MB ChB Year 1: Nutrition and Energy

Lecture 14: Introduction to metabolic regulation

Dr John Illingworth

If you lose the printed handout, you can download another copy here.

The "purpose" of metabolism is to supply the energy and raw materials that the body needs to stay alive and reproduce. Not only must these systems operate efficiently in "ideal" situations, but they must also handle shortages and unexpected demands: fighting, natural disasters, pregnancy, lactation, famine, injury and disease. Metabolic control mechanisms are complex, but they normally work very well. They are essential for survival.

diabetic ulcer

1) It is of central importance to keep blood glucose close to 5mM. This is essential for normal cerebral functions. The brain can and does use other fuels, such as ketones and amino acids, but only glucose can cross the blood-brain barrier in sufficient quantities to support normal activity. Confusion and coma supervene if blood glucose falls below 3mM, serious vascular damage follows through protein glycation if it exceeds 8mM for significant periods.

Long-term damage caused by protein glycation includes ulcers, kidney failure, blindness, strokes and ischaemic heart disease.

Glycation is the non-enzymatic condensation of the aldehyde and ketone groups in sugars with amino groups in proteins to initially yield Schiff bases. These then undergo further chemical reactions to produce "advanced glycation end products" or AGEs. Kumar & Clarke rather confusingly call this process "glycosylation" in chapter 19. Strictly speaking this term is not chemically accurate, but it is widely used. Glycation damages collagen in blood vessel walls, increasing their stiffness, and leading to inflammation and atherosclerosis. This process is now considered to be the major contributor to diabetic pathology, and this has resulted in greater clinical emphasis on good glycaemic control. Clinically, measurement of glycated (also called "glycosylated") haemoglobin and serum albumin are used to assess the adequacy of blood sugar regulation in diabetic patients.

Protein glycation mechanism and effects

Click here to read a recent review on AGEs: Ahmed N. (2005) Advanced glycation endproducts—role in pathology of diabetic complications. Diabetes Research and Clinical Practice 67(1), 3-21.

It is possible to enter a vicious circle where hyperglycaemia causes inflammation, and inflammation makes the diabetes worse. The "metabolic syndrome" characterised by abdominal obesity, insulin resistance (type 2 diabetes), dislipidaemia, chronic low-grade inflammation, hypertension and cardiovascular disease is a common, serious medical problem throughout the developed world. We shall return to this topic in lecture 26.

2) Circulating blood glucose at 5mM is only sufficient for a few minutes normal activity. It is actively defended by the liver, "creaming off" when glucose goes too high, and "topping up" if it drops too low. Both the supply and the demand for glucose may vary more than 20-fold over a 24 hour period. Both can change suddenly and sometimes without warning.

Human energy stores and requirements for a healthy 70kg male

Liver glycogen is the short-term glucose buffer. Long term surplus glucose is converted into fats via lipogenesis. Long term shortages are made good via gluconeogenesis from non-carbohydrate precursors.

short term
long term


too high

make glycogen

make triglyceride (lipogenesis)



no action

no action


too low

split glycogen

make glucose (gluconeogenesis)

3) Liver both takes up and secretes glucose, depending on the circumstances. Internal hepatic glucose concentrations are similar to those in the blood. In contrast to this, most other tissues have a major barrier to glucose entry at the plasmalemma. Glucose is only allowed into these cells during intense metabolic activity, or when the hormone insulin is circulating in the blood. Liver, enterocytes and kidney tubule cells can all export glucose to the blood, but most other tissues cannot do this, so their glycogen reserves are strictly for internal use.

4) Liver [and enterocytes] express a different gene for the glucose phosphorylation enzyme compared with most other tissues in the body. The liver enzyme (glucokinase) has a much higher Km for glucose than the hexokinase expressed in extra-hepatic tissues, reflecting the differing intracellular glucose concentrations in these different tissues.

Glucose phosphorylation systems in liver and peripheral tissues

Glucose concentrations in portal venous blood can easily reach 20mM after a meal. Much of this excess is removed by the liver. In addition, the hormone insulin allows peripheral tissues such as muscle and adipose tissue to take up glucose from the circulation. Some of this surplus glucose is stored locally as glycogen but it is mostly converted into fats.

5) In order to hit the 5mM target, the body uses a variety of sensory mechanisms to monitor blood glucose levels and initiate corrective action. These systems “look ahead” whenever it is possible to do so. The primary glucose sensors are located in the pancreatic islets, and also in the carotid bodies, medulla and the hypothalamus. Inputs from the eyes, nose, taste buds and gut alert the control systems when food is on the way. Fear and worry about stressful situations help prepare the body to face difficult times ahead.

The first glucose sensors to be discovered were the pancreatic b cells in the Islets of Langerhans (image left) which manufacture the hormone insulin and release it into the bloodstream when the glucose concentration rises. Islet tissue also contains a cells which manufacture the antagonistic hormone glucagon, but these a cells rely on the b cells for guidance. Glucose sensors have subsequently been discovered in the brain, in the hypothalamus and in the nucleus of the solitary tract in the medulla. Additional sensors are found in the carotid bodies (although these organs mainly respond to oxygen) and in mouse portal vein, although the existence of this feature is disputed in humans.

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 largely control the autonomic nervous system, and manage a spectrum of sensations ranging from comfortable satiation to abject terror. Fear and worry may be subjectively unpleasant, but they prepare the body for action and increase our chances of survival.

6) The osmotic pressure of hydrolysed foodstuffs in the gut constrains the body to reassemble the monomeric digestion products into osmotically inactive polymers and fat globules as rapidly as possible. If it were not for this reassembly we would have to drink an impossibly large volume of water with every meal.

The gut lacks the kidney's ability to generate hyper- and hypo-osmolar solutions. Digestion and absorption are generally isotonic processes. Isotonic in this context means having almost the same osmotic pressure as blood. In addition to the fluids that we drink, considerable volumes of liquid are secreted by the upper gastrointestinal tract. Both the solutes and the water are resorbed in the lower gut. The osmotic pressure of nutrient solutions is a practical issue where patients must be fed intravenously.

Calculate the quantities of water and alkali that are required to dissolve the hydrolysis products of a typical meal as a neutral isotonic solution (300 milliosmoles/litre). Assume that the subject consumes 12MJ/day in three main meals, and that 10% of the energy is derived from protein, 60% from starch and 30% from fat. The energy yields are 17kJ/g (dry) from both proteins and polysaccharides and 37kJ/g from fat. The average molecular weight for an amino acid residue in a protein is 120, glucose is 180, a C16 fatty acid is 256 and glycerol is 92.

It should work out to rather a large volume. You can click here to check your answers.

You could not drink so much water with each meal, nor could you eat sufficient sodium salts to drive glucose and amino acid uptake, if each ion were used only once. The process works because the water and the ions are recycled many times. It is essential to conserve water by re-assembling the digested foodstuffs back into fat globules or glycogen as rapidly as possible. The insolubility or high molecular weight of these storage materials ensures a very low osmotic pressure. It is also desirable to keep the solute concentrations within the intestinal lumen as low as possible to discourage bacterial growth. Local hormones from the mid-gut stimulate the production of digestive juices by the liver and pancreas and restrain the stomach from releasing food too quickly. Sensory cells in the gut walls also warn the downstream processing systems in the pancreas, liver and adipocytes of the imminent arrival of osmotically active sugars and calorigenic fats. The insulin response to oral glucose with all these sensory cues intact is more accurate and better timed than the response to the same amount of intravenous glucose. The local gut hormones that signal this information are known as incretins.

Why do alert and active animals store mainly fats, while sedentary plants store mainly carbohydrates?

propertyfats and oilscarbohydrates

energy content (kJ/gram)

37 kJ/gram

16 kJ/gram

percent water in vivo


about 80%

A typical human being has energy reserves totalling about 500MJ. How much extra would we weigh if this were all stored as glycogen? Some plants store oils in their seeds or in their fruit, but store carbohydrate in their roots and tubers. Suggest some reasons why this might have evolved.

7) Carbohydrates are a wet and bulky calorie store but fats pack in ten times more energy per gram. Most of our food reserves are stored as protein and triglyceride, with very limited carbohydrate stocks. This is the most efficient storage system, but it requires lipogenesis to dispose of surplus glucose after feeding, and gluconeogenesis to make new glucose during exercise, illness and starvation.

All our major dietary components can be oxidised via the Krebs cycle to provide energy. In addition, the Krebs cycle is a metabolic clearing house. After feeding, surplus protein and carbohydrate are converted via Krebs cycle intermediates into fats. When fasting protein amino acids are converted into carbohydrates via the Krebs cycle and gluconeogenic pathways to maintain our blood glucose levels. Fats provide energy and are mostly oxidised to CO2 and water.

Fats cannot be converted into carbohydrates, EXCEPT for the glycerol component (6% by weight of the triglyceride molecule) which makes an important contribution to blood glucose during starvation.

Students often ask how much they are expected to know, especially when faced with pages of molecular structures. We don't expect you to learn ANY chemical structures, and we won't test you on them in the exams, however the subject is much easier to follow, and makes a lot more sense if you are familiar with the principal metabolites. Dr Whittle will cover this in the next four lectures. Although we don't expect you to draw chemical structures from memory, you should at least be able to recognise the compounds listed below if you want to follow these lectures easily:

compoundwhy do I need to know this?features


our main energy source (as starch)

very limited store (as glycogen)


our main energy store

hydrolysed to yield free fatty acids and glycerol

free fatty acids

major product of fat mobilisation

our major routine energy source


by-product of fat mobilisation (6%)

recycled into glucose by the liver


glycolytic product from "white" muscle

recycled into glucose by the liver


main amino acid released during starvation

structurally related to lactate and pyruvate


main amino acid in the bloodstream

structurally related to glutamate and oxoglutarate


life-threatening excess in acute diabetes

important source of energy during starvation

Glutamate is the main amino acid that particpates in metabolism, and is also a key intermediate in the final common pathway of nitrogen excretion. However, it is also a neurotransmitter and not the sort of stuff to leave lying around, so the main bloodstream form is the closely related glutamine.

8) Medical students should be familiar with the following compounds circulating in the blood and understand why they are important: glucose, triglycerides, "free" (i.e. non-esterified) fatty acids, glycerol, lactate, alanine, glutamine and acetoacetate.

What are the principal "food" stores in the human body, and how are these used to protect the cerebral energy supply?

Liver glycogen provides a short-term source of carbohydrate for emergency use. It is mobilised by adrenalin and glucagon, signalling via calcium ions and 3'5' cyclic AMP, but the total reserve is only sufficient for a few hours use. Adipocytes provide the major energy store in humans, but muscle proteins are also degraded when food intake is inadequate. Most amino acids [except for leucine and lysine] are glycogenic: their carbon skeletons can be converted (at least partially) into glucose via Krebs cycle intemediates. Fatty acids cannot be be converted into glucose, but triglyceride droplets contain 6% by weight glycerol, which the liver converts into sugar phosphates. The glycerol component is crucial for survival.


  1. These figures are for a 70kg male. [MJ = MegaJoules: 1 MJ will keep a 2kW electric kettle boiling for 8.3 minutes.] Typical daily energy intakes are about 12 MJ per day for males, 9.2 MJ for females, so the total stores would last about 40 days, providing water is available and blood glucose can be maintained through gluconeogenesis. In practice food withdrawal may not be complete, and reduced physical activity lowers the fasting energy requirements. Human beings have evolved to withstand a bad winter in a primitive hunter-gatherer society.

  2. There is no net synthesis of amino acids under physiological conditions, but in the case of the non-essential amino acids it may be possible to "rob Peter to pay Paul".

9) Most peripheral tissues (except the brain) require insulin or nervous stimulation before they are allowed to use blood glucose. Basal metabolic needs are largely met from fat metabolism.

Carbohydrate stores are wet and bulky and their energy density is low. They are very useful for emergencies, but they are not a cost-effective fuel for an active species like ourselves. It is clear from the diagram above that our carbohydrate stores would only supply about 3 hours average waking activity, much less time when working hard. Our strategy is therefore to conserve our limited carbohydrate stores, and most of our basal metabolic activity is fueled by fats.

Fats operate a series of metabolic master switches that suppress the oxidation of carbohydrates. Given a choice, most aerobic tissues, like cardiac muscle for example, actively prefer fats. This is reinforced by insulin signalling. In the absence of insulin (or, for some organs, direct nervous stimulation) most tissues other than liver and brain take up very little glucose from the blood.

10) Successful blood glucose control depends on concerted action between several circulating hormones, including insulin, glucagon, cortisol, growth hormone and adrenalin, plus the operation of the autonomic nervous system.

Insulin alone could not control the delicate balance between competing activities in complex organisms like ourselves. Metabolic activity may increase 20-fold during exercise, and this requires an orderly mobilisation of reserves. At other times we fall asleep and this provides an opportunity for growth and repairs. Our children grow from babies into adults, with very different metabolic needs. We may suffer injuries or infections, both of which require metabolic adjustments. Our food supply might alter, may become irregular, and this requires an orderly series of adaptations to cope with a deteriorating situation. Low temperatures may call for an increased basal metabolic rate.

As a result we have evolved a bewildering variety of different hormones, which regulate different aspects of metabolism and collectively enable us to cope with almost anything that life can throw at us. Sometimes this system fails, and requires medical intervention to get it right again. We will discuss these issues in the next ten lectures. Some of the key players are listed below:

effects on
hormones and cytokines
insulin glucagon / adrenalin growth hormone cortisol TNF-α
























TNF-α (tumour necrosis factor alpha) is the best known member from a group of pro-inflammatory cytokines which also includes interleukin-1 (IL-1) and interleukin-6 (IL-6) which are collectively responsible for the fever and inflammation associated with infections and serious disease.

11) Blood glucose homeostasis in inextricably bound up with the complex mechanisms that regulate the immune system, body temperature, feeding behaviour and body weight. A large number of cytokines and hormones are involved in this.

Life would be much simpler if evolution had allocated one hormone or signalling system to regulate each particular aspect of metabolism. Unfortunately life is not so easy. The functions of the various hormones massively overlap, so that if anything changes it tends to affect everything else. No engineer would design a system like this, but unfortunately medical students are stuck with the bodies we have got. In practice the considerable "cross-talk" between the various signals does not seem to cause serious problems, and it might even work better than a more rational arrangement.

New hormones and messengers are still being discovered, and the list has expanded greatly in recent years. The systems that regulate the immune system, blood glucose and feeding behaviour are immensely complex, and unfortunately they are all inextricably bound together, a situation that has considerable implications for patient care.

12) In order to achieve overall accuracy, the body uses a combination of short-term, medium-term and long-term control mechanisms. We use liver glycogen as the short-term (minutes to hours) buffer for blood glucose, but rely on lipogenesis and gluconeogenesis and changes in gene expression for long term adaptation.

We will discuss this in the remainder of the course. Do not be surprised to find a multiplicity of mechanisms, all regulating the same thing, but on very different time scales. There are exceptions to everything, but as a general rule, expect to find:

13) Major deviations in any of the blood components are harmful and may lead to disease. Ingestion, absorption, utilisation and excretion are all regulated to achieve the overall goals.

An urban myth

A young woman lay asleep, peacefully dreaming of a holiday abroad. Her bed was warm and comfortable but she stirred slightly in the small hours as the sky began to lighten and her stomach gently reminded her that it was almost time for breakfast...

Suddenly she awakes and looks at the clock. "Oh ****!" she says, leaping from the bed and frantically pulling on her clothes. Skipping breakfast and her morning wash she races from her house and sprints desperately for the bus stop at the far end of the street. She makes the bus with seconds to spare and collapses panting on a seat to recover her breath.

By the time she gets to work about 30 minutes later she has almost regained her composure. She puts her head round the bosses door: "I missed my breakfast, but have I got time to do my hair before the interview?"

"It's okay" says the bosses secretary "he's rung in sick. You can get your breakfast in the staff canteen."

By this stage she is really hungry, and orders poached eggs on toast with sausages and baked beans, washed down with a big mug of coffee, and then she eats some more toast and marmalade. As she settles down to read the newspaper, she realises that she needs to visit the loo...

Worse things happen at sea! Human beings regularly survive war zones and shipwrecks, major injuries and infectious disease. Our ability to live a free and independent life depends on the precision and reliability of our metabolic control systems. Over the next 20 years this young woman will travel widely, raise a family, and cope with all of life's vicissitudes while relying on survival strategies that started two thousand million years ago.

Some self-directed learning (lectures 19-26):

[See chapters 18 & 19 in Kumar & Clark Clinical Medicine (6th ed.), chapter 19 in Sherwood Human Physiology, chapter 13 in Nelson & Cox Biochemistry, or chapters 13 & 18 in Tortora & Derrikson Principles of Anatomy & Physiology.]

Which hormone was released in waves from her pituitary gland as she dreamed of her holiday abroad?
[It acted mainly on her liver, which released a second polypeptide hormone with widespread effects.]

Which hormone was released in larger quantities as dawn was breaking?
Where did it come from and what did it do?

Which hormone was released as she sprinted for the bus?
Where did it come from and what did it do?

How did she control her blood sugar as she recovered on the bus and prepared for her interview?
Which hormones were active?

Which systems were activated as she watched the sausages sizzling in the pan?
How did they "know" what to expect?

Which hormones were being released as she put the lid back on the marmalade?
What did they do?

How did she know how much to eat, and why did she need the loo?

Over the remainder of the Nutrition and Energy course we will look at:

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