Essential. Biochemistry. CHARLOTTE W. PRATT. Seattle Pacific University with Donald Voet and Judith G. Voet, of Fundamentals of Biochemistry, published . Third Edition Essential Biochemistry This page is intentionally left blank Third Edition Essential Biochemistry CHARLOTTE W. PRATT Seattle Pacific University . Pratt C., Cornely K. Essential Biochemistry. Файл формата pdf; размером 28,32 МБ. Добавлен пользователем Tyma ; Отредактирован.
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Concise writing, a focus on clinical applications, and superb illustrations make Netter's Essential Biochemistry, by Peter Ronner, PhD, the perfect choice for a. PDF | On Dec 21, , Farhat Bano and others published Essential Biochemistry SAQs. d[P1 dt. • The reaction rate (velocity, v) can be described in several ways. – Disappearance of substrate, S. – Appearance of product, P. • These equations relate.
Viroids are infectious for a variety of higher plants including potato, tomato, avocado, ornamental plants and coconut palm, and can cause disease leading to significant agricultural damage. By contrast, viroids have not been observed as infectious agents in animals or humans. Viroids, as isolated RNA molecules with the complete biology of a virus, received a lot of scientific attraction 6—8.
More than a decade after the discovery of the circularity of viroid RNA 9 , cellular circular RNAs circRNA were observed as genomic transcripts with potential functions in gene regulation Thus, viroids were not only molecules of enormous biological interest on their own, but stimulated the developments of new experimental and conceptual approaches.
Novel methods of nucleic acid purification and gel electrophoresis developed during viroid research were later applied to nucleic acid research in general. Combining the experimental and theoretical approaches, the concept of metastable structures was developed and could be verified in vivo, when the replication cycle of viroids was studied in detail.
The application of the improved electrophoretic methods showed that nucleic acids are not essential for prion infectivity, confirming that prions are indeed infectious proteins.
Analysis of a viroid fragment by nuclear magnetic resonance NMR spectroscopy demonstrated directly that hydrogen bonds in RNA have partially covalent character. Predictions from evolution theory about the relationship between error rate and genome size were verified with viroids. In the following we will describe developments in RNA technology. Indeed, it may be the only biochemistry book you need. The amount of energy contained in food is typically measured in calories; a dietary calorie C is actually a thousand calories kcal a calorie is defined as the amount of heat energy that is required to increase the temperature of 1 gram of water by 1 degree Celsius.
Carbohydrates a hydrated energy source and proteins produce about 4 kcal per gram, while fat an anhydrous energy source produces about 9 kcal of heat per gram. They vary widely in their complexity, and in the speed with which they are digested and metabolised.
Sugars are a class of carbohydrates. Sugar monosaccharides include glucose, fructose and galactose. Disaccharides, composed of two monosaccharide units, include sucrose common table sugar, glucose and fructose , lactose found mostly in milk , glucose and galactose Figure 1. Polysaccharides are polymers of monosaccharides. Starch is a polysaccharide composed of amylose, an essentially linear polysaccharide, and amylopectin, a highly branched polysaccha- ride; both are polymers of D-Glucose.
Amylose Figure 1. Amylopectin differs from amylose in being highly branched. Short side chains of about 30 glucose units are attached with 1—6 linkages approximately every 20—30 glucose units along the chain. Starch and glycogen polysaccharides provide structures that are used for energy storage, in plants and animals respectively. Fibre is a polymer carbohydrate. Medium GI 56—69 Whole wheat products, brown rice, basmati rice, sweet potato, table sugar, ice cream.
Low GI foods release glucose more slowly and steadily; high GI foods cause a more rapid rise in blood glucose levels. The latter are suitable for energy recovery after endurance exercise or for a person with diabetes experiencing hypoglycaemia.
Only foods containing carbohydrates have a glycaemic index. Fats and proteins have little or no direct effect on blood sugar. Fat is a normal and healthy constituent of the body, cushioning internal organs from shock and providing heat insulation. As an energy source, fat contains over twice the energy per gram as does carbohydrate.
Carbohydrates in the form of glucose are typically used to provide rapid energy, while fat is burned during sustained exercise.
Fat is the primary fuel of choice during slow aerobic exercise, while glucose is used during fast aerobic or anaerobic exercise. Lipids include fats and oils; oils tend to be liquid at room temperature, fats tend to be solid. A fat molecule consists of one molecule of glycerol, bonded by dehydration synthesis the loss of water to three fatty acid molecules this is a triacylglycerol, Figure 1.
The glycerol backbone is bonded to three fatty acids R1 , R2 and R3. During dehydration synthesis, three fatty acid molecules each bond to one of the three —OH groups of the glycerol. Phospholipids Figure 1. In a phospholipid molecule, one fatty acid is replaced with a phosphate group, to which is attached X a nitrogen-containing molecule, for example choline, ethanolamine, serine or inositol giving the phospholipid phosphatidylcholine, phos- phatidylethanolamine, phosphatidylserine or phosphatidylinositol, respectively.
The amphipathic phospholipid molecule contains a polar head group and non-polar tail; this is crucial to the ability of such molecules to self assemble in water to form lipid membranes. Consisting of a polar charged head group and a pair of non-polar fatty acid tails, they are amphipathic molecules Figure 1.
Lipids may be saturated or unsaturated or polyunsaturated , depending on whether their fatty acids contain carbon—carbon double bonds Figure 1. Common sources of saturated fats are beef, veal, lamb, pork and dairy products made from whole milk, as well as coconut and palm oil.
Food manufacturers frequently employ trans-fats Figure 1. These may further be hydrogenated. Margarine and shortening contain hydrogenated fats. Certain fatty acids must be included in the food we consume essential fatty acids. Two essential fatty acids are the polyunsaturated omega-3 linolenic acid and omega-6 fatty acids linoleic acid Figure 1.
Amino acids that cannot be synthesised by the body are referred to as essential amino acids Table 1. All tissues have some capability for synthesis of non-essential amino acids, through the inter- conversion transamination of amino acids and their keto-acid carbon skeletons Figure 1.
Lysine and leucine are the only amino acids that are solely ketogenic; these give rise to acetyl-CoA or acetoacetyl-CoA, both of which can enter the TCA cycle, but neither of which can bring about net glucose produc- tion.
In times of dietary surplus, the potentially toxic nitrogen of amino acids is eliminated via transamination, deamination and urea formation. Unlike fat and carbohydrate, nitrogen has no designated storage depots in the body. Young children, adults recovering from major illness and pregnant women are often in positive nitrogen balance; intake of nitrogen exceeds loss as net protein synthesis proceeds.
The levels of acetone are much lower than those of the other two ketone bodies; it cannot be converted back to acetyl-CoA and so is excreted in the urine or breathed out. Acetyl-CoA results from the breakdown of carbohydrates, lipids and certain amino acids. Normally, the acetyl group of acetyl-CoA enters the citric acid cycle to generate energy in the form of ATP, but it can also form ketone bodies; this happens if acetyl-CoA levels are high and the TCA cycle capacity is exceeded the limiting factor is the availability of oxaloacetate.
This happens in untreated type I diabetes diabetic ketosis and also in alcoholics after heavy drinking and subsequent starvation alcoholic ketosis. This lowers the concentration of pyruvate, which is the immediate cause of the inhibition of gluconeogenesis from lactate.
A low pyruvate concentration reduces the rate of the pyruvate carboxylase reaction, one of the rate-limiting reactions of gluconeogenesis. The body is unable to synthesise enough glucose to meet its needs, thus creating an energy crisis resulting in fatty acid metabolism and ketone body formation.
Excess acetyl-CoA increases fatty acid synthesis and fat deposits in the liver fatty liver. An accumulation of fat in the liver can be observed after just a single night of heavy drinking.
Glycerol is an important by-product of fat metabolism. Glycerol enters the reaction sequence: They must be supplied in the diet or in the form of dietary supplements. Fat-soluble vitamins include vitamins A, D, E and K; they are absorbed, transported, metabolised and stored along with fat. Water-soluble vitamins include vitamin C, and those of the B- complex group: They function mainly as coenzymes and prosthetic groups.
In pregnancy, supplementa- tion of certain vitamins may be recommended. The role of vitamins in the body is summarised in Table 1. Vitamin A — Skin and mucous Green leafy 1 mg Yes. Vitamin B1 — Prevention of Dried yeast, 1. Vitamin B2 — Cell growth; general Milk, yeast, 1.
Vitamin B3 — Reducing blood Lean meat, whole 19 mg No, but contra niacin, nicotinic pressure; lowering wheat, tuna, indicatory for acid cholesterol levels; anchovy, yeast, individuals with preventing pellagra.
Doses antibodies and red molasses and over 2 g can lead blood cells. Vitamin B12 Protein and fatty Clams, oysters, 2 mg No cyancobali-min, acid metabolism; beef, eggs and cobalamin production of red dairy products. It Water soluble greying. Vitamin C — Cell growth; bones, Citrus fruits, hot 60 mg Vitamin C is ascorbic acid gums and teeth; chilli peppers, non-toxic but Water soluble bacterial resistance; broccoli, not antioxidant activity; tomatoes, green recommended absorption of iron.
Fat soluble metabolism; products. The daily requirements of minerals can be obtained from a well-balanced diet. Enzymes are crucial to metabolism because they allow organisms to drive desirable but energetically unfavourable reactions usually anabolic by coupling them to favourable ones usually catabolic.
Enzymes also allow for the regulation of metabolic pathways. After a meal, glucose concentrations in the portal venous blood can easily reach 20 mM. Much of this excess will be removed by the liver. Stimulation of insulin release results in the uptake of glucose by the peripheral tissues muscle and adipose tissue. Surplus glucose is stored locally in tissues as glycogen, but mostly it is converted into fats.
This level of glucose is actively defended by the liver, which removes glucose when too high, and replenishes it when too low. Both the supply and the demand for glucose may vary more than fold over a 24 hour period; both can change suddenly and sometimes without warning. The liver can both uptake and secrete glucose; it is one of the few tissues in the body to permit bi-directional glucose transport enterocytes and kidney are others.
Internal hepatic glucose concentrations are similar to those in the bloodstream. Most tissues present a major barrier to glucose entry at the plasma membrane, and glucose is only allowed to enter the cells during periods of intense metabolic activity and in response to circulating insulin.
Unlike the liver, most tissues have no export pathway for glucose; their glycogen reserves are strictly for internal use. Long-term surplus glucose is converted into fats via lipogenesis. Long-term shortages are made good via gluconeogenesis from non-carbohydrate precursors.
Table 2. Fats affect a number of metabolic controls that suppress the oxidation of carbo- hydrates. Carbohydrate stores are wet and bulky and their energy density is low. They are useful for emergencies and short-term requirements, but are not a cost-effective fuel for longer-term requirements see Table 2. Carbohydrate stores supply about three hours of average waking activity. The strategy is therefore to conserve limited carbohydrate stores for emergency use , while fuelling basal metabolic activity with fats.
Liver glycogen provides a short-term source of carbohydrate for emergency use. Fat, in adipocytes, provides the major energy store in humans, although muscle proteins are also degraded when food intake is inadequate. Most amino acids except leucine and lysine are glucogenic, meaning that their carbon skeletons can be converted at least partially into glucose via tricarboxylic acid cycle TCA cycle intermediates.
This glycerol component is crucial for survival. An average-weight human has energy reserves totalling about MJ about Mcal. Required daily energy intakes are about 12 MJ per day for males, 9. This is a central pathway for the catabolism of carbohydrates in which the six-carbon sugars are split to three-carbon compounds, with subsequent net production of cellular energy in the form of ATP Figure 2.
Glycolysis can proceed under both anaerobic without oxygen and aerobic conditions. This pathway is almost universal to living organisms. Pyruvate is an intermediate in several metabolic pathways; mostly it is converted to acetyl- CoA to feed into the TCA cycle Figure 2. Through the Cori cycle, lactate produced in the skeletal muscles can be delivered to the liver and used to regenerate glucose, through gluconeogenesis. The 6-carbon sugar is then cleaved to two 3-carbon sugars.
In the energy generation stage, ATP is formed. As a consequence, for each molecule of glucose 6-carbon oxidised, two molecules of ATP are invested and four molecules of ATP are generated, giving a net production of two molecules of ATP.
Reactions 1—3 are exergonic and essentially irreversible. The Cori cycle refers to the metabolic pathway in which lactate, produced by anaero- bic glycolysis in the muscle, moves to the liver and is converted to glucose, through gluconeogenesis; glucose can then return to supply the muscle. Liver Glucose Muscle Glucose Gluconeogenesis 6 ATP Glucose 2 Pyruvate Blood 2 ATP Glycolysis 2 Lactate 2 Pyruvate 2 Lactate 2 Lactate Alternatively, in skeletal muscle, pyruvate can be transaminated to alanine which affords a route for nitrogen transport from muscle to liver ; in the liver alanine is used to regenerate pyruvate, which can then be diverted into gluconeogenesis.
This process is referred to as the glucose—alanine cycle. In glycolysis the oxidation of glucose produces two molecules of pyruvate; therefore, the complete oxidation of glucose requires two turns of the TCA cycle, to generate six molecules of NADH. Substrates are oxidised they lose an electron , and the electron passes through the redox chain, directionally from a low to a high redox potential, eventually being added to oxygen and reducing it to water.
As electrons pass through the different redox components, low to higher potential, they release energy. Certain of the mitochondrial respiratory complexes complexes I, III and IV can use this energy to pump protons hydrogen ions across the inner mitochondrial membrane, thereby generating a proton gradient. Complex II succinate dehydrogenase does not pump protons.
The mitochondria in brown fat contain a protein called thermogenin also called uncoupling protein 1. Thermogenin acts as a channel in the inner mitochondrial membrane to control the permeability of the membrane to protons.
Newborn babies contain brown fat in their necks and upper backs that serves the function of nonshivering thermogenesis. Muscle contractions that take place in the process of shivering use ATP and produce heat, but nonshivering thermogenesis is a hormonal stimulus for heat generation without the associated muscle contractions of shivering.
The process of thermogenesis in brown fat is initiated by the release of free fatty acids from the triacylglycerol stored in the adipose cells Figure 2. Activated adenyl cyclase leads to increased production of cAMP and the concomitant activation of cAMP-dependent protein kinase A PKA , resulting in phosphorylation and activation of hormone-sensitive lipase. The released fatty acids bind to thermogenin, triggering an uncoupling of the proton gradient and the release of the energy of the gradient as heat.
The mitochondrial electron transfer chain is localised within the inner mitochondrial membrane. Through the oxidation of NADH or succinate, electrons enter the chain, passing from one redox component to another, handing down a redox potential low redox potential to a higher redox potential , eventually being added to oxygen at complex IV to form water.
At complexes I, III and IV, the energy released by the electron is used to pump protons, from the inside matrix, across the inner membrane, to the intramembrane space the space between the inner and outer mitochondrial membranes. Both hormones cause the conversion of inactive glycogen phosphorylase b to the active glycogen phosphorylase a. The increase in cAMP activates protein kinase A, which phosphorylates and activates the hormone-sensitive lipase.
Fatty acids, from the lipolysis of triacyglycerol, bind to thermogenin, which is then able to transport protons across the inner mitochondrial membrane, effectively uncoupling the mitochondria and releasing the energy derived from electron transfer as heat.
Glycogen phosphorylase a cleaves the bond at the 1 position by substitution of a phosphoryl group. A second step involves a debranching enzyme to remove 5-linked glucose. The key regulatory enzyme in this process is the glycogen phosphorylase, which is activated by phosphorylation and inhibited by dephosphorylation.
Liver hepatic cells will either consume the glucosephosphate in glycolysis or remove the phosphate group using the enzyme glucosephosphatase and release the free glucose into the bloodstream for uptake by other cells.
Liver glycogen is a short-term glucose buffer, muscle glycogen a short-term energy supply. PKA phosphorylates phospho- rylase kinase, which in turn phosphorylates glycogen phosphorylase b, converting it into the active glycogen phosphorylase a. The goal of glycolysis, glycogenolysis and the TCA cycle, is to conserve energy as ATP from the catabolism of carbohydrates.
Gluconeogenesis takes place in the liver, and to a lesser extent in the kidneys. The process occurs during periods of starvation or intense exercise. It is an energetically unfavourable pathway that requires the coupling of exergonic and endergonic reactions. While most steps in gluconeogenesis are the reverse of those found in glycolysis, the three regulated and strongly exergonic reactions of glycolysis 1—3 in Figure 2.
The rate of gluconeogenesis is ultimately controlled through the control of the key enzyme fructose- 1,6-bisphosphatase. However, both acetyl-CoA and citrate activate pyruvate carboxylase and fructose-1,6-bisphosphatase, and also inhibit the activity of pyruvate kinase the corresponding negative free energy reaction in glycolysis , so promoting gluconeogenesis.
Glycogen synthesis depends on the demand for glucose and ATP energy ; if both are present in relatively high amounts then an excess of insulin will promote glucose conversion into glycogen for storage in liver and muscle cells.
Glucose is converted into glucosephosphate by the action of glucokinase GK liver or hexokinase muscle , which is then converted to glucosephosphate by the action of phos- phoglucomutase, passing through the intermediate glucose-1,6-phosphate. Glucosephosphate is converted to UDP-glucose by the action of uridyl transferase also called UDP-glucose pyrophosphorylase.
Although phosphoglycerate kinase is shared with glycolysis, in gluconeogenesis this reaction requires the input of ATP. Glycogen synthase is a tetrameric enzyme consisting of four identical subunits. Its activity is regulated by phosphorylation of serine residues in the subunit proteins. Phosphorylation of glycogen synthase reduces its activity towards UDP-glucose; in the non-phosphorylated state synthase a, active , glycogen synthase does not require glucosephosphate as an allosteric activator, but when phosphorylated synthase b, inactive , it does.
The addition of glucose to glycogen depends upon the presence of a pre-existing glycogen primer; glucose monomers are arranged and added to the primer by glyco- gen synthase, a key regulatory enzyme that is subject to control by covalent phosphorylation.
Glycerol is used by the liver for triacylglycerol synthesis or for gluconeogenesis following its conversion to 3-phosphoglycerate.
Fatty acids are the preferred energy source for the heart and an important energy source for skeletal muscle during prolonged exertion.
Activation is catalysed by fatty acyl-CoA ligase also called acyl-CoA synthetase or thiokinase. The net result of this activation process is the consumption of 2 molar equivalents of ATP. Clinical problems related to fatty acid metabolism. This can occur in newborns and particularly in pre-term infants. Treatment is by oral carnitine administration. Inheritance for all fatty acid oxidation defects is auto- somal recessive. Symptoms include vomiting, lethargy and frequently coma.
Excessive urinary excretion of medium-chain dicarboxylic acids, as well as their glycine and carnitine esters, is diagnostic of this condition. Disorders of glycerol metabolism. Fatty acid synthesis is discussed in Chapter 5. Transamination reactions Figure 2. Glucogenic amino acids are a major carbon source for gluconeogenesis when glucose levels are low. They can also be catabolised for energy or converted to glycogen or fatty acids for energy storage.
A smaller number of amino acids are degraded to acetyl-CoA or acetoacetyl-CoA. Neither acetyl-CoA nor acetoacetyl-CoA can yield a net production of oxaloacetate, the precursor for the gluconeogenesis pathway because for every 2-carbon acetyl residue entering the TCA cycle, two carbon atoms leave as CO2. These are referred to as the ketogenic amino acids; they can be catabolised for energy in the TCA cycle, or converted to ketone bodies or fatty acids, but they cannot be converted to glucose.
In addition, sweet detectors, similar to those on the tongue, have recently been documented in the epithelial lining of the duodenum. Primary sensors are located in the pancreatic islets, and also in the carotid bodies, medulla and the hypothalamus. Insulin secretion is a complex process, and the islet cells receive additional signals from the gut and the autonomic nervous system, which modulate the insulin release to match the food that has been eaten.
The hypothalamus and the solitary tract nucleus largely control the autonomic nervous sys- tem, and manage a spectrum of sensations ranging from a sense of well-being to one of terror. This is required for normal brain function at all physiological levels of blood glucose. However, in contrast to the rest of the central nervous system CNS , the cells of the arcuate nucleus contain GK.
This enzyme is considered to be a true glucose sensor because it catalyses the rate-limiting step of glucose catabolism, its activity being regulated by interaction with glucokinase regulatory protein, which functions as a metabolic sensor.
The glucokinase regulatory protein is best documented in hepatocytes, where it has been shown to bind to and move glucokinase, controlling both the activity and intracellular location of this key enzyme. That is, glucose stimu- lates hunger between meals and inhibits hunger after meals.
These receptors are involved in control of a diverse set of behavioural processes, including appetite, circadian rhythm and anxiety. AgRP is a receptor antagonist of CNS melanocortin receptors and appears to have an important role in the control of food intake.
Hypothala- mic POMC neurons are important mediators in the regulation of feeding behaviour, insulin levels and ultimately body weight. Additional signals, adrenocorticotrophic hormone ACTH and pituitary growth hormone pGH , act to increase blood glucose by inhibiting uptake by extrahepatic tissues.
Cortisol, the major glucocorticoid released from the adrenal cortex, is secreted in response to the increase in circulating ACTH, and also acts to increase blood glucose levels by inhibiting glucose uptake. The adrenal medullary hormone, adrenaline epinephrine , stimulates production of glucose by activating glycogenolysis in response to stressful stimuli.
The predominant tissue responding to signals that indicate reduced or elevated blood glucose levels is the liver. Elevated or reduced levels of blood glucose trigger hormonal responses to initiate pathways designed to restore glucose homeostasis Table 2.
The resultant increased level of GP in hepatocytes is hydrolysed to free glucose by glucosephosphatase, which then diffuses to the blood. The glucose enters extrahepatic cells, where it is re-phosphorylated by hexokinase to GP. Since muscle and brain cells lack glucosephosphatase, the GP is retained and oxidised by these tissues for energy.
In opposition to glucagon, insulin stimulates extrahepatic uptake of glucose from the blood and inhibits glycogenolysis in extrahepatic cells, conversely stimulating glycogen synthesis. As glucose enters hepatocytes, it binds to glycogen phosphorylase a, stimulating the de- phosphorylation of phosphorylase a and thereby inactivating it.
That glucose is not immediately converted to glucosephosphate in the liver is due to the presence in hepatocytes of the isoenzyme glucokinase, rather than hexokinase. Additionally, GK is not inhibited by its product GP, whereas hexokinase is.
Different internal glucose concentrations require different genes to be expressed in different cells. Most tissues use hexokinase to phosphorylate glucose to GP, so that it can be metabolised within the cells. In contrast, cells which routinely export glucose to the bloodstream, such as liver, gut wall and kidney tubules, express a different gene, for the isoenzyme GK.
This enzyme has a much higher K m for glucose, so that most of the intracellular glucose escapes phosphorylation and is available for export, or to inhibit phosphorylase a and glycogenolysis see also Section 9. Glucose transporters compose a family of at least 14 members.
GLUT2 transports both glucose and fructose. When the concentration of blood glucose increases in response to food intake, pancreatic GLUT2 molecules mediate an increase in glucose uptake, which leads to increased insulin secretion. GLUT5 is expressed in intestine, kidney, testes, skeletal muscle, adipose tissue and brain. Diabetes develops due to a diminished production of insulin type 1 or a resistance to its effects type 2 , including gestational diabetes.
This can lead to hyperglycaemia, which is largely responsible for the acute signs of diabetes, namely: Diabetes mellitus is characterised by recurrent or persistent hyperglycaemia, and is diagnosed by demonstrating any one of the following: Normally, glucose induces a biphasic pattern of insulin release. The generally accepted sequence of events involved in glucose-induced insulin secretion is as follows: Intracellular glucose is metabolised to ATP.
The cause of type 1 diabetes is not fully understood. Individuals may display genetic vulnerability; an observed inherited tendency to develop type 1 diabetes has been traced to particular human leukocyte antigen HLA genotypes the major histocompatibility complex MHC in humans is known as the HLA system. Type 1 diabetes is a polygenic disease different genes contribute to its expression ; it can be dominant, recessive or intermediate. The gene IDDM1, located in the MHC class II region on chromosome 6, is believed to be responsible for the histocompatibility disorder characteristic of type 1 diabetes.
Other associated genes are located on chromosomes 11 and Adults who contract type 1 diabetes may be misdiagnosed with type 2 diabetes. In addition, a small proportion of type 1 cases have the hereditary condition maturity onset diabetes of the young MODY , which can also be confused with type 2. Type 1 diabetes is treated with insulin replacement therapy, usually by insulin injection or insulin pump, along with attention to dietary management and careful monitoring of blood glucose levels.
With type 2 diabetes, proinsulin can be split into insulin and C-peptide; lack of C-peptide indicates type 1 diabetes. The presence of anti-islet antibodies to glutamic acid decarboxylase, insulinoma associated peptide-2 or insulin or absence of insulin resistance determined by a glucose tolerance test is also suggestive of type 1. With prevalence rates doubling in the USA between and , type 2 diabetes has been described as an epidemic. Traditionally considered a disease of adults, it is increasingly diag- nosed in children in parallel to rising obesity rates.
While the underlying cause of insulin resistance is unknown, there is a striking correlation between obesity, increased plasma lipids and resistance. Central obesity fat concentrated around the waist in relation to abdominal organs, but not subcutaneous fat is known to predispose individuals to insulin resistance. Abdominal fat is especially active hormonally, secreting a group of hormones called adipokines, which may possibly impair glucose tolerance. There is also a strong inheritable genetic connection in type 2 diabetes.
Additionally there is a mutation to the islet amyloid polypeptide gene that results in an earlier-onset, more severe form of diabetes. Environmental exposures may contribute to recent increases in the rate of type 2 diabetes.
For example, there is a positive correlation between concentration in the urine of bisphenol A, a constituent of polycarbonate plastic, and the incidence of type 2 diabetes. Rarer diabetic conditions include diabetes insipidus, where the urine is not sweet; this can be caused by either kidney or pituitary gland damage. Type 2 diabetes may go unnoticed for years; visible symptoms are typically mild, non- existent or sporadic, and usually there are no ketoacidotic episodes. However, severe long-term complications can result from unnoticed type 2 diabetes, including: The use of oral antidiabetic drugs may be necessary.
Insulin production is initially only moderately impaired in type 2 diabetes, so oral medication can often be used to improve insulin production e. It is a biguanide drug. Biguanides do not affect the output of insulin, unlike the sulphonylureas and meglitinides, and can therefore also be effective in type 1 patients in concert with insulin therapy.
Their exact mode of action is not fully elucidated. They can lower fasting levels of insulin in plasma, through their tendency to reduce gluconeogenesis in the liver. They also have effects in reducing insulin resistance in tissues; metformin has been shown to stimulate AMP-activated protein kinase AMPK , an enzyme responsible for glucose and fat metabolism as well as insulin signalling. It also helps reduce LDL cholesterol and triglyceride levels, and may aid weight loss.
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See Table 2. It is the insulin to glucagon ratio that is of most importance. With reference to Figure 2. With a lower oxaloacetate concentration, acetyl-CoA is prevented from entering the TCA cycle, adding to an increase in its cellular concentration. The result is increased ketogenesis. Glycation is the non-enzymatic and haphazard condensation of the aldehyde and ketone groups in sugars with amino groups in proteins, leading to their functional impairment the enzyme-controlled addition of sugars to protein or lipid molecules is termed glycosylation.
This process is now considered to be a major contributor to diabetic pathology and has resulted in greater clinical emphasis on good glycaemic control.
Clinical measurement of glycated haemoglobin HbA1c and serum albumin is used to assess the adequacy of blood sugar regulation in diabetic patients Table 2. Normal non-diabetic values of glycated haemoglobin are 4.
Long-term damage caused by protein glycation includes ulcers, kidney failure, blindness, strokes and ischaemic heart disease.
Hexokinase will return fructose to the glycolysis pathway by phosphorylating it to fructosephosphate. However, in uncontrolled diabetics with high blood glucose, the production of sorbitol is favoured.
The decreased concentration of these cofactors leads to decreased synthesis of reduced glutathione, nitric oxide, myoinositol and taurine. Myoinositol is particularly required for the normal function of nerves. Sorbitol may also glycate the amino nitrogen on proteins such as collagen, forming AGEs. In diabetic neuropathy, nerves may be affected by damage to small blood vessels surrounding the sheath, but also by an accumulation of sorbitol and fructose in Schwann cells, leading to de-myelination.
In myelinated axons, Schwann cells produce the myelin sheath. Obesity is a growing problem in children. This is useful as a guide, but BMI does not adequately distinguish fat from lean muscle mass. Separate norms should be used for men, women, children and different ethnic groups. The pathogenic mechanisms in diabetes seem to involve the non-enzymic glycation of con- nective tissue proteins, leading to microangiopathy followed by kidney, retinal and neurological problems.
Numerous other conditions are allegedly associated with obesity. BMR decreases with age and with the loss of lean body mass. Increasing muscle mass increases BMR.
Illness, previously con- sumed food and beverages, environmental temperature and stress levels can affect overall energy expenditure as well as the BMR. BMR is accurately determined by gas analysis direct or indirect calorimetry ; an estimation can be found using the equation: Such formulae are based on body weight, which does not take into account the difference in metabolic activity between lean body mass and body fat.
Mental states such as fear, depression and social interactions can all affect food intake. Such factors are of particular importance to clinicians because they can be manipulated to manage anorectic anorexigenic patients.
Additionally, the enteric hormone cholecystokinin CCK is well documented to induce satiety in experimental settings, while the hormone ghrelin seems to be a potent stimulator of appetite.
As nutrients are absorbed, their concentrations in blood rise, with changes in the concentration of several hormones, CCK, as well as insulin and glucagon. Cholecystokinin CCK: CCK is the best known member of a group of hormones incretins secreted by the duodenum in response to the partially digested output from the stomach chyme ; fatty meals are particularly effective. CCK delays gastric emptying, stimulates pancreatic enzyme production, causes the gall bladder to contract, promotes insulin release by the pancreas and produces a sensation of fullness or satiation.
CCK signals to the brain via the vagus nerve. Other incretins in the same group are gastric inhibitory peptide GIP , glucagon-like peptide 1 and glucagon-like peptide 2. In addition to its role in blood glucose homeostasis, insulin reduces food intake and plays a major part in appetite regulation. It is believed that insulin promotes phosphory- lation of leptin receptors and JAK2 janus kinase 2 , which enhances the phosphorylation of STAT3 signal transducer and activator of transcription 3 in the presence of leptin see Table 3.
Insulin levels are often raised in type 2 diabetes, which is associated with insulin resistance and obesity. It acts on the hypothalamus to stimulate growth hormone release by the pituitary.
Ghrelin is also produced locally by neurons within the hypothalamus, and in other parts of the intestine. Ghrelin receptors are found in most tissues, including many other parts of the brain, and ghrelin signalling is widely distributed throughout the vertebrate phylum.
The gastrointestinal tract has several distinct modes of operation; in one of these, coordinated patterns of electrical and muscular activity, known as migrating motility complexes, originate from the stomach and propagate through the small intestine, gently massaging the contents along the gut. In humans, and in all other vertebrates, information about smell, taste and gastric fullness is conveyed by the cranial nerves. Smell receptors transmit information via the olfactory nerve; taste buds are mainly innervated by the facial nerve and the glossopharyngeal; while the liver, stomach and duodenum are served by the vagus nerve.
Fundamental feeding assessments are made by the hindbrain, in the nucleus of the solitary tract, or possibly in the parabrachial nucleus nearby. The hypothalamus is a small volume of nervous tissue surrounding the third ventricle, with important neural connections to the hindbrain, and also to the pituitary gland.
Some of this tissue lies outside the blood—brain barrier, and is able to respond directly to circulating hormones, and to sense the glucose con- centration in the blood. It is uniquely placed to control both energy inputs and outputs. There are sensory pathways from the nucleus of the solitary tract to the hypothalamus.
All these signals are integrated by the hypothalamus to regulate physical activity, thermogenesis and feeding behaviour. The appetite centre in the arcuate nucleus appears to be composed of at least two classes of neurons: There is control of the anterior pituitary gland, and a direct control over the autonomic nervous system.
Orexins A and B are an important pair of neurotransmitters otherwise known as hypocretins 1 and 2 , derived from a common precursor. They have a major role in arousal and food- seeking behaviour. Damage to the orexin signalling system leads to narcolepsy a disorder that causes excessive sleepiness during the day and frequent and uncontrollable episodes of falling asleep.
Some of the best-known and most likely candidates are shown in Table 3. At least four distinct G-protein-linked receptors recognise the core heptapeptide sequence of the melanocortins. NPY delivers a powerful orexigenic appetite-promoting signal within the hypothalamus, which activates a neural pathway leading to the nucleus of the solitary tract. Serotonin central receptors appear to play a major role in glucose homeostasis. Experiments in obese mice have demonstrated that small doses of a classical serotonin ago- nist, metachlorophenylpiperazine mCPP , markedly lower plasma insulin levels and increase insulin sensitivity, without affecting food intake, body weight or fat mass.
The downstream target of the involved serotonin receptor appears to be melanocortin-4 receptors, in the arcuate nucleus of the hypothalamus. The hypothalamus controls energy expenditure via the ante- rior pituitary and the sympathetic nervous system.
An important output signal to the pituitary is thyrotropin-releasing hormone TRH , a small peptide secreted into the hypophyseal portal system which causes the anterior pituitary to release thyroid-stimulating hormone TSH. Thyroid hormone acts on peripheral tissues, increasing alertness, heat production and BMR. Thyroxin output falls during prolonged starvation, when metabolism and physical activity are severely restricted in order to conserve fuel stocks. Two other pituitary hormones are associated with fasting and gluconeogenesis: Hypoglycaemia and hypothermia both lead to sustained sympathetic responses.
Sympathetic activity is controlled by the hypothalamus, which instructs the adrenal medulla to secrete adrenalin. Parasympathetic activity can also respond to the hypothalamus, which controls the nucleus of the solitary tract. Normal brain tissue does not take up or metabolise fatty acids hence its depen- dence on glucose, or the switch to ketone body utilisation. However, the arcuate nucleus converts fatty acids to long-chain fatty acyl-CoA intermediates.
The exact mechanism of appetite control is unclear, but it is known that the long-chain fatty acyl-CoA intermediates formed in the arcuate nucleus dampen appetite and reduce food intake. Recently discovered in the suprachiasmatic nucleus, prokineticin 2 is a sig- nalling molecule that appears to help control hunger. This diet should be supplemented by an exercise programme to increase energy demand, leading to a gradual weight loss over several months.
They are not widely recommended by nutritionists, although the evidence against them is largely speculative and anecdotal. The feared dislipidaemia and cardiovascular problems with such diets have so far failed to materialise.
Leptin has major effects on reproductive behaviour sexual maturation is delayed by lack of food. Starving women, female athletes and anorexics with low fat stores experience secondary amenorrhea. Leptin signalling defects lead to gross obesity, but these are very rare in humans.
Essential Biochemistry for Medicine
Peptide tyrosine A gut hormone present Shown to inhibit gut motility and tyrosine PYY in endocrine cells in gastrointestinal and pancreatic secretions. Many of these gut peptides are incretin hormones, which also stimulate insulin release. Resistin A peptide hormone Polymorphism of the resistin gene is produced by associated with obesity.
Output is increased by thyroid hormone T4 but the physiological function is not yet understood. Adiponectin increases insulin secreted by sensitivity in target tissues, but also adipocytes, which also stimulates fatty acid oxidation and blocks the regulate energy differentiation of new adipocytes in bone homeostasis and the marrow. This loop normally acts illnesses. It potently reduces release insulin.
It is thought to regulate food intake, enterocytes in possibly by stimulating CCK production. It response to long-chain may be effective in its own right because it dietary fat. All the carbohydrates will be converted to glucose initially. This will result in a rapid and sustained elevation in blood glucose levels, stimulating insulin production. Insulin stimulates the body to store fat. Thus, a high-carbohydrate diet will provide excess of what is necessary for immediate energy usage.
Some will be converted to glycogen and stored in the liver, but most is converted into fat for storage in the body tissues. Fats, unlike carbohydrates, have a high satiety factor; fats make you feel full, and the satiety lasts for hours. Therefore, you tend to consume fewer calories on a high-fat diet than on a high-carbohydrate diet.
Also, with a lower carbohydrate intake, the levels of insulin are low. Therefore, the fat you eat tends not to be stored. Thus a high-fat diet, in the absence of carbohydrates, typically results in weight loss.
Liposuction to remove excess fat is not currently recommended, but gastric surgery is proving effective and popular. Table 3.
The gastrointestinal tract and oesophagus form the alimentary canal. The stomach is both a reservoir and a digestive organ. The mucosa epithelium, lamina propria and muscularis mucosae forms longitudinal folds gastric folds or rugae , which disappear when the stomach is fully distended. On the mucosal surface are small, funnel-shaped depressions gastric pits. Almost the entire mucosa is occupied by simple, tubular gastric glands which open into the bottom of the gastric pits Figure 4.
The surface epithelium simple, tall columnar does not change throughout the stomach. It contains mucus-producing cells which form a secretory sheath glandular epithelium. The mucus is alkaline and adheres to the epithelium, forming a protective layer.
The surface epithelium is renewed approximately every third day. The source of the new cells is the isthmus; that is, the upper part of the neck of the gastric glands, where cells divide and then migrate towards the surface epithelium and differentiate into mature epithelial cells. In contrast to the surface epithelium, the cellular composition and function of the gastric glands are specialised in the different parts of the stomach.
In the principal or corpus-fundic glands, there are four cell types: Parietal cells or oxyntic cells occur most frequently in the necks of the glands, where they reach the lumen. Parietal cells secrete the hydrochloric acid of the gastric juice. Parietal cells also secrete intrinsic factor, which is necessary for the absorption of vitamin B Vitamin B12 is a cofactor of enzymes which synthesise tetrahydrofolic acid, which in turn is needed for the synthesis of DNA components. An impairment of DNA synthesis will affect rapidly dividing cell populations, among them the haematopoietic cells of the bone marrow, which may result in pernicious anaemia.
This condition may result from a destruction of the gastric mucosa by, for example, autoimmune gastritis or the resection of large parts of the lower ileum, which is the main site of vitamin B12 absorption, or of the stomach.
The pit and the luminal surface are lined by surface mucous cells. Mucous neck cells are found in the neck, while chief and endocrine cells are present in the base of the gland. Parietal cells are actually scattered throughout the gland. Pharmacologic antagonists of each of these molecules can block acid secretion.
Gastrin is a linear peptide hormone produced by G cells of the duodenum and in the pyloric antrum of the stomach. It is secreted into the bloodstream its effect is paracrine. Gastrin is released in response to certain stimuli, including stomach distension, vagal stimulation, the presence of partially digested proteins amino acids and hypercalcaemia.
Its release is inhibited by the presence of acid in the stomach negative feedback , somatostatin, along with secretin, GIP gastroinhibitory peptide , glucagon and calcitonin.
Two cell types in the mucosa of the corpus of stomach are principally responsible for secretion of acid. A variety of substances can stimulate the ECL cell to secrete histamine, including PCAP, pituitary adenyl cyclase-activating peptide released from enteric nervous system interneurones in the gastric mucosa , and gastrin, both stimulating ECL cells via adenyl cyclase to raise intracellular levels of cAMP that lead to histamine secretion.
Bicarbonate ion production catalysed by carbonic anhydrase exits the cell on the basolateral surface, in exchange for chloride. Chloride and potassium ions are transported into the lumen of the cannaliculi by conductance channels.
Hydrogen ions are pumped out of the cell, into the gut lumen, in exchange for potassium, through the action of the proton pump; potassium is thus effectively recycled Figure 4. Cell surface polarity The apical membrane of a polarised cell is that part of the plasma membrane that forms its luminal surface, particularly so in the case of epithelial and endothelial cells.
The basolateral membrane of a polarised cell refers to that part of the plasma membrane that forms its basal and lateral surfaces. Proteins are free to move from the basal to lateral surfaces, but not to the apical surface; tight junctions, which join epithelial cells near their apical surfaces, prevent migration of proteins to the apical surface.
Accumulation of osmotically-active chloride which is required to maintain electroneutrality with hydrogen ions in the canaliculi generates an osmotic gradient that results in outward diffusion of water; the resulting gastric juice is about mM HCl and 15 mM KCl, with a small amount of NaCl.
The highly acidic environment causes denaturation of proteins, making them susceptible to proteolysis by pepsin which is itself acid-stable. Gastrin and vagus nerve stimulation trigger the release of pepsinogen from chief cells in the gastric glands.
Pepsinogen inactive is a zymogen which under acidic conditions autocatalytically cleaves itself to form pepsin active , an enzyme with a pH optimum of 1. It cleaves peptide bonds on the N-terminal side of aromatic amino acids; peptides are further digested by proteases in the duodenum. Two classes of drug, the histamine H2 -receptor antagonists and the proton pump inhibitors PPIs , achieve this goal with a high level of success.
PPIs, including omeprazole Figure 4. Omeprazole and lansoprazole are effective in the treatment of the Zollinger—Ellison syndrome. Zollinger—Ellison syndrome is characterised by increased levels of the hormone gastrin, causing the stomach to produce excess hydrochloric acid.
Often the cause is a tumour gastrinoma of the duodenum or pancreas. For further information, see Focus on: Controlling Gastric Acid Production. Gastrin-releasing hormone stimulates gastrin release through G-protein-coupled recep- tors. Together with cholecystokinin, it is the major source of negative-feedback signals that suppress feeding.
Another group of G-protein receptors opioid receptors are affected by enkephalins. Adhesins are produced by the bacterium, which binds to membrane-associated lipids and carbohydrates to maintain its attachment to epithelial cells. Large amounts of the enzyme urease are produced, both inside and outside of the bacterium.
Urease metabolises urea which is normally secreted into the stomach to carbon dioxide and ammonia which neutralises gastric acid , and is instrumental in the survival of the bacterium in the acidic environment. Pylori , including protease, catalase and certain phospholipases, causes damage to these cells. The risk of developing stomach cancer is thought to be increased with long-term infection with H.
It consists of the duo- denum, a short section that receives secretions from the pancreas and liver via the pancreatic and common bile ducts, the jejunum and the ileum. Enterocytes mature into absorptive cells of the epithelium. Two other major cell types are present: Villi Figure 4.
These cells live only for a few days, die and are shed into the lumen. Crypts of Lieberkuhn are moat-like invaginations of the epithelium around the villi, and are lined largely with younger epithelial cells, which are involved primarily in secretion. Toward the base of the crypts are stem cells, which continually divide and provide the source of all the epithelial cells in the crypts and on the villi.
Table 4. Gastric parietal cells and chief cells have Reduces shear stress on the epithelium. Cells have rapid turnover rates, usually a Abundant carbohydrates in mucin bind bacteria, few days. Stem cells, in the middle of gastric pits and The effects of toxins are minimised by their crypts, provide continual replenishment. Gastric and duodenal epithelial cells secrete bicarbonate to their apical faces to maintain a neutral pH along the epithelial plasma membrane.
Their location, adjacent to crypt stem cells, suggests they have a role in defending epithelial cell renewal. The gastrointestinal tract is the largest endocrine organ in the body and the endocrine cells within it are referred to collectively as the enteric endocrine system. Normal proliferation of gastric and intestinal epithelial cells, as well as proliferation in response to such injury as ulceration, is known to be affected by a large number of endocrine and paracrine factors.
Prostaglandins are synthesised within the mucosa from arachidonic acid through the action of cyclooxygenases. Con- siderable effort is being made to develop NSAIDs that fail to inhibit mucosal prostaglandin synthesis.
Two peptides that have received attention for their potential role in barrier maintenance are epidermal growth factor EGF and transforming growth factor-alpha TGF-alpha. EGF is secreted in saliva and from duodenal glands, while TGF-alpha is produced by gastric epithelial cells. Both peptides bind to a common receptor and stimulate epithelial cell proliferation.
In the stomach they also enhance mucus secretion and inhibit acid production. Trefoil proteins are a family of small peptides that are secreted by goblet cells in the gastric and intestinal mucosa, and coat the apical face of the epithelial cells.
Their distinctive molecular structure appears to render them resistant to proteolytic destruction. They appear to play an important role in mucosal integrity, repair of lesions and limiting epithelial cell proliferation, as well as in protecting the epithelium from a broad range of toxic chemicals and drugs. Mice with targeted deletions in trefoil genes showed exaggerated responses to mild chemical injury and delayed mucosal healing. Nitric oxide NO appears to play a crucial role in mucosal integrity and barrier function, but paradoxically also contributes to mucosal injury in a number of digestive diseases.
Nitric oxide is synthesised from arginine through the action of one of three isoenzyme forms of nitric oxide synthetase NOS. Research in this area has focused on understanding the effects of applying NO donors, such as glyceryltrinitrate, or NOS inhibitors.
Similarly, healing of gastric ulcers in rats has been accelerated by application of NO donors. NOS inhibitors are under investigation for treatment of situations in which NO overproduction appears to contribute to mucosal injury.
An important part of barrier function is to prevent transit of bacteria from the lumen through the epithelium. Paneth cells are epithelial granulocytes located in small intestinal crypts of many mammals. These peptides have antimicrobial activity against a number of potential pathogens, including several genera of bacteria, some yeasts and Giardia trophozoites.Adiponectin increases insulin secreted by sensitivity in target tissues, but also adipocytes, which also stimulates fatty acid oxidation and blocks the regulate energy differentiation of new adipocytes in bone homeostasis and the marrow.
Textbook Solutions. These are referred to as the ketogenic amino acids; they can be catabolised for energy in the TCA cycle, or converted to ketone bodies or fatty acids, but they cannot be converted to glucose.
Proteins are free to move from the basal to lateral surfaces, but not to the apical surface; tight junctions, which join epithelial cells near their apical surfaces, prevent migration of proteins to the apical surface. In skeletal muscle, insulin may also recruit pumps stored in the cytoplasm or activate latent pumps already present in the membrane.
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