1The parts of a feedback loop

Every loop has the same parts, whatever it controls:

• a stimulus: a change in a variable (blood glucose rises);
• a sensor (receptor) that detects it (β cells in the pancreas);
• a control that compares it with the set point and sends a signal (the same β cells, releasing insulin);
• an effector that carries out the response (liver, muscle and fat cells);
• the response, which changes the variable.

The type of feedback is decided by one question only: does the response reduce the stimulus, or increase it?

Figure 1 shows the difference. Under negative feedback (the solid line) the variable wanders a little above and below the set point but each departure is corrected, so it stays within a normal range. Under positive feedback (the dashed line) a small change grows, and grows faster.

2Negative feedback: blood glucose

Glucose in the blood is held at about 70 to 100 mg $\text{dL}^{-1}$ in a healthy person who has not eaten recently. Two hormones from the pancreas, with opposite effects, do it.

When glucose rises (after a meal), β cells in the pancreas detect it and release insulin. Insulin binds receptors on liver, muscle and fat cells. Their responses: they take up glucose from the blood, and liver and muscle cells link glucose into glycogen to store it. Blood glucose falls. As it falls, the β cells release less insulin. The response has removed its own stimulus.

When glucose falls (between meals, during exercise), α cells in the pancreas release glucagon. Glucagon acts on liver cells, which break glycogen down and release glucose into the blood. Blood glucose rises, and glucagon release falls.

Two hormones acting in opposite directions give fine control: the system can push either way.

Negative feedback works at every level, which the CED expects you to know:

• Molecular: the end product of an enzyme pathway inhibits the first enzyme (feedback inhibition). When the product builds up, its own production slows.
• Cellular: a signalling pathway switches its relays off as the response develops (topic 4.2), so the response does not run on.
• Organismal: blood glucose, body temperature, water balance.

Negative feedback opposes the change and holds a variable steady; positive feedback adds to the change and drives a process to an end point.

3Positive feedback: three examples

In each case, notice the end point that stops the loop.

The onset of labour. The baby's head presses on the cervix. Stretch receptors send nerve impulses to the brain, which makes the pituitary release oxytocin. Oxytocin makes the muscle of the uterus contract harder, which presses the head harder on the cervix, which causes more oxytocin release. Contractions grow stronger and more frequent. The loop ends when the baby is born and the pressure on the cervix stops.

Lactation. A baby suckling stimulates nerve endings in the nipple, which make the pituitary release the hormones that cause milk to be made and let down. Milk flows, the baby keeps suckling, and the stimulus continues. The loop runs while feeding goes on and stops when the baby stops.

Fruit ripening. A ripening fruit makes ethylene. Ethylene speeds up ripening, and ripening fruit makes more ethylene. Ethylene is a gas, so it also reaches nearby fruit and starts them ripening, and they add their own ethylene. One ripe fruit in a bag speeds up the rest. The loop ends when the fruit is fully ripe.

Positive feedback is useful when the body needs a fast, complete change rather than a steady state: a birth, a let-down of milk, a crop of fruit ripening at once.

4Predicting what happens when a loop is disrupted

A loop is a chain, like a pathway in topic 4.3. Break any part and the variable is no longer corrected.

Type 1 diabetes. The immune system destroys the β cells. No insulin is released, so a rise in blood glucose is not corrected: glucose stays high after a meal and cells that need insulin to take up glucose are starved of it.

Type 2 diabetes. Insulin is made, but target cells respond weakly to it, for example because the insulin receptor's pathway signals less well. Glucose falls only slowly after a meal.

A worked example with data. An invented data set: blood glucose (mg $\text{dL}^{-1}$) in two adults after drinking the same glucose drink at time 0.

Describe A first. Glucose rises from 90 to 150 by 30 minutes, a rise of

$$\frac{150 - 90}{90} \times 100 = 66.7\%$$

then falls back to 92 by 120 minutes, close to the starting value. The rate of fall between 30 and 90 minutes, using rate $= \frac{dY}{dt}$:

$$\frac{100 - 150}{90 - 30} = -0.83\ \text{mg dL}^{-1}\,\text{min}^{-1}$$

A shows a working negative feedback loop: the rise triggered a response that brought glucose back to the set point.

B starts higher (110), keeps rising until 60 minutes (230), and at 120 minutes is still 200, almost double its starting value. Claim: B's glucose feedback loop is impaired. Evidence: B's glucose had not returned to its starting value by 120 minutes (200 against 110), while A's had (92 against 90). Reasoning: if insulin were released and acting normally, cells would have taken up glucose and the level would have fallen back toward the set point. These data cannot tell you whether B makes too little insulin or responds too little to it. You would need insulin measurements to decide.

Disrupting positive feedback. A drug that blocks oxytocin receptors in the uterus would weaken contractions and slow labour, because the loop's amplifying step is cut. Removing ethylene from a fruit store (or blocking its receptors) slows ripening.