Homeostasis in mammals

1. Overview

Homeostasis keeps the internal environment of the body within narrow limits. Blood glucose concentration is one of the most tightly controlled factors, held near a set point of about $5\text{ mmol dm}^{-3}$ by negative feedback. Two hormones from the pancreas act antagonistically: insulin lowers blood glucose and glucagon raises it. Glucagon shows the principles of cell signalling, in which a hormone binding outside a cell triggers a second messenger and an enzyme cascade inside it. Finally, glucose levels can be measured precisely using test strips and biosensors built around the enzymes glucose oxidase and peroxidase.

Key Definitions

• Homeostasis: the maintenance of a constant internal environment within narrow limits despite changes in external and internal conditions.
• Negative feedback: a control mechanism in which a change in a factor away from its set point triggers responses that return the factor towards the set point.
• Set point: the value at which a controlled factor is regulated, towards which negative feedback returns it after any deviation.
• Cell signalling: communication between cells in which a signal molecule (such as a hormone) binds to a receptor and triggers a response inside the target cell.
• Second messenger: a molecule, such as cyclic AMP, made inside a cell in response to a signal binding outside, which relays and amplifies the signal.
• Enzyme cascade: a series of reactions in which each activated enzyme activates many copies of the next enzyme, greatly amplifying the original signal.
• Insulin: a hormone from the beta cells of the pancreas that lowers blood glucose concentration by increasing glucose uptake and storage.
• Glucagon: a hormone from the alpha cells of the pancreas that raises blood glucose concentration by stimulating the breakdown of glycogen in the liver.
• Glycogenolysis: the breakdown of glycogen to glucose.
• Biosensor: a device that uses a biological molecule, such as an enzyme, to detect and measure the concentration of a specific substance.

Content

Why blood glucose must be controlled

Glucose is the main respiratory substrate, so cells need a steady supply. Problems arise if the concentration drifts too far in either direction:

• Too high (hyperglycaemia): the blood water potential falls, drawing water out of tissues by osmosis; at very high levels, glucose is also lost in the urine.
• Too low (hypoglycaemia): cells - especially brain cells - cannot respire fast enough.

The body therefore corrects deviations in either direction, keeping the concentration close to a set point of around $5\text{ mmol dm}^{-3}$.

Negative feedback and the antagonistic hormones

The pancreas contains the islets of Langerhans, which hold two cell types that act as detectors and effectors. Beta cells detect a rise in blood glucose and secrete insulin; alpha cells detect a fall and secrete glucagon. Because they push the concentration in opposite directions they are described as antagonistic, and together they form two negative feedback loops.

The table below summarises the antagonistic pair:

Feature	Insulin	Glucagon
Source cell	beta cells (islets of Langerhans)	alpha cells (islets of Langerhans)
Released when blood glucose is	too high	too low
Main target cells	muscle cells, adipose (fat) cells, liver cells	liver cells only
Main action	increases glucose uptake; stores glucose as glycogen (glycogenesis)	breaks glycogen down to glucose (glycogenolysis); makes new glucose (gluconeogenesis)
Net effect on blood glucose	lowers it	raises it

When blood glucose rises (for example after a meal), insulin is released and:

• increases the number of glucose transporter (GLUT4) proteins in the cell surface membranes of muscle cells and adipose (fat) cells, so these cells take up more glucose from the blood
• activates enzymes in liver and muscle cells that convert glucose to glycogen (glycogenesis) for storage
• increases the rate of respiration of glucose and its conversion to fat in adipose tissue

Note on the liver: liver cells take up glucose through a different, insulin-independent transporter (GLUT2). Insulin does not raise their uptake by inserting GLUT4 - instead it speeds up the conversion of glucose into glycogen inside them.

These responses lower blood glucose back towards the set point. The fall in glucose is detected by the beta cells, which then secrete less insulin - this is the negative feedback that prevents an overcorrection.

When blood glucose falls (for example during fasting or exercise), glucagon is released and acts on liver cells to:

• stimulate the breakdown of glycogen to glucose (glycogenolysis)
• stimulate the formation of glucose from non-carbohydrate sources such as amino acids and glycerol (gluconeogenesis)

The glucose released by the liver raises blood glucose back towards the set point.

It is important that glucagon acts on the liver, not muscle. Liver cells can release free glucose into the blood, whereas muscle cells lack glucagon receptors and also cannot release free glucose into the blood (they keep any glucose from their own glycogen for their own respiration). The liver is therefore the main store that buffers whole-body blood glucose.

Cell signalling: how glucagon triggers a response

Glucagon is a small protein, so it cannot cross the cell surface membrane. Instead it works through cell signalling, a sequence that lets a signal outside the cell change events inside it. Using the liver cell as the example:

1. Hormone binds to a cell surface receptor. Glucagon binds to a specific complementary receptor protein in the cell surface membrane, causing the receptor to undergo a conformational (shape) change.
2. G-protein is activated. The shape change activates a membrane-bound G-protein, which moves along the inside of the membrane and stimulates the enzyme adenylyl cyclase.
3. The second messenger cAMP is formed. Adenylyl cyclase catalyses the conversion of ATP into cyclic AMP (cAMP). cAMP is the second messenger - it carries the signal from the membrane into the cytoplasm.
4. Protein kinase A is activated. cAMP activates protein kinase A, which begins an enzyme cascade.
5. The signal is amplified. Each activated enzyme activates many copies of the next enzyme by adding phosphate groups (phosphorylation). Because each step multiplies the number of active molecules, one glucagon molecule leads to the activation of a very large number of enzymes - this amplification is the key advantage of a cascade.
6. Cellular response. The final enzyme in the pathway, glycogen phosphorylase, is activated and catalyses the breakdown of glycogen, releasing glucose units as glucose phosphate (glucose-1-phosphate). The liver then converts this to free glucose, which leaves the cell and raises blood glucose concentration. (This last step is one reason only the liver can release glucose into the blood.)

This pathway shows why second messengers and cascades are so effective: a tiny amount of hormone produces a large, fast response inside the target cell.

Measuring glucose: test strips and biosensors

Glucose concentration in blood and urine can be measured using test strips and electronic biosensors, both of which rely on enzymes for specificity.

A test strip carries the immobilised enzyme glucose oxidase. When the strip contacts the sample, glucose oxidase catalyses the oxidation of glucose to gluconic acid, producing hydrogen peroxide as a by-product. A second enzyme, peroxidase, then catalyses a reaction between the hydrogen peroxide and a colourless chemical on the strip, forming a coloured product. The intensity of the colour depends on the amount of glucose present, so it is matched against a colour chart to estimate concentration.

A biosensor uses the same two enzyme reactions but converts the result into an electrical signal rather than a colour. The reaction is detected by an electrode, and the size of the electrical current is proportional to the glucose concentration, which is then shown as a number on a digital meter. Because glucose oxidase is specific to glucose, these devices measure glucose accurately even though blood and urine contain many other substances.

Worked example

Exam-style question: Glucagon binds to a receptor on the surface of a liver cell yet causes the breakdown of glycogen inside the cell. Explain how the binding of glucagon leads to this response, and explain the advantage of the pathway involved. [4]

Model answer:

• Glucagon binds to a complementary receptor in the cell surface membrane, causing a conformational change that activates a G-protein, which stimulates adenylyl cyclase.
• Adenylyl cyclase converts ATP to cyclic AMP (cAMP), a second messenger, which activates protein kinase A and starts an enzyme cascade.
• The final enzyme, glycogen phosphorylase, is activated and catalyses the breakdown of glycogen to glucose.
• The cascade amplifies the signal - each enzyme activates many of the next - so a small amount of glucagon produces a large, rapid response.

Worked example

Exam-style question: In a glucose tolerance test, two people each drank a glucose solution at time 0. Their blood glucose concentration was measured for the next 2 hours.

Time / min	Person A blood glucose / mmol dm⁻³	Person B blood glucose / mmol dm⁻³
0	5	6
30	8	12
60	6	14
120	5	13

Person A has normal glucose control. Person B has untreated diabetes. Using the data, describe and explain the difference between the two people in terms of insulin and negative feedback. [4]

Model answer:

• In person A, blood glucose rises to a peak of $8\text{ mmol dm}^{-3}$ at 30 min then returns to the starting value of $5\text{ mmol dm}^{-3}$ by 120 min; in person B it rises higher (to $14\text{ mmol dm}^{-3}$) and stays high.
• In person A the rise is detected by beta cells, which secrete insulin; insulin increases glucose uptake by muscle and fat cells and storage as glycogen, lowering blood glucose back to the set point - this is negative feedback.
• In person B insulin is not made (or the cells do not respond to it), so glucose is not taken up or stored effectively and blood glucose remains high.
• Person A's value returns close to the set point, showing the feedback loop has corrected the deviation, whereas person B's does not, showing the loop is not working.

Key Equations

This topic is qualitative; no calculations are required. The only quantitative reference point to remember is the typical blood glucose set point of about $5\text{ mmol dm}^{-3}$.

Common Mistakes to Avoid

• Being vague about where hormones are made and released. State precisely that insulin comes from the beta cells and glucagon from the alpha cells of the islets of Langerhans in the pancreas. Pinpointing the exact source earns the mark.
• Saying glucagon acts on muscle cells. Glucagon acts on the liver, which can release free glucose into the blood. Muscle cells lack glucagon receptors and cannot release glucose into the blood, so they do not contribute to raising blood glucose.
• Confusing the two storage and breakdown terms. Glycogenesis is making glycogen (stimulated by insulin), glycogenolysis is breaking glycogen down (stimulated by glucagon), and gluconeogenesis is making new glucose from non-carbohydrate sources. Spell each one carefully.
• Leaving steps out of the signalling pathway. Write the full ordered sequence - receptor and conformational change, G-protein, adenylyl cyclase, cAMP, protein kinase A, cascade with amplification, then glycogen phosphorylase. Skipping the second messenger or the amplification step loses marks.
• Describing negative feedback in one direction only. Explain that a rise triggers insulin and a fall triggers glucagon, and that the corrected level is then detected so hormone secretion changes again - it is a two-way, self-correcting loop.
• Muddling the two enzymes in test strips. Glucose oxidase oxidises glucose (giving gluconic acid and hydrogen peroxide); peroxidase then uses the hydrogen peroxide to form the coloured product. Naming the wrong enzyme for the wrong step is a common slip.

Exam Tips

• For cell-signalling questions, write the pathway as a numbered chain and use the exact terms - second messenger, enzyme cascade and amplification are the words that secure full marks.
• Match the detail to the marks: a 2-mark outline wants only the milestones (receptor binding, cAMP second messenger, cascade, glycogen phosphorylase), whereas a 5-6 mark describe in detail needs every named step in order, including the G-protein, adenylyl cyclase, protein kinase A and amplification by phosphorylation.
• When asked why glucagon acts on the liver, give the reason (only the liver releases free glucose into the blood), not just the fact.
• In negative feedback answers, always name the detector (alpha or beta cells), the corrective action and the return towards the set point - all three are usually needed.
• For biosensor and test strip questions, link the result to a measurable output: a colour matched to a chart for a strip, and an electrical signal proportional to concentration for a biosensor.
• Use comparative language when contrasting insulin and glucagon (for example "insulin promotes glycogen storage whereas glucagon promotes glycogen breakdown") rather than describing each in isolation.
• For data questions like a glucose tolerance test, always quote figures from the table (with units) and then explain the trend using insulin and negative feedback - description alone is not enough for full marks.