetyl-CoA is linked to β-oxidation of fatty acids. Fatty acids are first converted to acyl-CoA. Acyl-CoA is then degraded in a four-step cycle of oxidation, hydration, oxidation and thiolysis catalyzed by four respective enzymes, namely acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and thiolase. The cycle produces a new fatty acid chain with two fewer carbons and acetyl-CoA as a byproduct.

Functions

Intermediates in various pathways

• In Cellular Respiration
• Citric acid cycle:
  • Through a series of chemical reactions, stored energy is released through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins into adenosine triphosphate (ATP) and carbon dioxide.
• Fatty acid metabolism
  • Acetyl-CoA is produced by the breakdown of both carbohydrates (by glycolysis) and lipids (by β-oxidation). It then enters the citric acid cycle in the mitochondrion by combining with oxaloacetate to form citrate.
  • Two acetyl-CoA molecules condense to form acetoacetyl-CoA, which gives rise to the formation of acetoacetate and β-hydroxybutyrate. Acetoacetate, β-hydroxybutyrate, and their spontaneous breakdown product acetone are frequently, but confusingly, known as ketone bodies (as they are not "bodies" at all, but water-soluble chemical substances). The ketone bodies are released by the liver into the blood. All cells with mitochondria can take ketone bodies up from the blood and reconvert them into acetyl-CoA, which can then be used as fuel in their citric acid cycles, as no other tissue can divert its oxaloacetate into the gluconeogenic pathway in the way that the liver does. Unlike free fatty acids, ketone bodies can cross the blood-brain barrier and are therefore available as fuel for the cells of the central nervous system, acting as a substitute for glucose, on which these cells normally survive. The occurrence of high levels of ketone bodies in the blood during starvation, a low-carbohydrate diet, prolonged heavy exercise, and uncontrolled type-1 diabetes mellitus is known as ketosis, and in its extreme form in out-of-control type-1 diabetes mellitus, as ketoacidosis.
  • On the other hand, when the insulin concentration in the blood is high, and that of glucagon is low (i.e. after meals), the acetyl-CoA produced by glycolysis condenses as normal with oxaloacetate to form citrate in the mitochondrion. However, instead of continuing through the citric acid cycle to be converted to carbon dioxide and water, the citrate is removed from the mitochondrion into the cytoplasm. There it is cleaved by ATP citrate lyase into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to the mitochondrion as malate (and then converted back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion). This cytosolic acetyl-CoA can then be used to synthesize fatty acids through carboxylation by acetyl-CoA carboxylase into malonyl CoA, the first committed step in the synthesis of fatty acids. This conversion occurs primarily in the liver, adipose tissue and lactating mammary glands, where the fatty acids are combined with glycerol to form triglycerides, the major fuel reservoir of most animals. Fatty acids are also components of the phospholipids that make up the bulk of the lipid bilayers of all cellular membranes.
  • In plants, de novo fatty acid synthesis occurs in the plastids. Many seeds accumulate large reservoirs of seed oils to support germination and early growth of the seedling before it is a net photosynthetic organism.
  • The cytosolic acetyl-CoA can also condense with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) which is the rate-limiting step controlling the synthesis of cholesterol. Cholesterol can be used as is, as a structural component of cellular membranes, or it can be used to synthesize steroid hormones, bile salts, and vitamin D.
  • Acetyl-CoA can be carboxylated in the cytosol by acetyl-CoA carboxylase, giving rise to malonyl-CoA, a substrate required for synthesis of flavonoids and related polyketides, for elongation of fatty acids to produce waxes, cuticle, and seed oils in members of the Brassica family, and for malonation of proteins and other phytochemicals. In plants, these include sesquiterpenes, brassinosteroids (hormones), and membrane sterols.
• Steroid synthesis:
  • Acetyl-CoA participates in the mevalonate pathway by partaking in the synthesis of hydroxymethyl glutaryl-CoA.
• Acetylcholine synthesis:
  • Acetyl-CoA is also an important component in the biogenic synthesis of the neurotransmitter acetylcholine. Choline, in combination with acetyl-CoA, is catalyzed by the enzyme choline acetyltransferase to produce acetylcholine and coenzyme A as abyproduct.
• Melatonin synthesis
• Acetylation
  • Acetyl-CoA is also the source of the acetyl group incorporated onto certain lysine residues of histone and nonhistone proteins in the posttranslational modification acetylation. This acetylation is catalyzed by acetyltransferases. This acetylation affects cell growth, mitosis, and apoptosis.
• Allosteric regulator
  • Acetyl-CoA serves as an allosteric regulator of pyruvate dehydrogenase kinase (PDK). It regulates through the ratio of acetyl-CoA versus CoA. Increased concentration of acetyl-CoA activates PDK.
  • Acetyl-CoA is also an allosteric activator of pyruvate carboxylase.