History of diabetes

The disease of diabetes mellitus has been described since antiquity. The earliest known record is in an Egyptian papyrus dating from around 1500 BC. The Greek physician Aretaeus of Cappadocia named the disease 'diabetes' in the first century AD and described the short and painful life of sufferers 'it consists in the flesh and bones running together into urine the patients are tortured with an unquenchable thirst the whole body wastes away '. It is often claimed that the English physician,...

Nervous system and cardiovascular responses during aerobic exercise

Two components of the nervous system are intimately involved with metabolic regulation during aerobic exercise. The somatic nervous system carries the stimuli for contraction of the appropriate muscles, and the arrival of a nervous impulse at the end-plate triggers both contraction and a coordinated activation of glycogen breakdown (Fig. 8.8). This is true just as much during aerobic exercise, and there appears to be 'obligatory' breakdown of muscle glycogen associated with muscle contraction,...

Type 1 diabetes mellitus

Type 1 diabetes results from destruction of the insulin-secreting cells of the islets of Langerhans. This destruction is auto-immune in nature - i.e. it is brought about by the body's own natural defences, but directed against one of its own tissues. The liability to develop Type 1 diabetes is to some extent inherited, but Fig. 10.1 A sufferer from Type 1 diabetes mellitus in the early days of insulin therapy, before (left) and after (right) treatment with insulin. Reproduced from Bliss (1983)....

The pituitary gland

The pituitary gland, about the size of a pea, is situated on the under-surface of the brain (Fig. 5.1), attached through a little stalk to the area of the brain known as the hypothalamus. The pituitary gland is also known as the hypophysis, or 'growth underneath' removal of the pituitary gland is the operation called hy-pophysectomy. The hypothalamus, which itself lies under the thalamus, is the seat of integration of incoming signals from nerves with specialised 'sensing' functions, and...

Relationship between plasma triacylglycerol and HDLcholesterol concentrations

In studies of large numbers of individuals, an inverse relationship is usually observed between plasma triacylglycerol and HDL-cholesterol concentrations the higher the subject's plasma triacylglycerol concentration, the lower tends to be the HDL-cholesterol concentration. We can now see how this inverse relationship is brought about. Because the hydrolysis of the triacylglycerol-rich lipoproteins by lipopro-tein lipase is accompanied by the transfer of cholesterol and other surface components...

Fat metabolism during endurance exercise

The activity of muscle hexokinase is sufficient, in principle, for all the energy for sustained aerobic exercise to be derived from uptake of plasma glucose. In fact, as we have seen, this would reduce the length of time during which the exercise can be sustained at the highest rate. Simultaneous oxidation of glucose and fatty acids therefore produces the longest possible period of sustained high intensity exercise. The availability of fatty acids to the muscles also reduces the rate of glucose...

Liver metabolism

By understanding how the liver is placed within the circulatory system, we can understand the rationale behind many of its metabolic functions. It is the first organ to 'get its pick' of the nutrients which enter the body from the intestine after a meal, and we might therefore predict that it would have a major role in energy storage after a meal. This is indeed so, at least for carbohydrate storage and later release of glucose are major functions of the liver. It also has an important role in...

HDLcholesterol plasma triacylglycerol and coronary heart disease

Although an elevated LDL-cholesterol concentration is certainly an important marker for risk of coronary heart disease, it is also true that if people who suffer a heart attack, especially those who do so at a relatively early age, are studied, a large proportion will not have elevated cholesterol concentrations. In terms of total risk in the population, factors other than LDL-cholesterol are more important. One important marker of risk is the combination of reduced HDL-cholesterol and elevated...

HDL metabolism

Whilst LDL particles regulate the cholesterol content of cells by delivering cholesterol, HDL particles bring about the opposite process - the removal of cholesterol, which is transported to the liver for ultimate excretion. 9.2.3.1 HDL and reverse cholesterol transport HDL particles begin their life as apolipoprotein AI molecules secreted from the liver and intestine, associated with some phospholipid. These nascent particles are called pre- HDL from their migration pattern on electrophoresis....

Metabolic changes in obesity

Many of the metabolic changes in obesity seem to stem from the associated insulin resistance. For instance, it was discussed in Section 10.2.3 how insulin resistance could, in a susceptible individual, lead to the development of Type 2 diabetes. In addition, insulin resistance has effects on lipid metabolism, discussed in Box 10.1. The typical metabolic picture in obesity is of a tendency to elevation of LDL-cholesterol concentration, a depression of HDL-cholesterol and an elevation of plasma...

Untreated Type 1 diabetes

The metabolic picture in untreated Type 1 diabetes, outlined in Fig. 10.3, is very much what we might predict from knowledge of the normal role of insulin. It is a catabolic state, i.e. there is breakdown of fuel stores and tissues. Lack of insulin leads to a net mobilisation of glycogen. Glucagon secretion is increased in this condition, perhaps because the general 'stress' state leads to increased sympatho-adrenal activity. This, together with lack of insulin, leads to increased...

The early phase

We have already looked at the pattern of metabolism in very short-term starvation (Section 6.5.1), namely the postabsorptive state after overnight fast. A gentle decrease in the concentration of glucose in the plasma led to a small decrease in the ratio of insulin glucagon, stimulation of hepatic glycogenolysis and liberation of fatty acids from adipose depots. The availability of fatty acids in the plasma leads tissues such as muscle to use fat, and spare glucose, as their major metabolic...

Some Mechanisms Involved in Metabolic Regulation

2.1 How is metabolic regulation achieved Metabolic regulation, as we have discussed it in Chapter 1, is achieved by controlling the flow of metabolites along metabolic pathways according to the body's needs.1 There are various aspects to this. One is the partitioning of nutrients or metabolic substrates between tissues and organs in different nutritional states. This may be achieved by the expression of particular enzymes or proteins that impart specific metabolic properties to that tissue. For...

Further reading

Articles marked * all come from a Nature Insight section on Diabetes in which there are also other good reviews Nature 2001 414 781-827. General diabetes, insulin resistance Reaven, G.M. (1988) Role of insulin resistance in human disease. Diabetes 37 1595-1607. This is a 'classic' article in which Gerald Reaven set out the now well-accepted idea that insulin resistance was an underlying feature of several conditions associated with increased risk of developing Type 2 diabetes and coronary heart...

Mht

Ketogenesis Lipogenesis Gluconeogenesis Fig. 4.6 Outline of amino acid metabolism in the liver. The intracellular effects of glucagon are relatively long-term, particularly increased expression of the enzymes for transamination and of the urea cycle. TCA cycle, tricarboxylic acid cycle. and that of aspartic acid is oxaloacetate. The last two are intermediates of the tricarboxylic acid cycle. Each of these may lead to glucose synthesis by the pathway of gluconeogenesis (Box 4.2). Alternatively,...

The pancreas

5.2.1 General description of the pancreas and its anatomy The pancreas is a fish-shaped organ, about the size of a medium herring, lying under the liver (Fig. 5.1). It has a distinct head and a narrow tail, and the head end is wrapped around the small intestine. The pancreas is a complex organ since it contains both exocrine and endocrine tissues. The exocrine function of the pancreas consists of the liberation of digestive juices into the small intestine the endocrine function consists of the...

Metabolic alterations in Type 2 diabetes

The plasma glucose concentration in Type 2 diabetes varies according to the severity of the condition, but if a patient neglects his or her treatment and then attends a diabetic clinic, it would not be uncommon to find a plasma glucose concentration of 20 mmol l. The plasma glucose concentration is consistently raised throughout the day (Fig. 10.4), with an exaggerated response to meals. This highlights the important role of insulin in minimising the postprandial 'excursions' in plasma glucose...

The overall control of protein synthesis and breakdown

There are some generalisations that can be made about the regulation of protein synthesis and breakdown (summarised in Fig. 6.19). Two hormones have a general anabolic role (stimulating net protein synthesis) in the body insulin and growth hormone. In people with a deficiency of insulin (insulin-dependent diabetes mellitus see Chapter 10) there is marked loss of protein from the body - the 'melting of flesh into urine'. Treatment with insulin restores body protein. Growth hormone acts through...

Absorption from the small intestine 331 Monosaccharides

The hydrolysis of the digestible carbohydrates proceeds to the stage of mon-osaccharides, some of which are liberated by the enzymes of the brush border membrane. These must then enter the enterocytes, the absorptive cells of the intestinal mucosa. Mechanisms by which sugars cross cell membranes were summarised in Box 2.2. The role of the various monosaccharide transporters in carbohydrate absorption is summarised in Fig. 3.7. Glucose and galactose enter by active transport mediated by the...

H

Fig. 1.4 Chemical structures of some lipids. A typical saturated fatty acid (palmitic acid) is shown with its polar carboxylic group and non-polar hydrocarbon tail. Glycerol is a hy-drophilic alcohol. However, it is a component of many lipids as its hydroxyl groups may form ester links with up to three fatty acids, as shown. The resultant triacylglycerol has almost no polar qualities. The phospholipids are derived from phosphatidic acid (diacylglycerol phosphate) with an additional polar group,...

Important Concepts

1.1 Metabolic regulation in perspective To many students, metabolism sounds a dull subject. It involves learning pathways with intermediates with difficult names and even more difficult formulae. Metabolic regulation may sound even worse. It involves not just remembering the pathways, but remembering what the enzymes are called, what affects them and how. This book is not simply a repetition of the molecular details of metabolic pathways. Rather, it is an attempt to put metabolism and metabolic...

The adrenal glands

The two adrenal glands sit like cocked hats over each kidney (Fig. 5.9) (hence their name - additions to the renal organ, or kidney). Each gland has an inner core and an outer layer of cells, the adrenal medulla and adrenal cortex respectively. The cortex (outer layer) makes up about nine-tenths of the bulk of the gland its cells under the microscope are rich in lipid. The medulla stains darkly for microscopy with chromic salts, showing the presence of so-called chromaffin cells, characterised...

Dieting from the viewpoint of metabolic regulation

Obesity, as we have seen, results from an excess of energy intake over energy expenditure. If the obese or overweight person wants to lose weight, then the solution is simple and unarguable energy expenditure must exceed energy intake for a suitable length of time. The only alternative is surgery to remove some excess fat. Of course, this message is simple in principle, but extraordinarily difficult to put into practice. Here, we shall consider why it is difficult, and also look at dieting from...

Carbohydrate and fat metabolism

Lipogenesis means the synthesis of lipid. More strictly, the term de novo lipogenesis means the synthesis of fatty acids and triacylglycerol from substrates other than lipids - particularly glucose, although amino acids which can be converted to acetyl-CoA can in principle also be substrates. The pathway itself was outlined in Box 4.3. It provides a means by which excess carbohydrate can be laid down for storage as triacylglycerol (since, as we have seen, this is the most energy-dense storage...

General description of the liver and its anatomy

The word 'liver' seems to come from old Norse, lifr. The adjective 'hepatic', describing things to do with the liver, comes from the Greek hepatos. The adult human liver weighs 1-1.5 kg and lies immediately under the diaphragm. It is supplied with blood from below through two major vessels the hepatic artery (which supplies about 20 of the blood) and the hepatic portal vein, often called simply the portal vein. The portal vein carries blood which has passed through the complex system of blood...

Pkb

Further regulation is brought about by glucose itself. Glucose binds to a specific site on phosphorylase a, causing a conformational change that makes the enzyme a better substrate for dephosphorylation by protein phosphatase-1G. Thus, in the liver, an increase in the intracellular glucose concentration will itself lead to inactivation of phosphorylase. Insulin acts via PKB to phosphorylate and inactivate glycogen synthase kinase-3 (GSK-3 see Fig. 2.4.1, Box 2.4). It also activates protein...

The period of adapted starvation

From about three weeks of total starvation onwards, the body appears to be fully adapted to starvation and there is a kind of steady state, in which there is gradual depletion of the body's protein mass (minimised by the mechanisms discussed earlier), and steady depletion of the fat stores. Ketone body concentrations in the blood reach about 6-8 mmol l, and ketone bodies provide about two-thirds of the metabolic requirement of the brain. Other tissues that require glucose (erythrocytes, renal...

Neurotransmitters and receptors

There are an enormous number of neurotransmitters, including amino acids and derivatives, amines, peptides and acetylcholine. Much of the diversity of transmitters occurs within the CNS, and also within the enteric nervous system. With regard to metabolic regulation, we will be considering mainly adrenergic and cholinergic transmission. Fig. 7.4 The neuromuscular junction. Fig. 7.4 The neuromuscular junction. 7.2.3.1 Adrenergic transmission The pathway for synthesis of noradrenaline and...

The components of energy expenditure

We expend energy continuously over each 24-hour period. Some of this energy expenditure represents the basic requirements for staying alive at the cellular level, pumping of ions across membranes to maintain normal gradients, turnover of proteins and other cellular constituents at the organ level, pumping of blood around the body, respiration, etc. This 'basal' level of metabolic activity is known as the basal metabolic rate. Basal metabolic rate is measured after an overnight fast, in a room...

The effects of training

Exercise training has a number of effects, which cannot be discussed at length in this book. They occur over various time-spans. A single bout of exercise will bring about some metabolic changes that are relevant to the theme of this book. Expression of muscle lipoprotein lipase increases after exercise, and this increase lasts around 24-48 hours. We can imagine that this is an adaptation allowing the muscle to use more circulating triacylglycerol-fatty acids. It has a clear consequence. The...

Atp

Anaerobic exercise 225, 229-33 generation of lactate 76, 232 marathon running 238 per glucose molecule 234, 251 ATP generation glucose lactate 76 skeletal muscle 105, 107-10 ATP-binding cassette (ABC) proteins 40, 263 atrophy 179 atropine 200-201 autonomic nervous system 195, 199201, 210-11 hormone secretion 210-11 parasympathetic sympathetic 195, 199-201 basal metabolic rate 307 basolateral transport 76 bile acids and salts 72, 74-5, 83 biliary system 83 blood blood plasma and serum 24-5...

The period of adaptation to starvation

The changes listed in Table 8.2 come into place gradually over the first three weeks or so of total starvation this is the period of adaptation. Blood glucose concentrations fall very gradually in prolonged starvation and they are followed by the plasma insulin concentration. Glucagon concentrations, on the other hand, rise, so that the ratio of insulin glucagon reaching the liver must change considerably from early to late starvation. The plasma leptin concentration also falls. In longer...

The small intestine

Structure Single Villus

The small intestine is often said to be about 6 m (20 feet) long and about 2.5 cm (one inch) in diameter. This is a generalisation and its length actually differs in life and after death in life, it is somewhat contracted by virtue of the 'tone' of its muscular walls. Measurements made by passing tubes through the small intestine in adult, living humans show the length to vary between about 3 and 4.5 m. Of this, the first 25 cm (or so) is the duodenum, curving downwards after leaving the...

Info

1 I 1 2 3 4 5 6 Time after meal (hours) Fig. 6.9 Plasma non-esterified fatty acid (NEFA) concentrations after an overnight fast and following a meal. The meal was the same as described in Fig. 6.4. The plasma insulin concentration (expressed in nmol l) is shown as a dotted line. Mean values for eight normal subjects are shown data taken from Frayn et al. (1993). 1 I 1 2 3 4 5 6 Time after meal (hours) Fig. 6.9 Plasma non-esterified fatty acid (NEFA) concentrations after an overnight fast and...

Carbohydrate metabolism

Glucose is always present in the blood. It is not static glucose molecules are continually being removed from the blood and replaced by new glucose molecules, so that the concentration remains relatively constant, at close to 5 mmol l in humans (Fig. 6.1). In fact, amongst all the energy substrates circulating in the blood, the concentration of glucose is by far the most constant. One reason for this is that it is necessary to provide a constant source of energy for those tissues in which the...

Keith N Frayn ScD PhD FRCPath

Professor of Human Metabolism University of Oxford, Oxford, UK Portland Press Ltd 1996 Keith Frayn 2003 Blackwell Science Ltd, a Blackwell Publishing 9600 Garsington Road, Oxford OX4 2DQ, UK Tel +44 (0)1865 776868 Blackwell Science, Inc., 350 Main Street, Malden, MA 02148-5018, USA Tel +1 781 388 8250 Iowa State Press, a Blackwell Publishing Company, 2121 State Avenue, Ames, Iowa 50014-8300, USA Tel +1 515 292 0140 Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton South, Victoria...

Stimuli for activation of the sympathetic nervous system and adrenal medulla

The sympathetic nervous system affects many bodily functions. It would clearly be a very inefficient means of control if the whole system had to be activated at once, and this is not so particular branches of the sympathetic nervous system are activated specifically under different conditions. This could make a complete description of sympathetic activation very complex, but for the most part it is still reasonable to think of the general effects of the whole system. Not only does the whole of...

Metabolic regulation during aerobic exercise

In Section 8.4.1, anaerobic and aerobic exercise were described as the two ex- Fig. 8.7 Concentrations of ATP and of phosphocreatine (PCr) in Type II fibres in human muscle during contractions brought about by electrical stimulation. After 6 contractions (each 1.6 sec long i.e. at 10 sec) and after 12 contractions ( 20 sec) a muscle biopsy was taken and rapidly frozen, and later the Type I and Type II fibres were separated for analysis. With repeated contractions, the force generated decreases...

Metabolic effects of catecholamines

Adrenaline and noradrenaline are both amines derived from the catechol nucleus, and the term catecholamines is often used to cover them both (see Fig. 5.10). It will be appreciated that the catecholamines have indirect effects on metabolism which are mediated through 'physiological' changes - heart rate, blood flow, etc. They also have indirect effects mediated through changes in hormone secretion, as well as direct effects in some tissues. In the liver, the catecholamines stimulate glycogen...

Insulin and triacylglycerol metabolism

The enzyme lipoprotein lipase is activated in adipose tissue by insulin, as noted in previous chapters (see Section 4.5.3.1). Thus, in the postprandial period, clearance of the triacylglycerol-rich lipoproteins is increased, and this increase in clearance occurs at the time of the peak triacylglycerol concentration in plasma, a few hours after a fatty meal. The removal of chylomicron-triacyl-glycerol is a saturable process, reflecting limited activity of lipoprotein lipase. After a fat-rich...

Introduction to lipoprotein metabolism

The major energy store of the body is a hydrophobic compound, triacylglycerol, for reasons discussed in earlier chapters. Other hydrophobic molecules play important roles in cellular function, particularly the sterol cholesterol and its esters (cholesteryl esters). Mechanisms for transporting these non-water soluble lipid species in the blood have therefore evolved. Non-esterified fatty acids are carried in the plasma bound to albumin. Some fat-soluble micronutrients and regulators of...

Alpf Vat Does It Mean

Fig. 1.7 Some simple sugars and disaccharides. Glucose and fructose are shown in their 'ring' form. Even this representation ignores the true three-dimensional structure, which is 'chair'-shaped if the middle part of the glucose ring is imagined flat, the left-hand end slopes down and the right-hand end up. Glucose forms a six-membered ring and is described as a pyranose fructose forms a five-membered ring and is described as a furanose. In solution the a- and P- forms are in equilibrium with...

How does obesity develop

If an individual is overweight or obese, then clearly that individual must have been through a period when his or her intake of energy was consistently greater than his or her energy expenditure. (Note that this is true for everyone during the period of growth.) It does not necessarily follow that this is true now an obese subject may be in energy balance, with a stable weight. Then we can ask the question if energy intake was greater than energy expenditure, did this arise through (1) an...

Disturbances of lipoprotein metabolism 941 Cholesterol and atherosclerosis

Lipoprotein metabolism has come to prominence because of its link with coronary heart disease. Coronary heart disease means a blockage - partial or complete - of one or more of the coronary arteries which supply blood to the muscular walls of the heart (the myocardium) (see Section 4.5). It arises initially because of the development of fatty deposits in the arterial walls - the process known as atherosclerosis. Atherosclerosis may affect arteries anywhere in the body, and can lead to impaired...

Carbohydrate metabolism during endurance exercise

Oxidation of glucose provides a major source of energy for the working muscles during aerobic exercise. During aerobic exercise at a high rate (e.g. 80-90 of maximal oxygen consumption, typical of an elite marathon runner) the rate of energy expenditure is around 80 -90 kJ per minute. The proportion of this supplied by glucose oxidation varies according to the preceding diet and other factors, but 50 might be a reasonable estimate (i.e. 40-45 kJ min from glucose). Oxidation of 1 g of glucose...

The stomach

After swallowing, the chewed food is propelled rapidly, in a matter of seconds, through the oesophagus to enter the stomach. The stomach is a distensible muscular sac, about 25 cm long, with a volume of around 50 ml when empty, but which can expand to hold up to 1.5 litres or more. Its muscular walls are made of three layers of smooth muscle running in different directions, giving the stomach the ability to churn food around and physically break it up further and mix it with the stomach's own...

Brown adipose tissue and the concept of uncoupling

Brown adipose tissue has a unique metabolic feature. Like most other tissues, it can oxidise substrates, via the tricarboxylic acid cycle, in its mitochondria unlike in any other tissue, this process can be 'uncoupled' from the generation of ATP when the tissue is stimulated by the sympathetic nervous system (Fig. 4.14). In all tissues that have mitochondria, the electron transport chain pumps hydrogen ions (protons) out of the mitochondrial matrix (the inside of the mitochondrion) into the...

Chylomicron metabolism the exogenous pathway

The metabolism of chylomicrons is often called the exogenous pathway of lipoprotein metabolism. Exogenous means 'from outside the body', since this is the pathway for transporting fat from outside the body - in fact, fat which has been eaten. The pathway is summarised in Fig. 9.2. We have already seen how triacylglycerol and cholesterol are absorbed and re-esterified in the cells of the intestinal wall, and secreted as chylomicron particles, via the lymphatics, into the circulation Section...