Physiology, Metabolism

Issues of Concern

The chemical reactions by which metabolism occurs are almost the same in all living organisms, including animals, plants, bacteria, and fungi. All these chemical reactions are mediated by proteins that act as catalysts under specific environmental conditions such as pH and temperature. The synthesis of many of the catalysts that mediate chemical reactions throughout our body has its origins in DNA. DNA is the molecule residing within the nucleus and is made of 4 bases: adenine, guanine, cytosine, and thymine. RNA is the molecule used by some living organisms instead of DNA, and this molecule's components include ribose and uracil instead of thymine. The environment, primarily plants, uses sunlight to transform water and carbon dioxide to synthesize carbohydrates. Living organisms do the opposite, consuming carbohydrates and other organic materials to produce energy.

Thermodynamics

It is impossible to discuss metabolism without taking a look at the laws of thermodynamics. The first 2 laws merit particular attention. The first 2 laws of thermodynamics state that energy can neither be created nor destroyed and that the outcome of physical and chemical changes is to increase entropy in the universe. The energy that is useful, or free energy, is that kind of energy capable of doing work under no difference in temperature. Less valuable forms of energy become liberated in the form of heat.[1]

Cellular Level

The chemical carrier of energy is called ATP. The synthesis of ATP takes place within an intracellular organelle bounded by an external membrane and an inner membrane. The dissociation of water to a molecule of hydrogen and a hydroxyl group that takes place in the internal milieu of the body is essential for the synthesis of ATP. The catabolic reactions, which this topic reviews later, release significant amounts of protons, most of which are transported to the mitochondria to produce ATP. These protons are transported through a series of complexes in the inner membrane of the mitochondria to activate an ATPase, using the energy released by the electron chain transport mechanism. 

Organisms process the food they eat in 3 different stages. The first stage involves reducing complex molecules to simple molecules; this includes the breakdown of complex proteins to oligopeptides and free amino acids to facilitate absorption, the breakdown of complex sugars to disaccharides or monosaccharides, and breaking down lipids to glycerol and free fatty acids. These processes are called digestion and only makeup about 0.1% of energy production, which cannot be used by the cell. In the second phase, all these small molecules undergo incomplete oxidation. Oxidation means the removal of electrons or hydrogen atoms. The end-product of these processes is water and carbon dioxide, and 3 principal substances, namely acetyl coenzyme A, oxaloacetate, and alpha–oxoglutarate. Of these, the most common compound is acetyl coenzyme A, which forms 2/3 of the carbon in carbohydrates and glycerol, all the carbon in fatty acids, and half the carbon in amino acids. The third and final phase of this process occurs on a cycle called the Krebs cycle, discovered by Sir Hans Krebs. In this cycle, acetyl coenzyme A and oxaloacetate come together and form citrate. In this stepwise reaction occurs a liberation of protons, which are transferred to the respiration chain to synthesize ATP. 

The imbalance between anabolism and catabolism can lead to obesity and cachexia, respectively. Metabolic energy is transported by high-energy phosphate groups like ATP, GTP, and creatine phosphate or by electron carriers like NADH, FADH, and NADPH.[2][3]

Organ Systems Involved

The pancreas is the key metabolic organ that regulates the number of carbohydrates in the blood, either by releasing significant amounts of insulin to downregulate the levels of blood glucose or by releasing glucagon to upregulate them. The utilization of carbohydrates and lipids by the organism is called the Randle cycle, regulated by insulin.

The liver is the organ in charge of processing the absorbed amino acids and lipids from the small intestine. It also regulates the urea cycle and essential metabolic processes like gluconeogenesis and glycogen deposition.[4]

Function

Characteristics of carbohydrates include being soluble, relatively easy to transport, and nontoxic molecules that serve as the substrate of energy when oxygen levels are compromised.

The most energy-dense molecule is lipids and is the principal energy molecule for mammals and tissues. Because they are not soluble, they are not readily transportable in the blood, are not usable anaerobically, and require more oxygen to extract energy from them (2.8 ATP/oxygen molecule). They cannot cross the blood-brain barrier, and erythrocytes or renal cells are unable to use them. Amino acids act as substrates to produce glucose only in states of prolonged starvation, exhibiting the depletion of glycogen stores.  

The metabolism of these 3 principal substrates converges into 1 molecule, acetyl–CoA, in the mitochondria. Metabolism of this intermediate molecule generates 3 NADH, 1 FADH, 1 GTP, and 2 CO2, all of which participate in the respiratory chain in the mitochondria to synthesize ATP.[5]

Mechanism

Carbohydrate Metabolism

It focuses on one specific kind of sugar, glucose. After a cell uptakes a molecule of glucose, it gets immediately metabolized to glucose-6-phosphate, which cannot exit the cell. The catalyzing enzyme in this reaction is called hexokinase (in the liver and pancreas) or glucokinase in every other tissue. This metabolite is usable by almost every metabolic process, including glycolysis and glycogenesis. Carbohydrates are stored as glycogen granules for rapid mobilization of glucose when required.

Glycogen is a polymer of glucose, assembled by the glycogen synthase, with branch points every 10 glucose molecules, which gives the glycogen a tree-like structure, which is beneficial for glucose mobilization. Some tissues utilize glycogen for their maintenance, like skeletal muscle; some other tissues use glycogen to maintain serum glucose levels stable, such as the liver. The liver can store almost 100 g of glycogen that supplies glucose for 24 hours; the skeletal muscle stores 350 g, which is sufficient for 60 minutes of muscle contraction. Glucose is metabolized by glycolysis in all cells to form pyruvate. This process does not use oxygen, and it generates 2 molecules of pyruvate, 2 NADH and 2 ATP.

Pyruvate may have 3 fates within the cell: it can be transported into the mitochondria and generate acetyl–CoA, it can remain in the cytosol and generate lactate, or it can be used in glyconeogenesis by the enzyme alanine aminotransferase (ALT). The fate of pyruvate in tissues depends on hormonal regulation, oxygen availability, and the particular tissue. For example, in the liver, excess pyruvate is metabolized to acetyl–CoA, and then this is used for lipid synthesis, whereas in muscle, it undergoes complete oxidation to CO2.

Glucose–6–phosphate is also usable by the pentose phosphate pathway. This pathway synthesizes nucleotides, synthesizes specific lipids, and maintains glutathione in its active form. This process is under the regulation of glucose–6–phosphate dehydrogenase.

Carbohydrate metabolism is regulated mainly by insulin, as it stimulates glycolysis and glycogenesis. Catecholamines, glucagon, cortisol, and growth hormone stimulate gluconeogenesis and glycogenolysis.[6]

Lipid Metabolism

Fatty acids serve as energy production in oxidative tissues. Some of them are amphipathic and potentially toxic, and they are transported bound to albumin. The intestines absorb fatty acids in the form of micelles; these get engulfed by the enterocytes in the intestinal wall. Once inside, these molecules of fat get broken down into smaller molecules, free fatty acids and glycerol that are posteriorly conjugated to form triglycerides. These are bound to proteins to form chylomicrons outside the enterocyte.

These chylomicrons are very rich in cholesterol and triglycerides, which are transported by the portal vein system to the liver. The liver processes these complex molecules to extract a fraction of cholesterol and triglycerides. The liver secretes a new form of a complex molecule called VLDL that transports endogenous lipids and fat to peripheral tissues that express hormone-sensitive lipase and lipoprotein lipase.

This enzyme reduces VLDL into LDL, which contains more cholesterol than the other molecules, and it finally gets engulfed by target tissues. All this process is called "forward cholesterol metabolism." When too much fat or cholesterol exists in peripheral tissues, it travels within a lipoprotein called HDL, which enters the biliary system for excretion. This process is called "reverse cholesterol metabolism." Both are regulated by insulin, which stimulates lipases in the organism but suppresses lipolysis.[7][8][9][10]

Amino Acid Metabolism

We consume almost 100 g of protein per day. The body contains nearly 10 kg of protein that is metabolized by 300 g per day. The structural units comprising proteins are amino acids. Some of these are essential (meaning that the body cannot synthesize them and must obtain them from the diet), and some are non–essential amino acids (which the body can synthesize). Proteins are absorbed in the form of amino acids by the enterocytes. Amino acids contain a nitrogen group and a 2-carbon skeleton called 2–2-oxoacid.

Metabolism of amino acids generates ammonium, which is a toxic molecule, especially for the CNS. Ammonium can be metabolized in the liver for excretion into the ornithine (urea) cycle. Amino acid metabolism occurs in 2 kinds of chemical reactions. The first is called transamination, in which alanine aminotransferase (ALT) and aspartate aminotransferase (AST) participate. These 2 reactions require a 3-carbon skeleton to interchange the amino group; the skeleton for these 2 enzymes is alpha-ketoglutarate. In the response regulated by ALT, alanine transfers the amino group to alpha-ketoglutarate to form pyruvate and glutamate. In the AST-regulated reaction, the inverse situation occurs. It takes the donated amino group from glutamate to create aspartate to present a second amino atom to the Urea cycle. The second reaction is deamination, in which the glutamate dehydrogenase metabolizes glutamate to form alpha-ketoglutarate and ammonia, which have to be detoxified by the urea cycle.

After deamination, the skeleton undergoes intermediate metabolism. The metabolism of amino acids can yield 7 types of skeletons, namely: alpha-ketoglutarate, oxaloacetate, succinyl–CoA, fumarate, pyruvate, acetyl–CoA, and acetoacetyl–CoA. The first 5 have 3 or more carbons, and they are helpful for glyconeogenesis; the last 2 have only 2 carbons, and they are unusable for glyconeogenesis. Instead, they are used for lipid synthesis.

Like all the other metabolic pathways, insulin is the main regulator. In contrast, the regulators in the amino acid metabolism are cortisol and thyroid hormone, which mediate muscle breakdown.[11][12][13]

Clinical Significance

Diabetes Mellitus

The pancreas senses glucose concentrations in blood and some amino acids, such as arginine and leucine. High levels of these substances indicate nutritional repletion, and this message is sent to the body by the pancreas in the form of insulin. Insulin is the unique metabolic hormone in charge of the disposition of nutrients in the body, which means that insulin deficiency implicates pleiotropic changes in human metabolism. With insulin deficiency, there is less inhibition of catabolic responses; this drives a net mobilization of substrates from tissues. The pancreas senses metabolite status, and peripheral tissues sense insulin concentration status. When peripheral tissues feel a fall in insulin, they become catabolic, and substrates start to mobilize. The liver responds to low insulin by increasing glucose synthesis with gluconeogenesis and glycogenolysis. As seen in amino acid metabolism, the principal gluconeogenic substrate is alanine, resulting from muscle waste and proteolysis. Adipose tissue responds as well, augmenting lipolysis and leading to fatty acid accumulation and glycerol. Increased delivery of non-esterified fatty acids (NEFA) to the liver increases ketogenesis.[14]

Sepsis, Trauma, and Burns

Catabolism can also initiate from an excessive inflammatory reaction, characterized by the upregulation and expression of proinflammatory cytokines such as TNF-alfa, IL-6, and IL-1. This process is called systemic inflammatory response syndrome (SIRS). It has 3 phases regarding metabolism: the ebb or shock phase, the catabolic phase, and the anabolic phase. In these scenarios, there is a considerable mobilization of substrate throughout the body.[15]

G6PDH Deficiency

It is a deficiency well distributed in equatorial regions. It is X-linked and reduces levels of NADPH, hence decreasing levels of the active form of glutathione and increasing oxidative stress for red blood cells; this leads to hemolysis presented as a crisis, depending on the insult. It appears as Heinz bodies and blister cells on a peripheral blood smear.[16]