Although glucose is the major fuel whose oxidation leads to energy-coupled insulin secretion there are other means for stimulated insulin secretion.
The pyruvate is oxidized by the PDHc and the resulting acetyl-CoA is oxidized in the TCA cycle.
Science, Technology and Medicine open access publisher.Publish, read and share novel research. 2.1The Licensed Material may not be used in any final materials distributed inside of your company or any materials distributed outside of your company or to the public, including, but not limited to, advertising and marketing materials or in any online or other electronic distribution system (except that you may transmit comps digitally or electronically to your clients for their review) and may not be distributed, sublicensed or made available for use or distribution separately or individually and no rights may be granted to the Licensed Material. 2.2One copy of the Licensed Material may be made for backup purposes only but may only be used if the original Licensed Material becomes defective, destroyed or otherwise irretrievably lost. Millions of people around the world are diagnosed with diabetes every year, and even more are already suffering from this disorder. Some people swear by the effects of vitamins and how helpful they can be when it comes to treating diabetes. Fruits like blueberries are a great choice when it comes to eating foods to help with diabetes. Even though these natural treatments won’t cure your diabetes condition they will help keep your blood glucose levels under control.
Type 1 diabetes Type 1 diabetes - occurs when there is the destruction of pancreatic cells which are responsible for production of insulin. Type 2 diabetes - occurs when there is a decrease in insulin production, but mainly because of a malfunction. Over time the patient with diabetes also presents two of its damage pancreatic beta cells, and needs insulin. There are actually other types of diabetes such as gestational diabetes and diabetes by chronic pancreatitis, but that will be discussed separately.
Type 2 diabetesThe diagnosis of diabetes is normally performed after the second measurement (on different days) of blood glucose (glucose) after 8-12 hours fasting.
Thirst: Hyperglycemia increases the osmolarity of the blood and triggers the thirst mechanism. Excess urine: Normally the kidney does not eliminate glucose in the urine, but in situations of hyperglycemia, it makes it a regulator of the organism, which is excreted in excess. Hunger: As the cells fail to capture glucose, the body interprets this as a state of lack of food and causes hunger. Blurred vision: High glucose levels also cause changes in visual acuity, which sometimes can be mistaken by patients with myopia. They are often triggered by poor adherence to treatment, with uncontrolled blood glucose, but also by infections, drugs, heart attacks, strokes and other stress factors.
It is common to the formation of ulcers and in advanced cases may need limb amputation due to necrosis. A sad but common image, the patient is blind, with one leg amputated, connected to a hemodialysis machine and, after some years, dies of massive heart attack. One important process is referred to as the pyruvate cycle and involves coupling of amino acid metabolism to insulin secretion.
Within β-cells of the pancreas, this process, driven by mitochondrial malic enzyme serves as an important means for the use of amino acid carbon oxidation for the stimulated secretion of insulin.
SSD deficiency: In the absence of SSD, transamination of ?-aminobutyric acid (GABA) to succinic semialdehyde is followed by reduction to 4-hydroxybutyric acid (?-hydroxybutyrate [GHB]).
Localization of purine metabolizing enzymes in bovine brain microvessel endothelial cells: an enzymatic blood-brain barrier for dideoxynucleosides?
Biochemical discrimination between luminal and abluminal enzyme and transport activities of the blood-brain barrier. Except as specifically provided in this Agreement, the Licensed Material may not be shared or copied for example by including it in a disc library, image storage jukebox, network configuration or other similar arrangement. Ninety percent of the people suffering from diabetes are suffering from type 2 diabetes where the body doesn’t produce enough insulin or the cells in the body are resistant to insulin.
You should talk to your doctor about the different kind of vitamins that are useful for diabetes and how much of them you should take on a daily basis. Magnesium is the mineral that these foods contain that helps keep blood sugar levels under control.
You want to eat a good amount of blueberries daily in order to keep your blood glucose under control. If you are living with diabetes you should defenitely give some of these natural remedies a try.
This disease occurs when there is an accumulation of glucose in the blood due to the inability of cells to consume it for energy production. The ribbons for evaluation of CBG are used to control diabetics already on treatment and are not intended to establish the diagnosis. The diabetic, especially when blood glucose is too high, drinks plenty of water and is very thirsty.
As sugar can not be urinated, glucose needs to be diluted with water, thus, the volume of urine increases. As the diabetic drinks a lot of water but it does not kill thirst, the same happens with hunger, eating much does not solve the problem.
Because the cells do not receive glucose, they must find another source to generate power not to die. The patient has severe dehydration, altered level of consciousness, rapid breathing and abdominal pain (the latter two are more common in diabetic ketoacidosis). The decrease in blood supply and nerve damage (diabetic neuropathy) of the lower limbs, decrease the sensitivity of the feet and legs causing injuries in this region without pain. You can not only lead the patient to dialysis as well as causing nephrotic syndrome by excessive loss of protein in the urine. The insulin secreting β-cells, in contrast to the liver, do not express the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) but do express robust levels of the gluconeogenic enzyme pyruvate carboxylase (PC). Indeed, this process is energetically equal to glucose-stimulated insulin secretion (GSIS).
Note how the blood vessels start branching in small capillaries while the pia disappears and the endothelium acquires the peculiar characteristics of a tight barrier that regulate the exchange of substances between blood and brain. Comparative analysis of the expression level of key enzymes regulating the glycolytic and TCA pathways strongly supported the gene array data (Panel A). Metabolic dysfunction and its link to Parkinson’s disease (PD): The role of dehydrogenases8. Prasad1 and L Cucullo1, 2[1] Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, TX,, USA[2] Vascular Drug Research Center,Texas Tech University Health Sciences Center, TX,, USA1.
Upon download of any film Licensed Material, you will be invoiced a non-refundable access service fee of one hundred fifty dollars ($150) USD or such other local currency amount as Getty Images may apply from time to time. However, when you use the right natural treatments it’s really possible to keep your condition under control without the need of medications.
What this does is cause glucose to build up in the bloodstream, which leads to high blood sugar. You want to consider taking some herbs or supplements as well because these can help lower blood sugar levels. Not only will magnesium assist with keeping your blood glucose levels under control, but it also helps with keeping the nerve and muscle functioning properly. To help with the production of insulin and making your cells more insulin resistant you can also focus on eating more zinc rich foods like oysters, lamb, pecans, and beef liver. Make sure you eat healthy and workout properly so that you can keep your blood glucose under control much more easily without medications. Obviously, high values in the ribbons suggest the diagnosis, but should always be confirmed with blood tests. Much glucose leaves the blood thick and with a very high osmolarity can lead to hyperosmolar coma. Pain is one of our major defense mechanisms and indicates that something wrong is happening. Low blood sugar in me causes much irritation, very tired and split vision(eyes are not in sinc).
Coupled with the activity of PC is the activity of malic enzyme which together, is the only means for pyruvate cycling in β-cells. TJ between adjacent endothelial cells form a diffusion barrier that selectively excludes most blood-borne and xenobiotic substances from entering the brain.
IntroductionDehydrogenase (DHO) is one of the most common types of enzyme that is crucial in oxidation reactions. Hyman, Localization of brain endothelial luminal and abluminal transporters with immunogold electron microscopy. The Licensed Material may only be used in materials for personal, noncommercial use and test or sample use, including comps and layouts. If Licensed Material featuring a person is used (i) in a manner that implies endorsement, use of or a connection to a product or service by that model; or (ii) in connection with a potentially unflattering or controversial subject, you must print a statement that indicates that the person is a model and is used for illustrative purposes only. This accumulation of blood glucose can cause several complications some of which include damage to the kidneys, eyes, or heart.
However, if you are currently taking some form of medication you should be cautious because some herbs actually interact badly with some medications used for diabetes. Eggs, chicken, and walnuts are a few more good sources of zinc that you should take advantage of. Type 1 diabetes usually occurs in young people and should be treated with insulin replacement. It's time to keep to a diet, lose weight and start exercising to prevent disease progression. The problem is that besides it does not generate as much energy as glucose, the metabolism of fats generates a tremendous amount of acids (called ketoacids) leading to ketoacidosis.
Patients with diabetic neuropathy do not notice when something is hurting their feet, so do not take appropriate steps to protect the skin. High blood sugar(same as untreated diabetic) blurry vision, very tired, sluggish, excessive hunger and extreme thirst(and going to the john too ofter) Hypoglycemia can lead to diabetes.
Cytoplasmic malic enzyme plays an important role in acetyl-CoA transport from the mitochondria to the cytosol for its use in lipid biosynthesis. In contrast to lipid soluble substances including alcohols, anesthetics and barbiturates, the BBB is highly impermeant to polar molecules or water soluble electrolytes. Branched Chain Alpha Ketoacid dehydrogenase (BCKDH) complex Deficiency – Maple syrup urine disease (MSUD)4.3. This enzyme oxidizes its specific substrate by a redox reaction in which one or more hydrides (H?) are transferred to an electron acceptor. Insulin is released from the pancreas when blood sugar levels are high, for example after eating, prompting cells in the liver, muscle, and fat tissue to take up the glucose from the blood and store it as glycogen. You should also be cautious about the kind of foods you are consuming on a regular basis as well, because some foods can also have bad reactions to the medication you’re taking for your condition.
The pH of the blood drops too and can reach levels incompatible with life if not treated quickly.
However, the passage of certain water soluble, but biologically important substances, such as D-glucose or phenylamine are regulated by a variety of specific carrier-mediated transport systems. Apart from energetics and ATP formation, DHOs are associated with both catabolic and anabolic pathways linked to normal functioning and homeostasis. Albrecht, Decreased glucose utilization in discrete brain regions of rat in thioacetamide-induced hepatic encephalopathy as measured with [3H]-deoxyglucose.
A good idea is to take a list of foods to your doctor and ask him or her which foods will actually help and wich ones will actually be bad for you to eat. The role of the mitochondrial malic enzyme is principally to provide the cell with an alternate source of pyruvate under conditions where glycolytic flux in reduced. By contrast, larger vessels (arterioles, small arteries and venous) differ from capillaries by the presence of smooth muscle cells in their walls and a less stringent vascular bed. In this chapter, we will cover different aspects of the major DHOs that play a role in the regulation of brain and blood-brain barrier (BBB) physiology starting from their role in bioenergetic metabolism.
Ogunshola, Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult. Galla, Blood-brain barrier characteristic enzymatic properties in cultured brain capillary endothelial cells. In these circumstances, the pyruvate generated by the actions of mitochondrial malic enzyme comes from fumarate precursors such as glutamine.
In born errors in metabolism (IEM) due to genetic deficiency in a single specific DHO have strong neurological implications.
Fredriksson, An improved in vitro blood-brain barrier model: rat brain endothelial cells co-cultured with astrocytes. Siesjo, Influence of blood glucose concentration on brain lactate accumulation during severe hypoxia and subsequent recovery of brain energy metabolism. Once you license a royalty-free product, you may use it multiple times for multiple projects without paying additional fees. When glutamine is de-aminated by glutaminase the resulting glutamate can also be de-aminated by glutamate dehydrogenase yielding 2-oxoglutarate (α-ketoglutarate) which can then be shunted to malate synthesis in the TCA cycle.


Create your slideshowBy using the code above and embedding this image, you consent to Getty Images' Terms of Use. Recent studies show convincing evidence associating altered DHO activity with the pathogenesis and progression of several neurological disorders such as Alzheimer’s and Parkinson’s disease. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Whether they are contributors to the etiology of the disease or symptomatic manifestation of these complex neurological disorders is still debatable; however, this link between DHOs and neurological disorders cannot be overlooked and will be further discussed in this chapter.
We will also cover neuronal signaling, neurotransmitter release and degradation emphasizing localized region-specific expression of some brain DHOs in these processes.
It is not possible to cover the detailed cerebral physiology and function in this chapter; however to summarize we will discuss the different types of DHOs in central nervous system (CNS) and BBB physiology, their key enzymatic action, their function in crucial metabolic pathways, and thus how their altered activity or expression can be linked to the underlying pathogenesis of various brain disorders. Structural and functional complexity of blood brain barrier (BBB) and cerebral physiology – A need for high energyThe BBB is a dynamic interface between the peripheral blood and the brain which controls the influx and efflux of substrates and metabolites necessary for normal neuronal function (see Figure 1]. The BBB is crucial in protecting the brain from harmful substances both endogenous and exogenous in nature.
Any alteration in normal BBB functions can play a central role in the pathogenesis and progression of broad variety of CNS disorders such as multiple sclerosis, Alzheimer's disease, neoplasia, hypertension, dementia, epilepsy, infection and trauma [1-4].At the cellular level, the BBB consists of microvascular endothelial cells (ECs) lining the brain microvessels together with closely associated astrocytic end-feet processes and pericytes [5-8].
These associated cells play a major role in EC differentiation and acquisition of morphological and functional characteristics unique to the BBB.
At the cellular level, the brain microcapillary endothelium is characterized by the presence of tight junctions (TJ), lack of fenestrations, and minimal pinocytotic vesicles [9;10]. In particular, TJs between the cerebral endothelial cells form a diffusion barrier, which selectively excludes most of the blood-borne substances from entering the brain, protecting it from systemic influences mediated by substances which are primarily polar in nature (such as electrolytes). Transport of nutrients (as well as other biologically important substances) from the peripheral circulation into brain parenchyma requires translocation through the capillary endothelium by specialized carrier-mediated transport systems.
On the other hand, potentially harmful substances that are lipid soluble are discharged back into the cerebral circulation. This is mediated by specialized active efflux systems belonging to the ATP-binding cassette transporters (ABC-transporter) superfamily (such as P-glycoprotein (P-gp) and Multidrug resistance Protein (MRP)) [11;12]. Apart from these ATP dependent pumps, energy independent transporters such as organic ion carriers add to the complexity of BBB transport functions [13]. Simultaneously, intake of essential nutrients such as glucose, amino acids, peptides, choline occurs through carrier mediated mechanisms [13-17]. Topographic membrane localization of these transporters is indicative of the polarity of the endothelial functions and differentiation that sets apart the BBB endothelium from other vascular beds.
The BBB ECs are also characterized by very high density of mitochondria denoting high metabolic activity [23] to support all the specialized cellular activities bestowed upon these highly specialized cells.
In addition, previous work from our group has shown that blood flow can modulate the bioenergetic behavior of the BBB endothelial cells favoring the expression of the key metabolic enzyme pyruvate dehydrogenase (switch controller from anaerobic to aerobic pathway) [19]. Contrarily, the RNA level of lactate dehydrogenase (switch controller from aerobic to anaerobic pathway) showed decreased expression. In parallel, TCA dehydrogenases such as acotinase, isocitrate dehydrogenase, succinate dehydrogenase were upregulated.
The brain on the other hand possesses an incredibly more complex physiology than the BBB vasculature. It is crucial for various functions such as homeostasis, behavior, perception and processing of information, motor control and memory formation. From a physiological stand point, brain functions depend on the ability of neurons to transmit and respond to electrochemical signals.
This complex crosstalk is controlled by a wide variety of biochemical and metabolic processes which involve interactions between neurotransmitters and receptors that take place at the synapses.
Before we begin describing the role of DHOs in energy metabolism, it is imperative to understand the various metabolic pathways in the brain involved in energy production.
Glucose enters the glycolytic pathway to produce pyruvate along with net production of 2ATP and 2NADH (reduced form of nicotinamide adenine dinucleotide) (see Figure 3].
ATP is first used up in the first part of glycolysis (until formation of glyceraldehyde phosphate-GAP) and is produced later during the second half. Another important step of glycolysis involving glyceraldehyde phosphate dehydrogenase (GAPDH), is the conversion of GAP to 1,3-bisphosphate glycerate [1,3- BPG) along with NADH formation.
Part of the 1,3-BPG thus formed can be further converted into 2,3-biphosphate glycerate [2,3-BPG) which can bind to hemoglobin enhancing its deoxygenation. The remaining 1,3-BPG undergoes further conversion along the glycolytic pathways and is finally converted into pyruvate.Pyruvate thus formed can either enter the citric acid chain (or Kreb’s cycle or Tricyclic acid cycle-TCA) or get converted to lactate which represents the end product of glycolysis. Pyruvate to lactate conversion is the last step of anaerobic form of respiration which occurs via lactate dehydrogenase and results in 2 molecules of ATP production.
Conversely, pyruvate can be further converted into acetyl co-A and then enter the TCA cycle. In this step, pyruvate dehydrogenase (PDH) decarboxylates pyruvate to its acetyl form along with addition of co-enzyme A. Acetyl co-A then combines with oxaloacetate [4C) in presence of water molecule to form citrate [6C). The citrate thus formed cycles through TCA forming oxaloacetate in the last step, which can re-enter the cycle reacting with a new acetyl co-A (see Figure 3].
The various steps in the TCA cycle involve various oxidation reactions involving various dehydrogenases such as isocitrate dehydrogenase, ?-ketoglutarate dehydrogenase, succinate dehydrogenase and malate dehydrogenase.
These reducing equivalents can then enter the electron transport chain and result in ATP formation or can be used by the cell to counteract the oxidative stress caused by reactive oxygen species (ROS) and free radicals. A complete cycling of two molecules of acetyl co-A (from a single molecule of glucose) results in the production of approximately 10 NADH and 2 FADH2. The complete metabolic conversion of a glucose molecule into water and CO2 (glycolysis and TCA cycles combined) results in the approximate production of 38 ATP molecules (including ATP formed indirectly through NADH and FADH2 which produce 3 and 2 ATP molecules respectively).
However, it is now accepted that lactate can be produced in the brain under aerobic conditions, this is known as aerobic glycolysis. Aerobic glycolysis under normal conditions contributes to about 10% of the total energy production in the brain, which can increase under ischemic conditions[29].
Lactate thus formed can then be shuttled between the various cell types in the brain, be converted back into pyruvate and be fully reutilized through complete aerobic respiration. Although this concept of lactate shuttle was proposed long ago, it received lot of resistance from the scientific community especially from those who believed that glucose is the sole substrate in the brain [30;31]. However now, it is getting accepted that lactose is also used as a main substrate for energy production under normal conditions [32-34].
The direction of lactate flow between various cell types in the brain as well as its relative contribution with respect to glucose to the overall energy production is still debatable and not yet fully understood. As far as the lactate flow between the different cell types in the brain there are two current schools of thoughts. This glucose is then metabolized to produce ATP through complete aerobic respiration (glycolysis and citric acid pathways). In the astrocytes, part of the glucose also gets converted into glycogen, as an energy reserve to be used under critical conditions of low oxygen supply.
Astrocytes can withstand low oxygen tension for a longer period of time than neurons and have proven to be more resilient to hypoxic insults [7;41-43]. Based on the concept of lactate shuttle, at the astrocytic level (under resting conditions), glucose can be converted to lactate. Lactate thus produced can shuttle first into the interstitial fluid (through monocarboxylate transporter –MCT-1 & 4]. Continuous glutamatergic activation of neurons results in a more exhaustive energy expenditure. As pyruvate utilization during the TCA cycle increases and its cytoplasmic levels decrease correspondingly, the condition becomes favorable for increasing both glucose and lactate utilization.
By the late phase of activation, glutamate released is taken up by the astrocytes for recycling. The lactate thus formed helps sustain the energy demands of astrocytes as well as replenishing the neurons.
During intense and prolonged neuronal stimulation which may occur under certain conditions, energy replenishment becomes crucially important. This is because the continuous glutamate reuptake by the Na+, glutamate co-transporter in astrocytes (GLutamate ASpartate Transporter – GLAST; glutamate transporter 1 –GLT1] must be paired with an equivalent intense activity of the Na+, K+ATPase to efflux the Na+ back in the extracellular space thus continuing the cycle.
When the extracellular glucose levels become insufficient to sustain this level of activity then glycogen stored in the astrocyte is mobilized to provide the extra glycosyl units necessary to support the cellular activity. Thus sustained activation of the neurons results in conversion of the stored energy substrate glycogen to glucose and further lactate production for shuttling to the neurons.
Lactate plays an equally important role especially during activation, neurotransmission and pathological conditions such as under ischemic insults. This further emphasizes the still dismissed importance of lactate dehydrogenase which represents the key switch in the metabolic pathway of glucose in the generation of lactate. In summary at the microcapillary level, the BBB acts as a functional interface which is charged with the critical task to fuel the brain with energy sources. Whether this is glucose or glucose-derived lactate the BBB is the main fuel distribution system to the brain and a safe for energy storage to which the brain can avail when normal fuel supplies are short.
IEMMutation in single gene leads to enzyme deficiency that results in type of genetic disorders termed as inborn error in metabolism (IEM) [46-50]. Metabolic errors lead to accumulation of toxic or absence of essential products in the brain with neurological implications such as ataxia- motor control, encephalopathy, mental deficits, learning disabilities and mental retardation with structural anomalies. Pyruvate dehydrogenase (PDH) deficiencyPyruvate dehydrogenase is a multi-enzyme complex which catalyzes the conversion of pyruvate (the end product of glycolysis) into acetyl-coA- a substrate that can enter citric acid cycle (for production of ATP and energy equivalents). PDH is a six subunit complex composed of E1-pyruvate dehydrogenase, E2-dihydrolipoyl transacetylase and E3-dihydrolipoyl dehydrogenase, E3BP- E3 binding protein and two regulatory subunits -pyruvate dehydrogenase kinase and pyruvate dehydrogenase phosphatase. Although several mutations in the PDH complex deficiency (such as point mutations, deletions, duplications) have been reported so far; deficiency in PDH E1-alpha subunit (abbreviated as PDHA1] is the most common type [51-53]. PDH deficiencies due to mutations in other subunits of the PDH complex are comparatively rare.
All mutations leading to PDH deficiency are X linked except, the one in regulatory units, which are autosomally recessive [54-57]. Since PDH results in acetyl co-A formation, the most common clinical manifestation of PDH deficiency is severe lactic acidosis.
Defects in energy metabolism can cause neurological deficits such as mental retardation, developmental delay as well as psychomotor retardation.
Structural anomalies (such as microcephaly, facial dysmorphism) and epilepsy (focal or generalized seizures- both have been reported) may develop in utero.
Chronic treatment strategies for PDH deficiency on the other hand, include incorporation of ketogenic diet consisting of high fat, low carbohydrate and low protein. Branched Chain Alpha Ketoacid dehydrogenase (BCKDH) complex Deficiency – Maple syrup urine disease (MSUD)Another important dehydrogenase deficiency leading to an inborn error in metabolism is that in the branched chain alpha ketoacid dehydrogenase (BCKDH) complex [61;62].
This complex is similar to PDH complex, and autosomal recessive mutations in the different subunits of the complex have been reported for this disease. In this disorder, accumulation of branched chain amino acids (BCAAs like isoleucine, leucine and valine) and branched chain alpha ketoacids (BCKAs) (with maple syrup odor to the urine) is observed along with neurological deficits and developmental disorders.
Neonates born normal, within 3-7 days of birth show symptoms such as lethargy, weight loss, metabolic dearrangement, encephalopathy with hypotonia and hypertonia. Treatment is initiated by high calories leucine free diet rich with BCAA-free formulas and an optimum supplementation of isoleucine and valine.
Hemodialysis or hemofiltration may be used to remove deposited BCAAs and BCKAs from the body. During acute MSUD, brain edema and hyponatremia can also occur but can be immediately treated by administration of mannitol or diuretic drugs. However, the burden of these pathologies can be decreased by treatment with appropriate standard drugs such as psychostimulants or antianxiety drugs. Although no direct drug is used to treat MSUD, recent studies have shown the role of phenylbutyrate in increasing BCKDH activity, reducing levels of BCAAs and BCKAs and causing relief in MSUD patients [63]. However, careful monitoring and routine biochemical testing is key in appropriate treatment in MSUD affected patients.
Succinic semialdehyde dehydrogenase (SSD) deficiency SSD deficiency is an autosomal recessive disorder of ?-hydroxybutyric acid (GABA) metabolism.
Oxidative conversion of succinate semialdehyde to succinic acid is impaired in this deficiency. Mild developmental delay, psychomotor retardation, hypotonia, ataxia are observed along with extrapyramidal symptoms such as dystonia, choreoathetosis and myoclonus. Neuroimaging screening generally reveals hyper intensities in globus pallidus, sub cortical white matter, cerebellar dentate nucleus and brain stem [68]. SSADH deficiency leads to significant accumulation of GHB and GABA.Current therapies are mostly symptomatic, directed at seizure treatment and amelioration of neurobehavioral symptoms.
Antiepileptic drugs such as carbamazepine and anti-anxiety drugs may be administered in conjunction with physical and occupational therapy.
IEM related to fatty acid oxidationFatty acids are a major source of energy in heart as well as muscle. MCAD is an enzyme that catalyzes breakdown of fatty acids for energy production during long periods of prolonged fasting.


Accumulation of octanoylcarnitine with Reye-like syndrome is typical clinical manifestation of this disorder [73;74]. Symptoms may appear from 2 days to 6.5 years of age, however the patient can also remain asymptomatic for long time. When left undiagnosed MCAD deficiency has a mortality of 20% and 10-15% are severely handicapped. The 30 year old man exhibited rhabdomyolysis, muscle weakness, acute encephalopathy after exertion in cold and fasting.
During acute episodes, symptomatic relief to overcome hypoglycemia cerebral edema, seizures or metabolic acidosis is the main line of treatment. Avoiding long periods of fasting is the best preventive measure that can be employed in cases with MCAD deficiency.Short chain acyl coenzyme A dehydrogenase deficiency (SCAD) is another autosomal recessive disorder in mitochondrial fatty acid oxidation. Clinical symptoms which appear early in life include developmental delay, hypotonia, epilepsy and behavioral disorders along with hypoglycemia and myopathy [76;77]. Unlike MCAD deficiency, if neonatally screened and followed up it is found to remain asymptomatic, thus the clinical disease outcome of SCAD deficiency is questionable. Avoidance of fasting for longer hours with age appropriate diet is the only recommendation for prevention of primary manifestation. Aging: The role of dehydrogenases in metabolic and mitochondrial dysfunctionAging or growing old is defined as a time related loss and decline in certain morphological, anatomical and functional features of body in comparison to its previous state. Beginning as a maturation process from childhood to young adulthood, it assumes the characteristic of decline through middle and late ages. Accumulation of molecular, cellular, or organ level damage leads to higher vulnerability of disease and eventually death.
There have been numerous theories and hypothesis for causes of aging but it is still under investigation and discussion.
Important to us is the "The Free Radical Theory of aging since it is closely associated with mitochondria, and linked DHOs [78-81].Broadly, both genetic as well as external environmental factors can be responsible for promoting the age associated decline in functionalities [82].
In totality, irregularities in function, oxidative changes and the piled up cellular damages can lead to homoeostatic imbalance which finally result in aging as well as age-related diseases. These free radicals can cause enzyme inactivation to different extent with different mechanisms (see Figure 6]. Studies show that mitochondrial enzymes are resistant to hydrogen peroxide free radical but are fairly affected by hydroxyl free radical.
On the other hand oxygen free radical by itself can cause significant oxidative damage with respect to inactivation of mitochondrial enzymes like NADH dehydrogenase, succinate dehydrogenase, NADH oxidase, succinate oxidase and ATPase 2. Link between aging and various dehydrogenase enzymes is based on the energy demand of our body which involves the participation of different dehydrogenases for production of ATP at cellular level (as elaborated in the earlier section of energy metabolism).
Several dehydrogenases involved in energy metabolism can exhibit altered activity or complete inactivation with aging. This can result in hampering energy production as well as accumulation of toxic metabolites in the body. Metabolic dysfunction and its link to Alzheimer’s disease: The role of dehydrogenasesAlzheimer’s disease is the most common form of dementia characterized by loss of memory, cognitive decline and change in perception and behavior. Pathological hallmarks include accumulation of amyloid beta protein (A?) and resulting plaque formation (a cleavage protein of amyloid precursor protein-APP) and formation of neurofibrillary tangles (due to hyper phosphorylation of microtubule associated protein of neurons in the brain). Genetic mutations in APP protein or ApoE protein (a protein linked to lipid and cholesterol in the body) as well as Down’s syndrome are some examples of genetic predispositions that increase the propensity to develop Alzheimer’s disease. Both vascular as well as metabolic dysfunction have been accredited as major factors prodromic to the pathogenesis and progression of Alzheimer’s disease [84]. Vascular dysfunction includes reduction in cerebral blood flow, reduced glucose uptake, and reduced amyloid beta clearance with cerebral amyloid angiopathy. Vascular structural anomalies in cerebral vessels (like increased pinocytic activity as well as swelling) have been seen in early AD further signifying the importance of vascular dysfunction in AD pathogenesis.
Defective glucose utilization has been observed earlier than reduced cerebral blood flow (CBF), indicating the role of glucose metabolism in AD development.
What is of primary interest to us is that it is slowly becoming well accepted that metabolic dysfunction, related oxidative stress and mitochondrial deficits can precede AD development [84-86].
High levels of oxidative stress (via measurement of hydrogen peroxide production and related lipid peroxidation), high A? levels with high levels of A? binding alcohol dehydrogenase (ABAD) was observed.
Decreased respiration was also observed in embryonic neurons, which continued till senescence leading to AD pathogenesis. Thus these studies clearly emphasized how mitochondrial dysfunction and resulting metabolic respiration preceded AD development.
Defective enzyme function(of dehydrogenases) in pathways of energy metabolism such as glycolysis, tricarboxylic acid pathway and electron transport chain have been well studied in AD progression.
Defective PDH, KGDHC, cytochrome oxidase along with reduced activity of hexokinase, phosphofructokinase are the major enzymes reported in AD so far [87]. In the paragraph below we will be further discuss some of these DHOs and their mechanism of metabolic dysfunction in AD.
We will also look at other DHOs apart from those directly involved in the bioenergetics which have an important role in pathogenesis of AD.One such DHO as mentioned earlier is A? binding alcohol dehydrogenase (ABAD).
ABAD acts on various substrates such as branched chain fatty acids, alcohols, amino acid catabolites and steroids. As the name suggests, ABAD directly binds to A? protein which is highly expressed in Alzheimer’s patients. These links suggest role of ABAD dehydrogenase in the pathophysiology of Alzheimer’s disease. Another crucial factor in causing AD as discussed earlier is mitochondrial dysfunction, related oxidative stress and hypometabolism.
In recent studies, it was hypothesized that ABAD can act as a crucial link between increased A? production and mitochondrial dysfunction in Alzheimer’s disease progression [90-92].To test this hypothesis, double transgenic mice with increased levels of ABAD and A? were developed (along with Tg mAP, Tg ABAD, and not Tg littermate controls)[93].
Neuron cultures derived from these Tg mice showed increased ROS, oxidative stress and relative decrease in ATP production.
Further studies indicated defective activity of mitochondrial Complex IV as the source of the ROS species, also such effect was not observed in single Tg mice with increased ABAD alone (suggesting A? acting as a crucial element linking the two). Data from the Tg mice also suggested reduced ATP production at 9 months of age along with reduced Complex IV activity. As expected, reduction in ABAD-A? complex formation accompanied with attenuated oxidative stress, increased oxygen consumption, increased activity of enzymes associated with mitochondrial respiratory chain, improvement in energy metabolism, and increased spatial memory [89]. Aldehyde dehydrogenase is observed as a key enzyme in the brain involved in metabolism and degradation of biogenic aldehydes, monoamine neurotransmitters such as norepinephrine, dopamine, diamines and GABA. Recent studies have also shown that patients with Down’s syndrome have reduced activity of ALDH enzyme [95]. Two dimensional analysis of proteins extracted from brain samples of nine aged patients with Down’s syndrome and nine controls showed that ALDH was down regulated in the patients with Down’s syndrome. This resulted in accumulation of aldehydes and further formation of tangles and plaques as observed in aged patients with Down’s syndrome.Oxidative stress and generation of ROS species has been implicated in Alzheimer’s disease as elaborated earlier. Lipid peroxidation produces toxic aldehydes such as 4-hydroxy-2-nonenal (HNE) in several disorders such as Alzheimer’s as well as Parkinson’s disease. In the brain, normally ALDH2- an isoform of aldehyde dehydrogenase oxidizes and degrades end product of lipid peroxidation such as HNE. The role of ALDH in oxidative stress and age dependent memory loss and decline in cognitive function was studied using a transgenic mouse model with defective ALDH2 [96].
A dominant negative form of ALDH2 mice was produced and its effect on the metabolic pathways as well as accumulation of toxic products was tested. Further testing of cognitive capability was performed using object recognition and water maze test. Decreased cognitive function in the transgenic mice was observed along with accumulation of tau phosphorylation (a typical pathological sign of Alzheimer’s disease). Metabolic dysfunction and its link to Parkinson’s disease (PD): The role of dehydrogenasesPD is a neurological disorder characterized by typical motor features such as tremor bradykinesia, rigidity, slowness of movement and postural instability.
Reduction in number of dopaminergic (DA) neurons located in substantia nigra pars compacta is the pathological cause of PD. It is also characterized by accumulation of ?-synuclein into inclusions called Lewy bodies. Mostly PD is idiopathic, however specific genetic mutations have shown to increase the risk to develop PD. After diagnosis of PD based on its classical symptoms and neuroimaging, treatment is usually done using levodopa (L-DOPA). L-DOPA is converted to dopamine in the brain and can temporarily alleviate the motor symptoms. Dopamine receptor agonists as well as selective monoamine oxidase-B (MAO-B) inhibitors are also administered along with L-DOPA [97;98]. Treatment thus helps to partially reduce the symptoms of PD, since the actual underlying cause of this disease is still unknown. Altered enzyme activity and mitochondrial dysfunction has been linked to PD as well.Aldehyde dehydrogenase plays an important role in detoxifying aldehydes in brain.
Reduced expression of isoforms of ALDH such as ALDH1A1 and ALDH2 is reported in PD patients. In addition impaired Complex I activity is documented in PD which can reduce the availability of NAD+ cofactor required by ALDHs to remove toxic biogenic aldehydes. Thus decreased ALDH function could be the underlying factor preceding the development of PD.
Using transgenic mice null for both ALDH1A1 and ALDH2, the risk to develop PD was tested [99]. L-DOPA administration alleviated the motor deficits suggesting a role of ALDHs in the pathophysiology of PD.Another DHO implicated in PD is glutamate dehydrogenase (GDH).
GDH is a key enzyme involved in interconversion of glutamate to alpha-ketoglutarate and ammonia using NADP(H) and NAD(H) as co factors.
It plays an important role in homeostasis by interconnecting amino acid and carbohydrate metabolism pathways.
Present in two isoforms in humans, the GDH isoform 2 (hGDH2] is overexpressed in the brain astrocytes and the sertoli cells in testis. ADP levels act as positive regulators for this enzyme and unlike the other isoform it is not inhibited by GTP.
Important in recycling glutamate in the brain astrocytes, this enzyme works in concert with glutamine synthetase (GS) providing ammonia as well as ATP for GS activity.
Two parallel studies have shown that increased levels of glutamate prepones the onset of the disease by 6 to 13 years [100].
Hemizygous individuals with a rare variation in hGDH2 (substitution of Ala for Ser445] was detected in these individuals. All together these results highlight the role of hGDH2 in the maintenance of brain homeostasis.ABAD associated with Alzheimer’s disease has also shown to play some role in PD disease. In mouse models of PD generated by administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) ABAD expression is significantly reduced. By contrast, overexpression of ABAD in transgenic mice is shown to attenuate MPTP-induced dopaminergic neurogeneration.
This strongly suggests that ABAD may contribute to the fate of DA neurons during the onset of PD.8. ConclusionThe brain as well as the BBB have complex structural and functional physiology which demands a continuous supply of high energy. Bioenergetic pathways in the brain utilize multiple pathways (such as glycolytic metabolism, TCA cycle etc) to ensure that the energy requirements of the different cell types in the brain are fulfilled at all time. The BBB acts as a critical interface to buffer and influx energy substrates into the brain. Various DHOs are a critical part of these bioenergetic pathways and occurrence of DHO defect can lead to inborn errors in the metabolism followed by strong neurological complications. PDH is an imporant IEM which is directly linked to bioenergectic pathways such as TCA cycle and aerobic respiration. Apart from energy metabolism, BCKDH and SSD are IEMs that correlate to other pathways in the brain such as amino acid metabolism and neurotransmitter degradation. DHOs (such as ALDHs) also play an important role to further degrade the biogenic aldehydes derived from the degradation pathways of neurotransmitters such as for epinephrine, norepinephrine and GABA which are commonly synthesized in the brain. This can ultimately facilitate the onset and progression of various neurological disorders such as Alzheimer’s disease and PD. They constitute an integral part of various metabolic pathways in the brain associated with energy metabolism, as well as synthesis and degradation of neurotransmitters. In born as well as acquired defects in DHOs have been shown to correlate with various CNS and BBB pathophysiologies.



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Comments

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    Author: VETERAN
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